A ketogenic diet modifies glutamate, gamma-aminobutyric acid and agmatine levels in the hippocampus of rats: A microdialysis study.

PubMed

Calderón, Naima; Betancourt, Luis; Hernández, Luis; Rada, Pedro

2017-03-06

The ketogenic diet (KD) is acknowledged as an unconventional option in the treatment of epilepsy. Several lines of investigation point to a possible role of glutamate and gamma-aminobutyric acid (GABA) as main contributors in this protective effect. Other biomolecules could also be involved in the beneficial consequence of the KD, for example, the diamine agmatine has been suggested to block imidazole and glutamate NMDA receptor and serves as an endogenous anticonvulsant in different animal models of epilepsy. In the present report, we have used microdialysis coupled to capillary electrophoresis to monitor microdialysate levels of GABA, glutamate and agmatine in the hippocampus of rats submitted to a KD for 15days compared to rats on a normal rat chow diet. A significant increase in GABA and agmatine levels while no change in glutamate levels was observed. These results support the notion that the KD modifies different transmitters favoring inhibitory over excitatory neurotransmitters. Copyright © 2017 Elsevier B.V. All rights reserved.

Nicotine intake and problem solving strategies are modified during a cognitively demanding water maze task in rats.

PubMed

Nesil, Tanseli; Kanit, Lutfiye; Pogun, Sakire

2015-11-01

Nicotine is the major addictive component in tobacco, and despite well-established adverse health effects of tobacco addiction, some smokers have difficulty quitting. The acute cognitive enhancement and/or the amelioration of the cognitive disruption during withdrawal that some smokers experience after smoking are among important factors that hinder quit attempts. The animal model presented in the current study is comparable to the human smoking condition although nicotine intake routes are different. Rats were exposed to a free choice of oral nicotine starting at adolescence, and given a water maze (WM) task as adults. This design allowed us to see if rats alter their nicotine intake during the WM task and if nicotine preference and intake modify abilities and strategies rats use for problem solving. Male and female rats were exposed to a free choice of oral nicotine/water for 24weeks, starting at five weeks of age. After this period, they were selected based on their nicotine intake and, together with control animals that received only water, were subjected to a place-learning task in the WM. Free-choice nicotine exposure continued during WM testing. Following acquisition, the probe trial presented the rats with a choice between using two different strategies for problem solving. Nicotine supported acquisition and rats increased their nicotine intake during WM testing; this effect was more pronounced in male rats with minimum nicotine preference and intake. Furthermore, nicotine modified the "female type" strategy in solving the place-learning task and nicotine treated female rats, unlike control females, behaved like males. The increase in nicotine intake during mental engagement, and the sexually dimorphic effect of nicotine on problem solving strategies that we have observed in rats, may suggest that implementing sex-specific smoking cessation approaches, especially under stressful and cognitively demanding conditions, may be useful in helping smokers quit. Copyright © 2015 Elsevier Inc. All rights reserved.

Petroselinum crispum extract attenuates hepatic steatosis in rats fed with fructose enriched diet.

PubMed

Nair, V Yuneesha; Balakrishanan, N; Antony Santiago, J Victor

2015-01-01

Non alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and ongoing research efforts are focused on understanding the underlying pathophysiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. This study investigated the Petroselinum crispum extract in hepatic steatosis in rats fed with fructose enriched diet. Rats were divided into the 4 groups: Group 1 rats received standard pellet diet with corn starch for the entire experimental period of 8 weeks. Group 2 rats received standard pellet diet and 2 gm/kg body weight crude Parsley leaf ethanol extract for the entire experimental period of 8 weeks. Group 3 rats received modified fructose diet. Group 4 rats received modified fructose diet and 2gm/kg crude Parsley leaf ethanol extract. Hepatic function and structure was evaluated in these rats. Modified fructose diet produced dyslipidemia, hepatic steatosis and infiltration of inflammatory cells in the liver and higher plasma hepatic markers. Petroselinum crispum extract reversed metabolic changes such as abnormal crispum extract attenuated chronic changes in modified fructose diet induced NAFLD (Tab. 2, Fig. 3, Ref. 43).

Cocoa Diet and Antibody Immune Response in Preclinical Studies

PubMed Central

Camps-Bossacoma, Mariona; Massot-Cladera, Malen; Abril-Gil, Mar; Franch, Angels; Pérez-Cano, Francisco J.; Castell, Margarida

2017-01-01

The ability of cocoa to interact with the immune system in vitro and in vivo has been described. In the latter context, a cocoa-enriched diet in healthy rats was able to modify the immune system’s functionality. This fact could be observed in the composition and functionality of lymphoid tissues, such as the thymus, spleen, and lymph nodes. Consequently, immune effector mechanisms, such as antibody synthesis, were modified. A cocoa-enriched diet in young rats was able to attenuate the serum levels of immunoglobulin (Ig) G, IgM, and IgA and also the intestinal IgM and IgA secretion. Moreover, in immunized rats, the intake of cocoa decreased specific IgG1, IgG2a, IgG2c, and IgM concentrations in serum. This immune-regulator potential was then tested in disease models in which antibodies play a pathogenic role. A cocoa-enriched diet was able to partially prevent the synthesis of autoantibodies in a model of autoimmune arthritis in rats and was also able to protect against IgE and T helper 2-related antibody synthesis in two rat models of allergy. Likewise, a cocoa-enriched diet prevented an oral sensitization process in young rats. In this review, we will focus on the influence of cocoa on the acquired branch of the immune function. Therefore, we will focus on how a cocoa diet influences lymphocyte function both in the systemic and intestinal immune system. Likewise, its potential role in preventing some antibody-induced immune diseases is also included. Although further studies must characterize the particular cocoa components responsible for such effects and nutritional studies in humans need to be carried out, cocoa has potential as a nutraceutical agent in some hypersensitivity status. PMID:28702458

Cocoa Diet and Antibody Immune Response in Preclinical Studies.

PubMed

Camps-Bossacoma, Mariona; Massot-Cladera, Malen; Abril-Gil, Mar; Franch, Angels; Pérez-Cano, Francisco J; Castell, Margarida

2017-01-01

The ability of cocoa to interact with the immune system in vitro and in vivo has been described. In the latter context, a cocoa-enriched diet in healthy rats was able to modify the immune system's functionality. This fact could be observed in the composition and functionality of lymphoid tissues, such as the thymus, spleen, and lymph nodes. Consequently, immune effector mechanisms, such as antibody synthesis, were modified. A cocoa-enriched diet in young rats was able to attenuate the serum levels of immunoglobulin (Ig) G, IgM, and IgA and also the intestinal IgM and IgA secretion. Moreover, in immunized rats, the intake of cocoa decreased specific IgG1, IgG2a, IgG2c, and IgM concentrations in serum. This immune-regulator potential was then tested in disease models in which antibodies play a pathogenic role. A cocoa-enriched diet was able to partially prevent the synthesis of autoantibodies in a model of autoimmune arthritis in rats and was also able to protect against IgE and T helper 2-related antibody synthesis in two rat models of allergy. Likewise, a cocoa-enriched diet prevented an oral sensitization process in young rats. In this review, we will focus on the influence of cocoa on the acquired branch of the immune function. Therefore, we will focus on how a cocoa diet influences lymphocyte function both in the systemic and intestinal immune system. Likewise, its potential role in preventing some antibody-induced immune diseases is also included. Although further studies must characterize the particular cocoa components responsible for such effects and nutritional studies in humans need to be carried out, cocoa has potential as a nutraceutical agent in some hypersensitivity status.

Diabetes-associated microbiota in fa/fa rats is modified by Roux-en-Y gastric bypass

PubMed Central

Arora, Tulika; Seyfried, Florian; Docherty, Neil G; Tremaroli, Valentina; le Roux, Carel W; Perkins, Rosie; Bäckhed, Fredrik

2017-01-01

Roux-en-Y gastric bypass (RYGB) and duodenal jejunal bypass (DJB), two different forms of bariatric surgery, are associated with improved glucose tolerance, but it is not clear whether the gut microbiota contributes to this effect. Here we used fa/fa rats as a model of impaired glucose tolerance to investigate whether (i) the microbiota varies between fa/fa and nondiabetic fa/+ rats; (ii) the microbiota of fa/fa rats is affected by RYGB and/or DJB; and (iii) surgically induced microbiota alterations contribute to glucose metabolism. We observed a profound expansion of Firmicutes (specifically, Lactobacillus animalis and Lactobacillus reuteri) in the small intestine of diabetic fa/fa compared with nondiabetic fa/+ rats. RYGB-, but not DJB-, treated fa/fa rats exhibited greater microbiota diversity in the ileum and lower L. animalis and L. reuteri abundance compared with sham-operated fa/fa rats in all intestinal segments, and their microbiota composition resembled that of unoperated fa/+ rats. To investigate the functional role of RYGB-associated microbiota alterations, we transferred microbiota from sham- and RYGB-treated fa/fa rats to germ-free mice. The metabolic phenotype of RYGB-treated rats was not transferred by the transplant of ileal microbiota. In contrast, postprandial peak glucose levels were lower in mice that received cecal microbiota from RYGB- versus sham-operated rats. Thus, diabetes-associated microbiota alterations in fa/fa rats can be modified by RYGB, and modifications in the cecal microbiota may partially contribute to improved glucose tolerance after RYGB. PMID:28524868

High-protein diet modifies colonic microbiota and luminal environment but not colonocyte metabolism in the rat model: the increased luminal bulk connection.

PubMed

Liu, Xinxin; Blouin, Jean-Marc; Santacruz, Arlette; Lan, Annaïg; Andriamihaja, Mireille; Wilkanowicz, Sabina; Benetti, Pierre-Henri; Tomé, Daniel; Sanz, Yolanda; Blachier, François; Davila, Anne-Marie

2014-08-15

High-protein diets are used for body weight reduction, but consequences on the large intestine ecosystem are poorly known. Here, rats were fed for 15 days with either a normoproteic diet (NP, 14% protein) or a hyperproteic-hypoglucidic isocaloric diet (HP, 53% protein). Cecum and colon were recovered for analysis. Short- and branched-chain fatty acids, as well as lactate, succinate, formate, and ethanol contents, were markedly increased in the colonic luminal contents of HP rats (P < 0.05 or less) but to a lower extent in the cecal luminal content. This was associated with reduced concentrations of the Clostridium coccoides and C. leptum groups and Faecalibacterium prausnitzii in both the cecum and colon (P < 0.05 or less). In addition, the microbiota diversity was found to be higher in the cecum of HP rats but was lower in the colon compared with NP rats. In HP rats, the colonic and cecal luminal content weights were markedly higher than in NP rats (P < 0.001), resulting in similar butyrate, acetate, and propionate concentrations. Accordingly, the expression of monocarboxylate transporter 1 and sodium monocarboxylate transporter 1 (which is increased by higher butyrate concentration) as well as the colonocyte capacity for butyrate oxidation were not modified by the HP diet, whereas the amount of butyrate in feces was increased (P < 0.01). It is concluded that an increased bulk in the large intestine content following HP diet consumption allows maintenance in the luminal butyrate concentration and thus its metabolism in colonocytes despite modified microbiota composition and increased substrate availability. Copyright © 2014 the American Physiological Society.

Vitamin E and vitamin C do not reduce insulin sensitivity but inhibit mitochondrial protein expression in exercising obese rats

PubMed Central

Picklo, Matthew J.; Thyfault, John P.

2016-01-01

Controversy exists as to whether supplementation with the antioxidants vitamin E and vitamin C blocks adaptation to exercise. Exercise is a first-line means to treat obesity and its complications. While diet-induced obesity alters mitochondrial function and induces insulin resistance (IR), no data exist as to whether supplementation with vitamin E and vitamin C modify responses to exercise in pre-existing obesity. We tested the hypothesis that dietary supplementation with vitamin E (0.4 g α-tocopherol acetate/kg) and vitamin C (0.5 g/kg) blocks exercise-induced improvements on IR and mitochondrial content in obese rats maintained on a high-fat (45% fat energy (en)) diet. Diet-induced obese, sedentary rats had a 2-fold higher homeostasis model assessment of insulin resistance and larger insulin area under the curve following glucose tolerances test than rats fed a low-fat (10% fat en) diet. Exercising (12 weeks at 5 times per week in a motorized wheel) of obese rats normalized IR indices, an effect not modified by vitamin E and vitamin C. Vitamin E and vitamin C supplementation with exercise elevated mtDNA content in adipose and skeletal muscle to a greater extent (20%) than exercise alone in a depot-specific manner. On the other hand, vitamin C and vitamin E decreased exercise-induced increases in mitochondrial protein content for complex I (40%) and nicotinamide nucleotide transhydrogenase (35%) in a muscle-dependent manner. These data indicate that vitamin E and vitamin C supplementation in obese rodents does not modify exercise-induced improvements in insulin sensitivity but that changes in mitochondrial biogenesis and mitochondrial protein expression may be modified by antioxidant supplementation. PMID:25761734

Early-life Sodium-exposure Unmasks Susceptibility to Stroke in hyperlipidemic-hypertensive Tg[hCETP]25-Rats

PubMed Central

Decano, Julius L.; Viereck, Jason C.; McKee, Ann C.; Hamilton, James A.; Ruiz-Opazo, Nelson; Herrera, Victoria L.M.

2009-01-01

Background Early-life risk factor exposure increases aortic atherosclerosis and blood pressure in humans and animal models, however, limited insight has been made into end-organ complications. Methods and Results We investigated the effects of early-life Na-exposure (0.23% vs 0.4%NaCl regular-rat chow) on vascular disease outcomes using the inbred, transgenic[hCETP]25 Dahl salt-sensitive hypertensive rat model of male-predominant coronary atherosclerosis, Tg25. Rather than the expected increased coronary heart disease, fetal 0.4%Na-exposure (≤2g-Na/2000cal/diet/day) induced adult-onset stroke in both sexes (ANOVA P<0.0001), with earlier stroke-onset in Tg25-females. Analysis of later onsets of 0.4%Na-exposure resulted in decreased stroke-risk and later stroke-onsets, despite longer 0.4%Na-exposure durations, indicating increasing risk with earlier onsets of 0.4%Na-exposure. Histological analysis of stroke+rat brains revealed cerebral cortical hemorrhagic infarctions, microhemorrhages, neuronal ischemia, microvascular injury. Ex-vivo MRI of stroke+ rat brains detected cerebral hemorrhages, microhemorrhages and ischemia with middle cerebral artery-distribution, and cerebellar non-involvement. Ultrasound micro-imaging detected carotid artery disease. Pre-stroke analysis detected neuronal ischemia, and decreased mass of isolated cerebral, but not cerebellar, microvessels. Conclusions Early-life Na-exposure exacerbated hypertension and unmasked stroke susceptibility with greater female vulnerability in hypertensive-hyperlipidemic Tg25-rats. The reproducible modeling in Tg25sp rats of carotid artery disease, cerebral hemorrhagic-infarctions, neuronal ischemia, microhemorrhages, and microvascular alterations suggests a pathogenic spectrum with causal interrelationships. This “mixed-stroke” spectrum could represent paradigms of ischemic-hemorrhagic transformation, and/or a microangiopathic basis for the association of ischemic-lesions, microhemorrhages, and strokes in humans. Altogether, the data reveal early-life Na-exposure as a significant modifier of hypertension and stroke disease-course, hence a potential modifiable prevention target deserving systematic study. PMID:19273719

Lipoic acid reduces ischemia-reperfusion injury in animal models.

PubMed

Freisleben, H J

2000-08-07

Hypoxia and reoxygenation were studied in rat hearts and ischemia and reperfusion in rat hindlimbs. Free radicals are known to be generated through these events and to propagate complications. In order to reduce hypoxic/ischemic and especially reoxygenation/reperfusion injury the (re)perfusion conditions were ameliorated including the treatment with antioxidants (lipoate or dihydrolipoate). In isolated working rat hearts cardiac and mitochondrial parameters are impaired during hypoxia and partially recover in reoxygenation. Dihydrolipoate, if added into the perfusion buffer at 0.3 microM concentration, keeps the pH higher (7. 15) during hypoxia as compared to controls (6.98). The compound accelerates the recovery of the aortic flow and stabilizes it during reoxygenation. With dihydrolipoate, ATPase activity is reduced, ATP synthesis is increased and phosphocreatine contents are higher than in controls. Creatine kinase activity is maintained during reoxygenation in the dihydrolipoate series. Isolated rat hindlimbs were stored for 4 h in a moist chamber at 18 degrees C. Controls were perfused for 30 min with a modified Krebs-Henseleit buffer at 60 mmHg followed by 30 min Krebs-Henseleit perfusion at 100 mmHg. The dihydrolipoate group contained 8.3 microM in the modified reperfusate (controlled reperfusion). With dihydrolipoate, recovery of the contractile function was 49% (vs. 34% in controls) and muscle flexibility was maintained whereas it decreased by 15% in the controls. Release of creatine kinase was significantly lower with dihydrolipoate treatment. Dihydrolipoate effectively reduces reoxygenation injury in isolated working rat hearts. Controlled reperfusion, including lipoate, prevents reperfusion syndrome after extended ischemia in exarticulated rat hindlimbs and in an in vivo pig hindlimbs model.

Two-Stage Modeling of Formaldehyde-Induced Tumor Incidence in the Rat—analysis of Uncertainties

EPA Science Inventory

This works extends the 2-stage cancer modeling of tumor incidence in formaldehyde-exposed rats carried out at the CIIT Centers for Health Research. We modify key assumptions, evaluate the effect of selected uncertainties, and develop confidence bounds on parameter estimates. Th...

Effects of type 2 diabetes mellitus on the pharmacokinetics of berberine in rats.

PubMed

Jia, Yuzhen; Xu, Binger; Xu, Jisen

2017-12-01

Berberine is an active alkaloid isolated from Rhizoma coptidis [Coptis chinensis Franch. (Ranunculaceae)] that is widely used for the treatment of diabetes, hyperlipidemia and hypertension. However, the pharmacokinetics of berberine in normal rats and type 2 diabetes mellitus (T2DM) model rats are not clear. This study compares the pharmacokinetics of berberine between normal and T2DM model rats. The T2DM model rats were fed with high fat diet for 4 weeks, induced by low-dose (30 mg/kg) streptozotocin for 72 h and validated by determining the peripheral blood glucose level. Rats were orally treated with berberine at a dose of 20 mg/kg and then berberine concentration in rat plasma was determined by employing a sensitive and rapid LC-MS/MS method. The significantly different pharmacokinetic behaviour of berberine was observed between normal and T2DM model rats. When compared with the normal group, C max , t 1/2 and AUC (0- t ) of berberine were significantly increased in the model group (17.35 ± 3.24 vs 34.41 ± 4.25 μg/L; 3.95 ± 1.27 vs 9.29 ± 2.75 h; 151.21 ± 23.96 vs 283.81 ± 53.92 μg/h/L, respectively). In addition, oral clearance of berberine was significantly decreased in the model group (134.73 ± 32.15 vs 62.55 ± 16.34 L/h/kg). In T2DM model rats, the pharmacokinetic behaviour of berberine was significantly altered, which indicated that berberine dosage should be modified in T2DM patients.

Lentiviral-induced high-grade gliomas in rats: the effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H.

PubMed

Lynes, John; Wibowo, Mia; Koschmann, Carl; Baker, Gregory J; Saxena, Vandana; Muhammad, A K M G; Bondale, Niyati; Klein, Julia; Assi, Hikmat; Lieberman, Andrew P; Castro, Maria G; Lowenstein, Pedro R

2014-07-01

In human gliomas, the RTK/RAS/PI(3)K signaling pathway is nearly always altered. We present a model of experimental gliomagenesis that elucidates the contributions of genes involved in this pathway (PDGF-B ligand, HRAS-G12V, and AKT). We also examine the effect on gliomagenesis by the potential modifier gene, IDH1-R132H. Injections of lentiviral-encoded oncogenes induce de novo gliomas of varying penetrance, tumor progression, and histological grade depending on the specific oncogenes used. Our model mimics hallmark histological structures of high-grade glioma, such as pseudopalisades, glomeruloid microvascular proliferation, and diffuse tumor invasion. We use our model of gliomagenesis to test the efficacy of an experimental brain tumor gene therapy. Our model allowed us to test the contributions of oncogenes in the RTK/RAS/PI(3)K pathway, and their potential modification by over-expression of mutated IDH1, in glioma development and progression in rats. Our model constitutes a clinically relevant system to study gliomagenesis, the effects of modifier genes, and the efficacy of experimental therapeutics.

[Validation of the modified algorithm for predicting host susceptibility to viruses taking into account susceptibility parameters of primary target cell cultures and natural immunity factors].

PubMed

Zhukov, V A; Shishkina, L N; Safatov, A S; Sergeev, A A; P'iankov, O V; Petrishchenko, V A; Zaĭtsev, B N; Toporkov, V S; Sergeev, A N; Nesvizhskiĭ, Iu V; Vorob'ev, A A

2010-01-01

The paper presents results of testing a modified algorithm for predicting virus ID50 values in a host of interest by extrapolation from a model host taking into account immune neutralizing factors and thermal inactivation of the virus. The method was tested for A/Aichi/2/68 influenza virus in SPF Wistar rats, SPF CD-1 mice and conventional ICR mice. Each species was used as a host of interest while the other two served as model hosts. Primary lung and trachea cells and secretory factors of the rats' airway epithelium were used to measure parameters needed for the purpose of prediction. Predicted ID50 values were not significantly different (p = 0.05) from those experimentally measured in vivo. The study was supported by ISTC/DARPA Agreement 450p.

Transcranial focal electrical stimulation via tripolar concentric ring electrodes does not modify the short- and long-term memory formation in rats evaluated in the novel object recognition test

PubMed Central

Rogel-Salazar, G; Luna-Munguía, H; Stevens, KE; Besio, WG

2013-01-01

Noninvasive transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCREs) has been under development by Besio as an alternative/complementary therapy for seizure control. TFS has shown efficacy attenuating penicillin, pilocarpine, and pentylenetetrazole– induced acute seizures in rat models. This study evaluated the effects of TFS via TCREs on the memory formation of healthy rats as a safety test of TFS. The short and long-term memory formation was tested after the application of TFS using the novel object recognition (NOR) test. Independent groups were used: naïve, control (without TFS), and TFS (treated). Naïve, control, and stimulated groups spent more time investigating the new object than the familiar one during the test phase. TFS via TCREs given once does not modify the short- and long-term memory formation in rats in the NOR test. Results provide an important step towards a better understanding for the safe usage of TFS via TCREs. PMID:23419871

Amitriptyline converts non-responders into responders to low-frequency electroacupuncture-induced analgesia in rats.

PubMed

Fais, Rafael S; Reis, G M; Rossaneis, A C; Silveira, J W S; Dias, Q M; Prado, W A

2012-07-26

The purpose of this study was to examine whether the use of intraperitoneal or intrathecal amitriptyline combined with electroacupuncture modifies the tail-flick reflex and incision pain in rats that normally do not have analgesia to electroacupuncture in the tail-flick test (non-responder rats). Changes in the nociceptive threshold of intraperitoneal or intrathecal saline- or amitriptyline-treated non-responder rats were evaluated using the tail-flick or incision pain tests before, during and after a 20-min period of electroacupuncture, applied at 2 Hz to the Zusanli and Sanynjiao acupoints. Amitriptyline was used at doses of 0.8 mg/kg or 30 μg/kg by intraperitoneal or intrathecal route, respectively. At these doses, amitriptyline has no effect against thermal or incision pain in rats. Rats selected as non-responders to the analgesic effect of electroacupuncture 2 Hz in tail-flick and incision pain tests become responders after an intraperitoneal or intrathecal injection of amitriptyline. Amitriptyline converts non-responder rats to rats that respond to electroacupuncture with analgesia in a model of thermal phasic pain and anti-hyperalgesia in a model of incision pain. Copyright © 2012 Elsevier Inc. All rights reserved.

Bone and muscle atrophy with suspension of the rat

NASA Technical Reports Server (NTRS)

Leblanc, A.; Marsh, C.; Evans, H.; Johnson, P.; Schneider, V.; Jhingran, S.

1985-01-01

In order to identify a suitable model for the study of muscle atrophy due to suspension in space, a modified version of the Morey tail suspension model was used to measure the atrophic responses of rat bone and muscle to 14-30 days of unloading of the hindlimbs. The progress of atrophy was measured by increases in methylene diphosphonate (MDP) uptake. It is found that bone uptake of methylene diphosphonate followed a phasic pattern similar to changes in the bone formation rate of immobilized dogs and cats. Increased MDP uptake after a period of 60 days indicated an accelerated bone metabolism. Maximum muscle atrophy in the suspended rats was distinctly different from immobilization atrophy. On the basis of the experimental results, it is concluded that the tail suspension model is an adequate simulation of bone atrophy due to suspension.

Joint feedback analysis modeling of nonesterified fatty acids in obese Zucker rats and normal Sprague-Dawley rats after different routes of administration of nicotinic acid.

PubMed

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-08-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor κB Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis.

PubMed

Elburki, Muna S; Rossa, Carlos; Guimarães-Stabili, Morgana R; Lee, Hsi-Ming; Curylofo-Zotti, Fabiana A; Johnson, Francis; Golub, Lorne M

2017-08-01

The purpose of this study was to assess the effect of a novel chemically modified curcumin (CMC 2.24) on NF-κB and MAPK signaling and inflammatory cytokine production in two experimental models of periodontal disease in rats. Experimental model I: Periodontitis was induced by repeated injections of LPS into the gingiva (3×/week, 3 weeks); control rats received vehicle injections. CMC 2.24, or the vehicle, was administered by daily oral gavage for 4 weeks. Experimental model II: Diabetes was induced in adult male rats by streptozotocin injection; periodontal breakdown then results as a complication of uncontrolled hyperglycemia. Non-diabetic rats served as controls. CMC 2.24, or the vehicle, was administered by oral gavage daily for 3 weeks to the diabetics. Hemimaxillae and gingival tissues were harvested, and bone loss was assessed radiographically. Gingival tissues were pooled according to the experimental conditions and processed for the analysis of matrix metalloproteinases (MMPs) and bone-resorptive cytokines. Activation of p38 MAPK and NF-κB signaling pathways was assessed by western blot. Both LPS and diabetes induced an inflammatory process in the gingival tissues associated with excessive alveolar bone resorption and increased activation of p65 (NF-κB) and p38 MAPK. In both models, the administration of CMC 2.24 produced a marked reduction of inflammatory cytokines and MMPs in the gingival tissues, decreased bone loss, and decreased activation of p65 (NF-κB) and p38 MAPK. Inhibition of these cell signaling pathways by this novel tri-ketonic curcuminoid (natural curcumin is di-ketonic) may play a role in its therapeutic efficacy in locally and systemically associated periodontitis.

RatLab: an easy to use tool for place code simulations

PubMed Central

Schönfeld, Fabian; Wiskott, Laurenz

2013-01-01

In this paper we present the RatLab toolkit, a software framework designed to set up and simulate a wide range of studies targeting the encoding of space in rats. It provides open access to our modeling approach to establish place and head direction cells within unknown environments and it offers a set of parameters to allow for the easy construction of a variety of enclosures for a virtual rat as well as controlling its movement pattern over the course of experiments. Once a spatial code is formed RatLab can be used to modify aspects of the enclosure or movement pattern and plot the effect of such modifications on the spatial representation, i.e., place and head direction cell activity. The simulation is based on a hierarchical Slow Feature Analysis (SFA) network that has been shown before to establish a spatial encoding of new environments using visual input data only. RatLab encapsulates such a network, generates the visual training data, and performs all sampling automatically—with each of these stages being further configurable by the user. RatLab was written with the intention to make our SFA model more accessible to the community and to that end features a range of elements to allow for experimentation with the model without the need for specific programming skills. PMID:23908627

Safety assessment of genetically modified rice expressing human serum albumin from urine metabonomics and fecal bacterial profile.

PubMed

Qi, Xiaozhe; Chen, Siyuan; Sheng, Yao; Guo, Mingzhang; Liu, Yifei; He, Xiaoyun; Huang, Kunlun; Xu, Wentao

2015-02-01

The genetically modified (GM) rice expressing human serum albumin (HSA) is used for non-food purposes; however, its food safety assessment should be conducted due to the probability of accidental mixture with conventional food. In this research, Sprague Dawley rats were fed diets containing 50% (wt/wt) GM rice expressing HSA or non-GM rice for 90 days. Urine metabolites were detected by (1)H NMR to examine the changes of the metabolites in the dynamic process of metabolism. Fecal bacterial profiles were detected by denaturing gradient gel electrophoresis to reflect intestinal health. Additionally, short chain fatty acids and fecal enzymes were investigated. The results showed that compared with rats fed the non-GM rice, some significant differences were observed in rats fed with the GM rice; however, these changes were not significantly different from the control diet group. Additionally, the gut microbiota was associated with blood indexes and urine metabolites. In conclusion, the GM rice diet is as safe as the traditional daily diet. Furthermore, urine metabonomics and fecal bacterial profiles provide a non-invasive food safety assessment rat model for genetically modified crops that are used for non-food/feed purposes. Fecal bacterial profiles have the potential for predicting the change of blood indexes in future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Alarm pheromone is detected by the vomeronasal organ in male rats.

PubMed

Kiyokawa, Yasushi; Kodama, Yuka; Kubota, Takahiro; Takeuchi, Yukari; Mori, Yuji

2013-10-01

It is widely known that a stressed animal releases specific pheromones, possibly for alarming nearby conspecifics. We previously investigated an alarm pheromone in male rats and found that this alarm pheromone evokes several responses, including increases in the defensive and risk assessment behaviors in a modified open-field test, and enhancement of the acoustic startle reflex. However, the role of the vomeronasal organ in these pheromone effects remains unclear. To clarify this point, vomeronasal organ-excising or sham surgeries were performed in male rats for use in 2 experimental models, after which they were exposed to alarm pheromone. We found that the vomeronasal organ-excising surgery blocked the effects of this alarm pheromone in both the modified open-field test and acoustic startle reflex test. In addition, the results of habituation/dishabituation test and soybean agglutinin binding to the accessory olfactory bulb suggested that the vomeronasal organ-excising surgery completely ablated the vomeronasal organ while preserving the functioning of the main olfactory system. From the above results, we showed that the vomeronasal organ plays an important role in alarm pheromone effects in the modified open-field test and acoustic startle reflex test.

An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timchalk, Chuck; Kousba, Ahmed A.; Poet, Torka S.

2007-08-01

Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometricallymore » scale both metabolism and tissue ChE levels. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent non-linear increase in CPF-oxon concentration may potentially result from the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that the PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.« less

Modified lingguizhugan decoction incorporated with dietary restriction and exercise ameliorates hyperglycemia, hyperlipidemia and hypertension in a rat model of the metabolic syndrome.

PubMed

Yao, Limei; Wei, Jingjing; Shi, Si; Guo, Kunbin; Wang, Xiangyu; Wang, Qi; Chen, Dingsheng; Li, Weirong

2017-02-28

Modified Lingguizhugan Decoction (MLD) came from famous Chinese medicine Linggui Zhugan Decoction. The MLD is used for the treatment of metabolic syndrome in the clinical setting. Our study focuses on the comprehensive treatment of MLD incorporated with dietary restriction and exercise in a rat model of the metabolic syndrome (MS). Rats were divided into five groups: control group (Cont), high-fat diet group (HFD), high-fat diet incorporated with dietary restriction group (HFD-DR), exercise incorporated with dietary restriction group (HFD-DR-Ex) and MLD incorporated with dietary restriction and exercise group (HFD-DR-Ex-MLD). Treatments were conducted for 1 week after feeding high-fat diet for 12 weeks. The effects of treatments on high fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance in rats of MS were examined. In addition, the tumor necrosis factor-α (TNF-α), leptin and protein kinase B (PKB) in rats serum and liver were also examined by enzyme-linked immunosorbent assay (ELISA). After a week's intervention by dietary restriction, dietary restriction incorporated with exercise or MLD, compared with HFD rats, the relative weight of liver and fat, levels of triglyceride, total cholesterol, low-density lipoprotein, free fatty acid, aspartate aminotransferase, glutamic-pyruvic transaminase and alkaline phosphatase, insulin, were significantly decreased (p < 0.05 or 0.01). This treatment also inhibited abnormal increases of TNF-α, leptin and PKB in serum and liver. MLD incorporated with dietary restriction and exercise treatment exhibit effects in alleviating high-fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance, which are possibly due to the down-regulation of TNF-α, leptin and PKB.

Neuroprotective effects and impact on caspase-12 expression of tauroursodeoxycholic acid after acute spinal cord injury in rats

PubMed Central

Dong, Yi; Miao, Lei; Hei, Long; Lin, Leilei; Ding, Huiqiang

2015-01-01

Objective: To observe the effects of tauroursodeoxycholic acid (TUDCA) on nerve function after acute spinal cord injury (SCI) in rats, observe its effect on neuronal apoptosis and caspase-12 expression levels, and investigate the underlying mechanism. Methods: We used a modified Allen’s weight-drop trauma method to establish a rat acute SCI model. The rats were randomly divided into three groups: group A (sham surgery group), group B (DMSO control group) and group C (TUDCA treatment group), with 36 rats in each group. At one minute and at 24 hours after successfully establishing the model, rats in group C received an intraperitoneal injection of TUDCA (200 mg/kg), while rats in group B received an equal amount of DMSO at the same time points. At 24 hours, three days, and five days after injury, a modified Tarlov scoring method and Rivlin’s oblique plate test were used to evaluate rat spinal cord nerve function recovery. Animals were sacrificed at 24 hours, three days, and five days after injury. Specimens were obtained from the center of the injury sites; the pathological changes in spinal cord tissue were observed after hematoxylin-eosin (HE) staining; apoptosis was detected using the TUNEL method, and the expression of caspase-12 was measured at the protein level using immunohistochemistry and Western blots. Results: Group C differed significantly from group B in Tarlov scores and the oblique table test as early as 24 hours after the injury (P < 0.05). The TUNEL assay test results showed that neurons underwent apoptosis after SCI, which peaked at 24 hours. The ratios of apoptotic cells in group C were significantly lower than those in group B at 24 hours, three days, and five days after injury (P < 0.01). The immunohistochemistry and Western blot results showed that the caspase-12 expression levels of group C were lower than those of group B at 24 hours, three days, and five days after injury (P < 0.05). Conclusion: TUDCA can inhibit the expression of caspase-12 in rat neurons after SCI, reduce cell apoptosis, and exert neuroprotective effects on rat secondary nerve injuries after SCI. PMID:26884858

Atrophy and growth failure of rat hindlimb muscles in tail-cast suspension

NASA Technical Reports Server (NTRS)

Jaspers, S. R.; Tischler, M. E.

1984-01-01

The primary objective of the present study is related to an evaluation of a modified tail-cast suspension model as a means of identifying metabolic factors which control or are associated with muscle atrophy and growth failure. Two different control conditions (normal and tail-casted weight bearing) were studied to determine the appropriate control for tail-cast suspension. A description is presented of a model which is most useful for studying atrophy of hindlimb muscles under certain conditions. Female Sprague-Dawley rats were employed in the experiments. Attention is given to growth rate and urinary excretion of urea and ammonia in different types of rats, the relationship between body weight and skeletal muscle weight, and the relationship between animal body weight and rates of protein synthesis and protein degradation.

Study on the effects of parecoxib on hypothalamus orexin neuron of cerebral infarction rats.

PubMed

Li, F-T; Yao, C-H; Yao, L; Huo, Z-F; Liu, J

2018-03-01

To explore the effect of parecoxib on cerebral infarction in rats and the regulatory mechanism on hypothalamus orexin neurons (orexin) and protein expression. 60 SD male rats were randomly divided into sham operation group, model group and treatment group (20 rats in each group). Cerebral infarction model was established by modified Longa method. Rats in the treatment group were given parecoxib (2.5 mg kg-1) in tail by intravenous injection, while both the sham operation group and the model group were given the equal volume of sterile PBS solution in the tail vein. Continuous intervention of 72h was carried out in the three groups. Immunofluorescence staining and Western blot were used to detect the expression of orexin neurons and orexin protein in the hypothalamus of rats, respectively. Immunofluorescence staining showed that the number of orexin positive cells in the model group was significantly less than that in the sham-operated group (p < 0.01). After treatment intervention, the number of orexin positive cells in the hypothalamus was significantly increased compared to that in model group (p < 0.01). Western blot analysis showed that compared with sham operation group, the expression of orexin in the hypothalamus of model group was significantly decreased (p < 0.01), whereas the expression of orexin protein was significantly elevated after parecoxib intervention (p < 0.01). Parecoxib plays a therapeutic effect on cerebral infarction by up-regulating the orexin neuron.

Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion

PubMed Central

Sandner, Guy; Angst, Marie-Josée; Guiberteau, Thierry; Guignard, Blandine; Nehlig, Astrid

2014-01-01

Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits. PMID:24478661

Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolff, J.A.; Fisher, L.J.; Xu, L.

1989-11-01

Rat fibroblasts were infected with a retroviral vector containing the cDNA for rat tyrosine hydroxylase. A TH-positive clone was identified by biochemical assay and immunohistochemical staining. When supplemented in vitro with pterin cofactors required for TH activity, these cells produced L-dopa and released it into the cell cultured medium. Uninfected control cells and fibroblasts infected with the TH vector were grafted separately to the caudate of rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Only grafts containing TH-expressing fibroblasts were found to reduce rotational asymmetry. These results have general implications for the application of gene therapy to human neurologicalmore » disease and specific implications for Parkinson disease.« less

Effects of modified Sanhuang decoction () enema on serum tumor necrosis factor-α and colonic mucosa interleukin-1β, interleukin-6 levels in ulcerative colitis rats.

PubMed

Wang, Shuai; Zhou, Tao; Zhai, Jun-Peng; Wang, Li-Hua; Chen, Jing

2014-11-01

To investigate the effects of Modified Sanhuang Decoction (, MSD) enema on the serum tumor necrosis factor alpha (TNF-α) and colonic mucosa interleukin-1β (IL-1β), interleukin-6 (IL-6) levels in experimental ulcerative colitis (UC) rats. Forty-five male Wistar rats were randomly divided into 4 groups: normal group (n=12), model group (n=11), salazosulfapyridine (SASP) group (n=11) and MSD group (n=11). The UC model was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS)/ethanol solution. Rats in the normal group and model group were clystered with 0.9% normal saline, while in the SASP group and MSD group were clystered with SASP and MSD enema, respectively. After drug administration (10 mL/kg body weight, for 7 days), colonic gross changes and colonic mucosa histology were observed, serum TNF-α and colonic mucosa IL-1β, IL-6 levels were tested by enzyme linked immunosorbent assay and radioimmunoassay, respectively. As compared with the normal group, the experimental UC rats, the colonic mucosal damage index scores (CMDIs), histopathological scores (HS) and the serum TNF-α and colonic mucosa IL-1β, IL-6 levels significantly increased (P<0.05 or P<0.01). In the MSD and SASP groups, the ulcer area significantly reduced, and edema disappeared. The CMDIs, HS, the serum TNF-α and colonic mucosa IL-1β, IL-6 levels in the MSD and SASP groups significantly decreased (P<0.05 or P<0.01) compared with the model group. The CMDIs in the MSD group were lower than that in the SASP group (P<0.05), but there were no significant differences in HS, serum TNF-α or colonic mucosa IL-1β, IL-6 levels between the MSD and SASP groups. MSD enema can improve colonic mucosa impairment and decrease serum TNF-α and colonic mucosa IL-1β, IL-6 levels in experimental UC.

Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache

PubMed Central

Oshinsky, Michael L.; Sanghvi, Menka M.; Maxwell, Christina R.; Gonzalez, Dorian; Spangenberg, Rebecca J.; Cooper, Marnie; Silberstein, Stephen D.

2014-01-01

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment. PMID:22963523

Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis.

PubMed

Hayami, Tadashi; Pickarski, Maureen; Zhuo, Ya; Wesolowski, Gregg A; Rodan, Gideon A; Duong, Le T

2006-02-01

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage destruction, subchondral bone sclerosis, and osteophyte formation. Subchondral bone stiffness has been proposed to initiate and/or contribute to cartilage deterioration in OA. The purpose of this study was to characterize subchondral bone remodeling, cartilage damage, and osteophytosis during the disease progression in two models of surgically induced OA. Rat knee joints were subjected either to anterior cruciate ligament transection (ACLT) alone or in combination with resection of medial menisci (ACLT + MMx). Histopathological changes in the surgical joints were compared with sham at 1, 2, 4, 6, and 10 weeks post-surgery. Using a modified Mankin scoring system, we demonstrate that articular cartilage damage occurs within 2 weeks post-surgery in both surgical models. Detectable cartilage surface damage and proteoglycan loss were observed as early as 1 week post-surgery. These were followed by the increases in vascular invasion into cartilage, in loss of chondrocyte number and in cell clustering. Histomorphometric analysis revealed subchondral bone loss in both models within 2 weeks post-surgery followed by significant increases in subchondral bone volume relative to sham up to 10 weeks post-surgery. Incidence of osteophyte formation was optimally observed in ACLT joints at 10 weeks and in ACLT + MMx joints at 6 weeks post-surgery. In summary, the two surgically induced rat OA models share many characteristics seen in human and other animal models of OA, including progressive articular cartilage degradation, subchondral bone sclerosis, and osteophyte formation. Moreover, increased subchondral bone resorption is associated with early development of cartilage lesions, which precedes significant cartilage thinning and subchondral bone sclerosis. Together, these findings support a role for bone remodeling in OA pathogenesis and suggest that these rat models are suitable for evaluating bone resorption inhibitors as potential disease-modifying pharmaco-therapies.

A Novel Mouse Model of Penetrating Brain Injury

PubMed Central

Cernak, Ibolja; Wing, Ian D.; Davidsson, Johan; Plantman, Stefan

2014-01-01

Penetrating traumatic brain injury (pTBI) has been difficult to model in small laboratory animals, such as rats or mice. Previously, we have established a non-fatal, rat model for pTBI using a modified air-rifle that accelerates a pellet, which hits a small probe that then penetrates the experimental animal’s brain. Knockout and transgenic strains of mice offer attractive tools to study biological reactions induced by TBI. Hence, in the present study, we adapted and modified our model to be used with mice. The technical characterization of the impact device included depth and speed of impact, as well as dimensions of the temporary cavity formed in a brain surrogate material after impact. Biologically, we have focused on three distinct levels of severity (mild, moderate, and severe), and characterized the acute phase response to injury in terms of tissue destruction, neural degeneration, and gliosis. Functional outcome was assessed by measuring bodyweight and motor performance on rotarod. The results showed that this model is capable of reproducing major morphological and neurological changes of pTBI; as such, we recommend its utilization in research studies aiming to unravel the biological events underlying injury and regeneration after pTBI. PMID:25374559

[Alternation of proteins in brain of Parkinson's disease model rats after the transplantation of TH-NTN gene modified bone marrow mesenchymal stem cells].

PubMed

Huang, Yue; Chang, Cheng; Zhang, Jie-wen; Gao, Xiao-qun

2012-09-04

To explore the effects of tyrosine hydroxylase-neurturin (TH-NTN) gene modified bone marrow mesenchymal stem cell (BMSC) transplantation in Parkinson's disease (PD) model rats and the alternations of correlated proteins. The PD rat model was established by the 2-point injection of 6-hydroxydopamine (6-OHDA) into unilateral (right) striatum. Successful modeling rats were separated into PD, BMSC and TH-NTN-BMSC groups. BMSC and TH-NTN-BMSC groups were transplanted into BMSCs and TH-NTN gene modified BMSC cells separately into right striatum. After transplantation, ethology detection in all groups was made with an intraperitoneal injection of apomorphine (APO). Dopamine (DA) and Dihydroxyphenylacetic Acid (DOPAC) in striatum were detected by high performance liquid electrochemical analysis. TH and NTN proteins in right striatum were also analyzed by immunohistochemistry and Western blot. Finally the density of dopamine receptors in post synaptic density of dopaminergic synapses of corpus striatum were compared between each group by post-embedding immunogold electron microscopy. After an injection of APO, rotation frequency decreased in TH-NTN-BMSC group, i.e. (5.7 ± 1.3) circles/min versus (10.8 ± 2.2), (9.9 ± 1.2) circles/min in PD and BMSC groups (P < 0.05). For proteins in right striatum, DA, (0.421 ± 0.113) and DOPAC, (0.093 ± 0.012) nmol/L increased significantly versus (0.208 ± 0.043), (0.043 ± 0.017) nmol/L in PD and (0.231 ± 0.082), (0.044 ± 0.023)noml/L in BMSC groups (P < 0.05). Also a lower density of D2 receptors at (623 ± 96)/µm(2) in TH-NTN-BMSC group versus (923 ± 132)/µm(2) in PD and (860 ± 116)/µm(2) in BMSC groups was also found. The combined therapy of TH and NTN genes increases the synthesis of DA and also protects the dopaminergic neurons to achieve double therapeutic effects. It may provide potential innovations of PD genetic therapy.

Tumorigenic action of beta, proton, alpha and electron radiation on the rat skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burns, F.J.

1980-01-01

Rat skin is utilized as a model system for studying dose and time related aspects of the oncogenic action of ionizing radiation, ultraviolet light and polycyclic aromatic hydrocarbons. Molecular lesions in the DNA of the epidermis, including strand breaks and thymine dimers, are measured and compared to the temporal and dose related aspects of tumor induction. The induction and repair kinetics of molecular lesions are compared to split dose recovery as modified by sensitizers and type of radition of oncogenic damage.

Joint Feedback Analysis Modeling of Nonesterified Fatty Acids in Obese Zucker Rats and Normal Sprague–Dawley Rats after Different Routes of Administration of Nicotinic Acid

PubMed Central

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-01-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague–Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague–Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration–response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the “degree of disease” can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2571–2584, 2014 PMID:24986056

Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis.

PubMed

McAuley, J D; Stewart, A L; Webber, E S; Cromwell, H C; Servatius, R J; Pang, K C H

2009-12-01

Inbred Wistar-Kyoto (WKY) rats have been proposed as a model of anxiety vulnerability as they display behavioral inhibition and a constellation of learning and reactivity abnormalities relative to outbred Sprague-Dawley (SD) rats. Together, the behaviors of the WKY rat suggest a hypervigilant state that may contribute to its anxiety vulnerability. To test this hypothesis, open-field behavior, acoustic startle, pre-pulse inhibition and timing behavior were assessed in WKY and Sprague-Dawley (SD) rats. Timing behavior was evaluated using a modified version of the peak-interval timing procedure. Training and testing of timing first occurred without audio-visual (AV) interference. Following this initial test, AV interference was included on some trials. Overall, WKY rats took much longer to leave the center of the arena, made fewer line crossings, and reared less, than did SD rats. WKY rats showed much greater startle responses to acoustic stimuli and significantly greater pre-pulse inhibition than did the SD rats. During timing conditions without AV interference, timing accuracy for both strains was similar; peak times for WKY and SD rats were not different. During interference conditions, however, the timing behavior of the two strains was very different. Whereas peak times for SD rats were similar between non-interference and interference conditions, peak times for WKY rats were shorter and response rates higher in interference conditions than in non-interference conditions. The enhanced acoustic startle response, greater prepulse inhibition and altered timing behavior with audio-visual interference supports a characterization of WKY strain as hypervigilant and provides further evidence for the use of the WKY strain as a model of anxiety vulnerability.

Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

NASA Astrophysics Data System (ADS)

Acquaviva, Joseph T.; Hasanjee, Aamr M.; Bahavar, Cody F.; Zhou, Fefian; Liu, Hong; Howard, Eric W.; Bullen, Liz C.; Silvy, Ricardo P.; Chen, Wei R.

2015-03-01

Laser immunotherapy (LIT) is being developed as a treatment modality for metastatic cancer which can destroy primary tumors and induce effective systemic anti-tumor responses by using a targeted treatment approach in conjunction with the use of a novel immunoadjuvant, glycated chitosan (GC). In this study, Non-invasive Laser Immunotherapy (NLIT) was used as the primary treatment mode. We incorporated single-walled carbon nanotubes (SWNTs) into the treatment regimen to boost the tumor-killing effect of LIT. SWNTs and GC were conjugated to create a completely novel, immunologically modified carbon nanotube (SWNT-GC). To determine the efficacy of different laser irradiation durations, 5 minutes or 10 minutes, a series of experiments were performed. Rats were inoculated with DMBA-4 cancer cells, a highly aggressive metastatic cancer cell line. Half of the treatment group of rats receiving laser irradiation for 10 minutes survived without primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 minutes had no survivors. Thus, Laser+SWNT-GC treatment with 10 minutes of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

Transcranial focal electrical stimulation via tripolar concentric ring electrodes does not modify the short- and long-term memory formation in rats evaluated in the novel object recognition test.

PubMed

Rogel-Salazar, G; Luna-Munguía, H; Stevens, K E; Besio, W G

2013-04-01

Noninvasive transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCREs) has been under development as an alternative/complementary therapy for seizure control. Transcranial focal electrical stimulation has shown efficacy in attenuating penicillin-, pilocarpine-, and pentylenetetrazole-induced acute seizures in rat models. This study evaluated the effects of TFS via TCREs on the memory formation of healthy rats as a safety test of TFS. Short- and long-term memory formation was tested after the application of TFS using the novel object recognition (NOR) test. The following independent groups were used: naïve, control (without TFS), and TFS (treated). The naïve, control, and stimulated groups spent more time investigating the new object than the familiar one during the test phase. Transcranial focal electrical stimulation via TCREs given once does not modify the short- and long-term memory formation in rats in the NOR test. Results provide an important step towards a better understanding for the safe usage of TFS via TCREs. Copyright © 2013 Elsevier Inc. All rights reserved.

[Effect of Capsicum annum L (pucunucho, ají mono) in gastric ulcer experimentally induced in rats].

PubMed

Delgado Montero, Rocío; Flores Cortez, Daisy; Villalobos Pacheco, Eduardo

2015-01-01

To examine the effects of the Capsicum annum L lyophilized fruit extract in experimentally-induced gastric ulcer in rats. We used the model of indomethacin gastric ulcer-induced and the gastric ulcer model induced by pylorus ligation in rats. The rats were divided in five treatment groups as follow: G1: Distilled water 1 ml/Kg; G2: Ranitidine 50 mg/kg, G3: Capsicum 10mg/kg, G4: Capsicum 100 mg/kg, G5: Capsicum 1000 mg/kg. The results of the first model showed an ulcer inhibition of 60,4% and 66,7% using the doses of Capsicum at 10 mg/kg and 100 mg/kg, respectively. The results of the second model showed that neither the pH nor the volume of the gastric content were modified by the administered extract (p >0.05); however, by using the doses of Capsicum at 100 mg/kg and 1000 mg/kg, there was clearly an ulcer inhibition of 75.59% and 81.63% respectively, which were even greater than the inhibition obtained by ranitidine (75.51%). Therefore, in this experiment we demonstrated that the Capsicum annum L lyophilized fruit extract has a gastroprotective effect in experimentally-induced gastric ulcer in rats.

Mesenchymal stem cells protective effect in adriamycin model of nephropathy.

PubMed

Magnasco, Alberto; Corselli, Mirko; Bertelli, Roberta; Ibatici, Adalberto; Peresi, Monica; Gaggero, Gabriele; Cappiello, Valentina; Chiavarina, Barbara; Mattioli, Girolamo; Gusmano, Rosanna; Ravetti, Jean Louis; Frassoni, Francesco; Ghiggeri, Gian Marco

2008-01-01

Mesenchymal stem cells (MSCs) may be of value in regeneration of renal tissue after damage; however, lack of biological knowledge and variability of results in animal models limit their utilization. We studied the effects of MSCs on podocytes in vitro and in vivo utilizing adriamycin (ADR) as a model of renal toxicity. The in vivo experimental approach was carried out in male Sprague-Dawley rats (overall 60 animals) treated with different ADR schemes to induce acute and chronic nephrosis. MSCs were given a) concomitantly to ADR in tail vein or b) in aorta and c) in tail vein 60 days after ADR. Homing was assessed with PKH26-MSCs. MSCs rescued podocytes from apoptosis induced by ADR in vitro. The maximal effect (80% rescue) was obtained with MSCs/podocytes coculture ratio of 1:1 for 72 h. All rats treated with ADR developed nephrosis. MSCs did not modify the clinical parameters (i.e., proteinuria, serum creatinine, lipids) but protected the kidney from severe glomerulosclerosis when given concomitantly to ADR. Rats given MSCs 60 days after ADR developed the same severe renal damage. Only a few MSCs were found in renal tubule-interstitial areas 1-24 h after injection and no MSCs were detected in glomeruli. MSCs reduced apoptosis of podocytes treated with ADR in vitro. Early and repeated MSCs infusion blunted glomerular damage in chronic ADR-induced nephropathy. MSCs did not modify proteinuria and progression to renal failure, which implies lack of regenerative potential in this model.

Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control.

PubMed

Work, L M; Ritchie, N; Nicklin, S A; Reynolds, P N; Baker, A H

2004-08-01

Adenovirus (Ad)-mediated gene delivery is a promising approach for genetic manipulation of the vasculature and is being used in both preclinical models and clinical trials. However, safety concerns relating to infection of nontarget tissue and the poor infectivity of vascular cells compared to other cell types necessitates Ad vector refinement. Here, we combine a transductional targeting approach to improve vascular cell infectivity through RGD peptide insertion into adenovirus fibers, combined with transcriptional targeting to endothelial cells using a approximately 1 kb fragment of the fms-like tyrosine kinase receptor-1 (FLT-1) promoter. Single- and double-modified vectors were characterized in human cell lines that either support or have silenced FLT-1 expression. In rat hepatocytes and endothelial cells, the double modification substantially shifted transduction profiles toward vascular endothelial cells. Furthermore, in intact aortae derived from spontaneously hypertensive rats that display enhanced alphav integrin expression on dysfunctional endothelium, enhanced levels of transduction were observed using the double-modified vector but not in aortae derived from normotensive control rats. Our data indicate that Ad-mediated transduction can be beneficially modified in vitro and in vivo by combining fiber modification and a cell-selective promoter within a single-component vector system.

Absence of “Warm-Up” during Active Avoidance Learning in a Rat Model of Anxiety Vulnerability: Insights from Computational Modeling

PubMed Central

Myers, Catherine E.; Smith, Ian M.; Servatius, Richard J.; Beck, Kevin D.

2014-01-01

Avoidance behaviors, in which a learned response causes omission of an upcoming punisher, are a core feature of many psychiatric disorders. While reinforcement learning (RL) models have been widely used to study the development of appetitive behaviors, less attention has been paid to avoidance. Here, we present a RL model of lever-press avoidance learning in Sprague-Dawley (SD) rats and in the inbred Wistar Kyoto (WKY) rat, which has been proposed as a model of anxiety vulnerability. We focus on “warm-up,” transiently decreased avoidance responding at the start of a testing session, which is shown by SD but not WKY rats. We first show that a RL model can correctly simulate key aspects of acquisition, extinction, and warm-up in SD rats; we then show that WKY behavior can be simulated by altering three model parameters, which respectively govern the tendency to explore new behaviors vs. exploit previously reinforced ones, the tendency to repeat previous behaviors regardless of reinforcement, and the learning rate for predicting future outcomes. This suggests that several, dissociable mechanisms may contribute independently to strain differences in behavior. The model predicts that, if the “standard” inter-session interval is shortened from 48 to 24 h, SD rats (but not WKY) will continue to show warm-up; we confirm this prediction in an empirical study with SD and WKY rats. The model further predicts that SD rats will continue to show warm-up with inter-session intervals as short as a few minutes, while WKY rats will not show warm-up, even with inter-session intervals as long as a month. Together, the modeling and empirical data indicate that strain differences in warm-up are qualitative rather than just the result of differential sensitivity to task variables. Understanding the mechanisms that govern expression of warm-up behavior in avoidance may lead to better understanding of pathological avoidance, and potential pathways to modify these processes. PMID:25183956

Effects of cococonut water and simvastatin in the treatment of sepsis and hemorrhagic shock in rats.

PubMed

Medeiros, Vanessa de Fátima Lima Paiva; Azevedo, Ítalo Medeiros; Carvalho, Marília Daniela Ferreira; Egito, Eryvaldo Sócrates Tabosa; Medeiros, Aldo Cunha

2016-12-01

To evaluate the effects of modified coconut water as fluid of resuscitation combined with simvastatin in hemorrhagic shock and sepsis model in rats. Four groups of Wistar rats with hemorrhagic shock and abdominal sepsis were studied (n=8/group). Rats were bled and maintained at a mean blood pressure 35mmHg for 60min. They were then resuscitated with: 1) saline 0.9%; 2) coconut water+3% NaCl; 3) coconut water+NaCl 3%+simvastatin microemulsion (10 mg/kg i.v.; 4) normal coconut water. At 8h post-resuscitation, blood and lungs were collected for exams. Clinical scores, TNF-α, IL-1β, liver/kidney proof levels, and lung injury were significantly reduced in coconut water+NaCl 3%+simvastatin group treated rats, comparing with the other resuscitation treatments. Resuscitation with coconut water with Nacl 3%+simvastatin had a significant beneficial effect on downregulating cytokines and decreasing lung injury in a rat model of abdominal sepsis and hemorrhagic shock. We also demonstrated that coconut water with Nacl 3%+simvastatin administration clearly made liver and kidney function better and improved clinical score.

Neuropathological changes in brain cortex and hippocampus in a rat model of Alzheimer's disease.

PubMed

Nobakht, Maliheh; Hoseini, Seyed Mohammad; Mortazavi, Pejman; Sohrabi, Iraj; Esmailzade, Banafshe; Rahbar Rooshandel, Nahid; Omidzahir, Shila

2011-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and Beta amyloid (ABeta) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 muL of ABeta (1-40) into the hippocampal fissure. In the present study, ABeta (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. ABeta injection CA1 caused ABeta deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group.

Effect of altered gravity on temperature regulation in mammals: Investigation of gravity effect on temperature regulation in mammals

NASA Technical Reports Server (NTRS)

Horwitz, B. A.; Horowitz, J. M.

1977-01-01

Male, Long-Evans hooded rats were instrumented for monitoring core and hypothalamic temperatures as well as shivering and nonshivering thermogenesis in response to decreased ambient temperature in order to characterize the nature of the neural controller of temperature in rats at 1G and evaluate chronic implantation techniques for the monitoring of appropriate parameters at hypergravic fields. The thermoregulatory responses of cold-exposed rats at 2G were compared to those at 1G. A computer model was developed to simulate the thermoregulatory system in the rat. Observations at 1 and 2G were extended to acceleration fields of 1.5, 3.0 and 4.0G and the computer model was modified for application to altered gravity conditions. Changes in the acceleration field resulted in inadequate heat generation rather than increased heat loss. Acceleration appears to impair the ability of the neurocontroller to appropriately integrate input signals for body temperature maintenance.

Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats.

PubMed

Reed, Abbey L; Anderson, Jeffrey C; Bylund, David B; Petty, Frederick; El Refaey, Hesham; Happe, H Kevin

2009-08-01

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

In vitro characterization of peptide-modified p(AAm-co-EG/AAc) IPN-coated titanium implants.

PubMed

Barber, Thomas A; Gamble, Lara J; Castner, David G; Healy, Kevin E

2006-07-01

Interpenetrating polymer networks (IPNs) of poly(acrylamide-co-ethylene glycol/acrylic acid) [p(AAm-co-EG/AAc)] functionalized with an -Arg-Gly-Asp- containing peptide derived from rat bone sialoprotein [bsp-RGD(15)] were grafted to titanium implants in an effort to modulate osteoblast behavior in vitro. Surface characterization data were consistent with the presence of an IPN, and ligand density measurements established that the range of peptide density on the modified implants spanned three orders of magnitude (0.01-20 pmol/cm2). In vitro biological characterization of the modified implants employing the primary rat calvarial osteoblast (RCO) model resulted in the identification of a critical ligand density (0.01

A modified beam-walking apparatus for assessment of anxiety in a rodent model of blast traumatic brain injury.

PubMed

Sweis, Brian M; Bachour, Salam P; Brekke, Julia A; Gewirtz, Jonathan C; Sadeghi-Bazargani, Homayoun; Hevesi, Mario; Divani, Afshin A

2016-01-01

The elevated plus maze (EPM) is used to assess anxiety in rodents. Beam-walking tasks are used to assess vestibulomotor function. Brain injury in rodents can disrupt performance on both of these tasks. Developing novel paradigms that integrate tasks like these can reduce the need for multiple tests when attempting to assess multiple behaviors in the same animal. Using adult male rats, we evaluated the use of a modified beam-walking (MBW) apparatus as a surrogate indicator for anxiety. We used a model of blast-induced traumatic brain injury (bTBI). A total of 39 rats were assessed before and at 3, 6, 24, 72, and 168h either post- bTBI (n=33) or no-injury (n=6) using both EPM and MBW. A novel anxiety index was calculated that encompassed peeks and re-emergences on MBW. The proposed MBW anxiety index was compared with the standard anxiety index calculated from exploration into different sections of EPM. Post- bTBI, rats had an increased anxiety index when measured using EPM. Similarly, they peeked or fully emerged less out of the safe box on MBW. It was found that this novel MBW anxiety index captured similar aspects of behavior when compared to the standard anxiety index obtained from EPM. Further, these effects were dissociated from the effects of bTBI on motor function simultaneously measured on MBW. Over the course of 168h post-bTBI, rats gradually recovered on both EPM and MBW. The MBW apparatus succeeded at capturing and dissociating two separate facets of rat behavior, motor function and anxiety, simultaneously. Copyright © 2015 Elsevier B.V. All rights reserved.

Sodium molybdate prevents hypertension and vascular prostanoid imbalance in fructose-overloaded rats.

PubMed

Peredo, H A; Andrade, V; Donoso, A S; Lee, H J; Puyó, A M

2013-10-01

(1) Fructose (F) overload produces elevated blood pressure (BP), hyperglycaemia, hypertriglyceridemia and insulin resistance, resembling human metabolic syndrome. Previously, we found altered vascular prostanoid (PR) production in this model. (2) Sodium molybdate (Mo), as well as sodium tungstate, causes insulin-like effects and normalizes plasma glucose levels in streptozotocin-treated diabetic rats. We studied the effects of Mo on BP, metabolic parameters and release of PR from the mesenteric vascular bed (MVB) in F-overloaded rats. (3) Four groups of male Sprague-Dawley rats were analysed: Control, tap water to drink; F, F solution 10% W/V to drink; CMo, Mo 100 mg kg day(-1) and FMo, both treatments. After 9 weeks, the animals were killed and MVBs removed and the released PRs measured. (4) F increased BP, glycemia, triglyceridemia and insulinemia. Mo treatment prevented the increases in BP and glycemia, but did not modify triglyceridemia or insulinemia. In addition, Mo decreased BP in controls. (5) Prostaglandins (PG) F2 alpha and E2, PG 6-ketoF1 alpha and thromboxane (TX) B2 , as well as inactive metabolites of prostacyclin (PGI2 ) and TXA2 were detected. F decreased the production of vasodilator PRs PGI2 and PGE2 in MVB. Mo prevented these alterations and increased PGE2 in controls. Vasoconstrict or PRs PGF2 alpha and TXA2 release was not modified. (6) Mo treatment, beyond its known lowering effect on glycemia, prevents the reduction in the vascular release of vasodilator PR observed in this model. This could be one of the mechanisms by which Mo avoids the increase in BP caused by F overload in the rat. © 2013 John Wiley & Sons Ltd.

A combined solenoid-surface RF coil for high-resolution whole-brain rat imaging on a 3.0 Tesla clinical MR scanner.

PubMed

Underhill, Hunter R; Yuan, Chun; Hayes, Cecil E

2010-09-01

Rat brain models effectively simulate a multitude of human neurological disorders. Improvements in coil design have facilitated the wider utilization of rat brain models by enabling the utilization of clinical MR scanners for image acquisition. In this study, a novel coil design, subsequently referred to as the rat brain coil, is described that exploits and combines the strengths of both solenoids and surface coils into a simple, multichannel, receive-only coil dedicated to whole-brain rat imaging on a 3.0 T clinical MR scanner. Compared with a multiturn solenoid mouse body coil, a 3-cm surface coil, a modified Helmholtz coil, and a phased-array surface coil, the rat brain coil improved signal-to-noise ratio by approximately 72, 61, 78, and 242%, respectively. Effects of the rat brain coil on amplitudes of static field and radiofrequency field uniformity were similar to each of the other coils. In vivo, whole-brain images of an adult male rat were acquired with a T(2)-weighted spin-echo sequence using an isotropic acquisition resolution of 0.25 x 0.25 x 0.25 mm(3) in 60.6 min. Multiplanar images of the in vivo rat brain with identification of anatomic structures are presented. Improvement in signal-to-noise ratio afforded by the rat brain coil may broaden experiments that utilize clinical MR scanners for in vivo image acquisition. 2010 Wiley-Liss, Inc.

SELENIUM MODIFIES THE METABOLISM AND TOXICITY OF ARSENIC IN PRIMARY RAT HEPATOCYTES

EPA Science Inventory

ABSTRACT
Selenium Modifies the Metabolism and Toxicity of Arsenic in Primary Rat Hepatocytes. Miroslav Styblo, David J. Thomas (2000) Toxicol. Appl. Pharmacol.
Arsenic and selenium are metalloids with similar chemical properties and metabolic fates. Inorganic arsenic (iAs...

State of spermatogenesis in rats flown aboard Kosmos-690 biosatellite. [Effects of space flight factors on. gamma. radiosensitivity of germ cells in male rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plakhuta-Plakutina, G.I.

1978-10-26

In studying the modifying effects of space flight factors on radiosensitivity of various physiological systems of the body, of definite interest is the reaction of critical organs, in particular the testes, which have a high degree of heterogenic sensitivity of spermatogenic epithelium. Impairment of proliferative activity of testicular epithelium is largely related to the radiovulnerability of cells of the stem type, spermatogonia. In determining the modifying effects of weightlessness and other factors of space flights, it is necessary to compare the cytological state and quantitative evaluation of the incidence of spermatogonia, spermatocytes, spermatids, and spermatozoa in order to determine themore » possible injury to specific stages of spectrogenesis, depending on the radiation doses during space flights and in ground-based model experiments. The effects of radiation under weightless conditions on the reproductive glands of 30 male Wistar rats flown aboard Kosmos-690 and submitted to prolonged ..gamma.. radiation on the 10th day of the flight were investigated.« less

Effects of genetically modified T2A-1 rice on the GI health of rats after 90-day supplement

PubMed Central

Yuan, Yanfang; Xu, Wentao; He, Xiaoyun; Liu, Haiyan; Cao, Sishuo; Qi, Xiaozhe; Huang, Kunlun; Luo, Yunbo

2013-01-01

Bacillus thuringiensis insecticidal toxin (Bt) rice will be commercialized as a main food source. Traditional safety assessments on genetically modified products pay little attention on gastrointestinal (GI) health. More data about GI health of Bt rice must be provided to dispel public' doubts about the potential effects on human health. We constructed an improved safety assessment animal model using a basic subchronic toxicity experiment, measuring a range of parameters including microflora composition, intestinal permeability, epithelial structure, fecal enzymes, bacterial activity, and intestinal immunity. Significant differences were found between rice-fed groups and AIN93G-fed control groups in several parameters, whereas no differences were observed between genetically modified and non-genetically modified groups. No adverse effects were found on GI health resulting from genetically modified T2A-1 rice. In conclusion, this study may offer a systematic safety assessment model for GM material with respect to the effects on GI health. PMID:23752350

[The metabolic profilings study of serum and spinal cord from acute spinal cord injury rats ¹H NMR spectroscopy].

PubMed

Hu, Hua-Hui; Huang, Xiao-Long; Quan, Ren-Fu; Yang, Zong-Bao; Xu, Jing-Jing

2017-02-25

To establish the rat model of acute spinal cord injury, followed by aprimary study on this model with ¹H NMR based on metabonomics and to explore the metabonomics and biomarkers of spinal cord injury rat. Twenty eight-week-old adult male SD rats of clean grade, with body weight of (200±10) g, were divided into sham operation group and model group in accordance with the law of random numbers, and every group had 10 rats. The rats of sham operation group were operated without damaging the spinal cord, and rats of model group were made an animal model of spinal cord incomplete injury according to the modified Allen's method. According to BBB score to observate the motor function of rats on the 1th, 5th, and 7th days after surgery. Postoperative spinal cord tissue was collected in order to pathologic observation at the 7th day, and the metabolic profilings of serum and spinal cord from spinal cord injury rats were studied by ¹H NMR spectroscopy. The hindlimb motion of rats did not obviously change in sham operation group, there was no significant difference at each time point;and rats of model group occurred flaccid paralysis of both lower extremities, there was a significant difference at each time; there was significant differences between two groups at each time. Pathological results showed the spinal cord structure was normal with uniform innervation in shame group, while in model group, the spinal cord structure was mussy, and the neurons were decreased, with inflammatory cells and necrotic tissue. Analysis of metabonomics showed that concentration of very low density fat protein (VLDL), low density fat protein (LDL), glutamine, citric acid, dimethylglycine (DMG) in the serum and glutathione, 3-OH-butyrate, N-Acetyl-L-aspartic acid (NAA), glycerophosphocholine (GPC), glutamic acid, and ascorbate in spinal cord had significant changes( P <0.05). There are significant differences in metabolic profile from serum and spinal cord sample between model group and sham operation group, it conduces to explain the changes of small molecular substances in serum and spinal cord tissue after spinal cord injury, this provides the research basis for targeted research on the role of metabolic markers in patients with acute spinal cord injury.

In Vitro and In Vivo Biocompatibility Evaluation of Polyallylamine and Macromolecular Heparin Conjugates Modified Alginate Microbeads.

PubMed

Vaithilingam, Vijayaganapathy; Steinkjer, Bjørg; Ryan, Liv; Larsson, Rolf; Tuch, Bernard Edward; Oberholzer, Jose; Rokstad, Anne Mari

2017-09-15

Host reactivity to biocompatible immunoisolation devices is a major challenge for cellular therapies, and a human screening model would be of great value. We designed new types of surface modified barium alginate microspheres, and evaluated their inflammatory properties using human whole blood, and the intraperitoneal response after three weeks in Wistar rats. Microspheres were modified using proprietary polyallylamine (PAV) and coupled with macromolecular heparin conjugates (Corline Heparin Conjugate, CHC). The PAV-CHC strategy resulted in uniform and stable coatings with increased anti-clot activity and low cytotoxicity. In human whole blood, PAV coating at high dose (100 µg/ml) induced elevated complement, leukocyte CD11b and inflammatory mediators, and in Wistar rats increased fibrotic overgrowth. Coating of high dose PAV with CHC significantly reduced these responses. Low dose PAV (10 µg/ml) ± CHC and unmodified alginate microbeads showed low responses. That the human whole blood inflammatory reactions paralleled the host response shows a link between inflammatory potential and initial fibrotic response. CHC possessed anti-inflammatory activity, but failed to improve overall biocompatibility. We conclude that the human whole blood assay is an efficient first-phase screening model for inflammation, and a guiding tool in development of new generation microspheres for cell encapsulation therapy.

Effect of chromium picolinate on modified forced swimming test in diabetic rats: involvement of serotonergic pathways and potassium channels.

PubMed

Khanam, Razia; Pillai, K K

2006-02-01

Depression occurs frequently in patients with diabetes mellitus. Chromium picolinate, an essential trace element is recommended for diabetes and also has been reported to benefit depression, but its mechanism is still debated. To investigate the mechanism, we studied its effects on serum insulin, serum glucose and on modified forced swimming test, a behavioural paradigm for depression in rats. The study involving co-administration of sub-active doses of glimepiride, a K(+) channel blocker and chromium picolinate on blood glucose levels and modified forced swimming test was also performed to probe any role of K(+) channels in its antidiabetic and antidepressants effects. Streptozotocin (55 mg/kg, intraperitoneally) was injected in rats to induce diabetes (Type 1). After a week, chromium picolinate (8 microg/ml in drinking water) was administered for 4 weeks. Normal rats received similar drug treatment. The sub-active doses of chromium picolinate (4 microg/ml in drinking water) and glimeperide (2.5 mg/kg, orally) were co-administered and their effects on modified forced swimming test and on glucose levels were measured. Chromium picolinate (8 microg/ml in drinking water) produced hypoglycaemia in diabetic and normal rats. It had no effects on the streptozotocin-induced reduction in insulin levels. Chromium picolinate (8 microg/ml in drinking water) increased swimming with subsequent decrease in immobility. The sub-active doses of chromium picolinate and glimeperide showed significant additive effects in modified forced swimming test and reduction in serum glucose concentrations, though statistically insignificant. In conclusion chromium picolinate shows antidepressant action on modified forced swimming test affecting only swimming that suggests serotonergic pathways involvement. The additive effects on swimming in modified forced swimming test and reduction in serum glucose levels shows involvement of K(+) channels in antidiabetic and antidepressant actions of chromium picolinate.

Evaluation of a Mathematical Model of Rat Body Weight Regulation in Application to Caloric Restriction and Drug Treatment Studies.

PubMed

Selimkhanov, Jangir; Thompson, W Clayton; Patterson, Terrell A; Hadcock, John R; Scott, Dennis O; Maurer, Tristan S; Musante, Cynthia J

2016-01-01

The purpose of this work is to develop a mathematical model of energy balance and body weight regulation that can predict species-specific response to common pre-clinical interventions. To this end, we evaluate the ability of a previously published mathematical model of mouse metabolism to describe changes in body weight and body composition in rats in response to two short-term interventions. First, we adapt the model to describe body weight and composition changes in Sprague-Dawley rats by fitting to data previously collected from a 26-day caloric restriction study. The calibrated model is subsequently used to describe changes in rat body weight and composition in a 23-day cannabinoid receptor 1 antagonist (CB1Ra) study. While the model describes body weight data well, it fails to replicate body composition changes with CB1Ra treatment. Evaluation of a key model assumption about deposition of fat and fat-free masses shows a limitation of the model in short-term studies due to the constraint placed on the relative change in body composition components. We demonstrate that the model can be modified to overcome this limitation, and propose additional measurements to further test the proposed model predictions. These findings illustrate how mathematical models can be used to support drug discovery and development by identifying key knowledge gaps and aiding in the design of additional experiments to further our understanding of disease-relevant and species-specific physiology.

Evaluation of a Mathematical Model of Rat Body Weight Regulation in Application to Caloric Restriction and Drug Treatment Studies

PubMed Central

Selimkhanov, Jangir; Patterson, Terrell A.; Scott, Dennis O.; Maurer, Tristan S.; Musante, Cynthia J.

2016-01-01

The purpose of this work is to develop a mathematical model of energy balance and body weight regulation that can predict species-specific response to common pre-clinical interventions. To this end, we evaluate the ability of a previously published mathematical model of mouse metabolism to describe changes in body weight and body composition in rats in response to two short-term interventions. First, we adapt the model to describe body weight and composition changes in Sprague-Dawley rats by fitting to data previously collected from a 26-day caloric restriction study. The calibrated model is subsequently used to describe changes in rat body weight and composition in a 23-day cannabinoid receptor 1 antagonist (CB1Ra) study. While the model describes body weight data well, it fails to replicate body composition changes with CB1Ra treatment. Evaluation of a key model assumption about deposition of fat and fat-free masses shows a limitation of the model in short-term studies due to the constraint placed on the relative change in body composition components. We demonstrate that the model can be modified to overcome this limitation, and propose additional measurements to further test the proposed model predictions. These findings illustrate how mathematical models can be used to support drug discovery and development by identifying key knowledge gaps and aiding in the design of additional experiments to further our understanding of disease-relevant and species-specific physiology. PMID:27227543

Internal desynchronization in a model of night-work by forced activity in rats.

PubMed

Salgado-Delgado, R; Angeles-Castellanos, M; Buijs, M R; Escobar, C

2008-06-26

Individuals engaged in shift- or night-work show disturbed diurnal rhythms, out of phase with temporal signals associated to the light/dark (LD) cycle, resulting in internal desynchronization. The mechanisms underlying internal desynchrony have been mainly investigated in experimental animals with protocols that induce phase shifts of the LD cycle and thus modify the activity of the suprachiasmatic nucleus (SCN). In this study we developed an animal model of night-work in which the light-day cycle remained stable and rats were required to be active in a rotating wheel for 8 h daily during their sleeping phase (W-SP). This group was compared with rats that were working in the wheel during their activity phase (W-AP) and with undisturbed rats (C). We provide evidence that forced activity during the sleeping phase (W-SP group) alters not only activity, but also the temporal pattern of food intake. In consequence W-SP rats showed a loss of glucose rhythmicity and a reversed rhythm of triacylglycerols. In contrast W-AP rats did not show such changes and exhibited metabolic rhythms similar to those of the controls. The three groups exhibited the nocturnal corticosterone increase, in addition the W-SP and W-AP groups showed increase of plasma corticosterone associated with the start of the working session. Forced activity during the sleep phase did not modify SCN activity characterized by the temporal patterns of PER1 and PER2 proteins, which remained in phase with the LD cycle. These observations indicate that a working regimen during the sleeping period elicits internal desynchronization in which activity combined with feeding uncouples metabolic functions from the biological clock which remains fixed to the LD cycle. The present data suggest that in the night worker the combination of work and eating during working hours may be the cause of internal desynchronization.

Interictal spike frequency varies with ovarian cycle stage in a rat model of epilepsy.

PubMed Central

D’Amour, James; Magagna-Poveda, Alejandra; Moretto, Jillian; Friedman, Daniel; LaFrancois, John J.; Pearce, Patrice; Fenton, Andre A.; MacLusky, Neil J.; Scharfman, Helen E.

2015-01-01

In catamenial epilepsy, seizures exhibit a cyclic pattern that parallels the menstrual cycle. Many studies suggest that catamenial seizures are caused by fluctuations in gonadal hormones during the menstrual cycle, but this has been difficult to study in rodent models of epilepsy because the ovarian cycle in rodents, called the estrous cycle, is disrupted by severe seizures. Thus, when epilepsy is severe, estrous cycles become irregular or stop. Therefore, we modified kainic acid (KA)- and pilocarpine-induced status epilepticus (SE) models of epilepsy so that seizures were rare for the first months after SE, and conducted video-EEG during this time. The results showed that interictal spikes (IIS) occurred intermittently. All rats with regular 4-day estrous cycles had IIS that waxed and waned with the estrous cycle. The association between the estrous cycle and IIS was strong: if the estrous cycles became irregular transiently, IIS frequency also became irregular, and when the estrous cycle resumed its 4-day pattern, IIS frequency did also. Furthermore, when rats were ovariectomized, or males were recorded, IIS frequency did not show a 4-day pattern. Systemic administration of an estrogen receptor antagonist stopped the estrous cycle transiently, accompanied by transient irregularity of the IIS pattern. Eventually all animals developed severe, frequent seizures and at that time both the estrous cycle and the IIS became irregular. We conclude that the estrous cycle entrains IIS in the modified KA and pilocarpine SE models of epilepsy. The data suggest that the ovarian cycle influences more aspects of epilepsy than seizure susceptibility. PMID:25864929

Differences in social interaction- vs. cocaine reward in mouse vs. rat.

PubMed

Kummer, Kai K; Hofhansel, Lena; Barwitz, Constanze M; Schardl, Aurelia; Prast, Janine M; Salti, Ahmad; El Rawas, Rana; Zernig, Gerald

2014-01-01

We previously developed rat experimental models based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of dyadic social interaction with a sex- and weight-matched male Sprague Dawley (SD) rat (1) reversed CPP from cocaine to social interaction despite continuing cocaine training, and (2) prevented the reacquisition/re-expression of cocaine CPP. In a concurrent conditioning schedule, pairing one compartment with social interaction and the other compartment with 15 mg/kg cocaine injections, rats spent the same amount of time in both compartments and the most rewarding sensory component of the composite stimulus social interaction was touch (taction). In the present study, we validated our experimental paradigm in C57BL/6 mice to investigate if our experimental paradigm may be useful for the considerable number of genetically modified mouse models. Only 71% of the tested mice developed place preference for social interaction, whereas 85% of the rats did. Accordingly, 29% of the mice developed conditioned place aversion (CPA) to social interaction, whereas this was true for only 15% of the rats. In support of the lesser likelihood of mice to develop a preference for social interaction, the average amount of time spent in direct contact was 17% for mice vs. 79% for rats. In animals that were concurrently conditioned for social interaction vs. cocaine, the relative reward strength for cocaine was 300-fold higher in mice than in rats. Considering that human addicts regularly prefer drugs of abuse to drug-free social interaction, the present findings suggest that our experimental paradigm of concurrent CPP for cocaine vs. social interaction is of even greater translational power if performed in C57BL/6 mice, the genetic background for most transgenic rodent models, than in rats.

Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model.

PubMed

Collins, K H; Paul, H A; Reimer, R A; Seerattan, R A; Hart, D A; Herzog, W

2015-11-01

Osteoarthritis (OA) may result from intrinsic inflammation related to metabolic disturbance. Obesity-associated inflammation is triggered by lipopolysaccharide (LPS) derived from the gut microbiota. However, the relationship between gut microbiota, LPS, inflammation, and OA remain unclear. To evaluate the associations between gut microbiota, systemic LPS levels, serum and local inflammatory profiles, and joint damage in a high fat/high sucrose diet induced obese rat model. 32 rats were randomized to a high fat/high sucrose diet (diet-induced obese (DIO), 40% fat, 45% sucrose, n = 21) or chow diet group (12% fat, 3.7% sucrose n = 11) for 28 weeks. After a 12-week obesity induction period, DIO animals were stratified into Obesity Prone (DIO-P, top 33% by change in body mass, n = 7), and Obesity Resistant groups (DIO-R, bottom 33%, n = 7). At sacrifice, joints were scored using a Modified Mankin Criteria. Blood and synovial fluid analytes, serum LPS, and fecal gut microbiota were analyzed. DIO animals had greater Modified Mankin scores than chow animals (P = 0.002). There was a significant relationship (r = 0.604, p = 0.001) between body fat, but not body mass, and Modified Mankin score. Eighteen synovial fluid and four serum analytes were increased in DIO animals. DIO serum LPS levels were increased compared to chow (P = 0.031). Together, Lactobacillus species (spp.) and Methanobrevibacter spp. abundance had a strong predictive relationship with Modified Mankin Score (r(2) = 0.5, P < 0.001). Increased OA in DIO animals is associated with greater body fat, not body mass. The link between gut microbiota and adiposity-derived inflammation and metabolic OA warrants further investigation. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

[Noncollagen bone proteins use in the composition of osteoplactic material Gapkol modified by vacuum].

PubMed

Volozhin, A I; Grigor'ian, A S; Desiatnichenko, K S; Ozhelevskaia, S A; Doktorov, A A; Kurdiumov, S G; Fionova, E V; Gurin, A N; Karakov, K G

2008-01-01

In rat experiments the ability of noncollagen bone proteins (NCBP) in the composition of osteoplactic modified material Gapkol (not tanned in formalin and subjected to vacuum extraction) to increase bone reparation in comparison with traditional Gapkol was studied. Quantitative evaluation was performed on rat parietal bone and qualitative evaluation was performed on rat mandible. It was shown that Gapkol with NCBP (not tanned in formalin and subjected to vacuum extraction) increased reparative osteogenesis.

Age differences in the impact of forced swimming test on serotonin transporter levels in lateral septum and dorsal raphe

PubMed Central

2014-01-01

Background Forced swimming test (FST) is an animal model which evaluates behavioral despair and the effect of antidepressants such as the selective serotonin reuptake inhibitors; the FST modifies the expression of some receptors related to antidepressant response, but it is not known whether serotonin transporter (SERT), their main target, is affected by this test in animals of different ages. Antidepressant response has shown age-dependent variations which could be associated with SERT expression. The aim of the present study was to analyze changes in the SERT immunoreactivity (SERT-IR) in dorsal raphe and lateral septum of male rats from different age groups with or without behavioral despair induced by their exposure to the FST, since these two structures are related to the expression of this behavior. Methods Prepubertal (24 PN), pubertal (40 PN), young adult (3–5 months) and middle-aged (12 months) male rats were assigned to a control group (non-FST) or depressed group (FST, two sessions separated by 24 h). Changes in SERT-IR in dorsal raphe and lateral septum were determined with immunofluorescence. Results Pubertal and middle-aged rats showed higher levels of immobility behavior compared to prepubertal rats on the FST. SERT-IR showed an age-dependent increase followed by a moderate decrease in middle-aged rats in both structures; a decreased in SERT-IR in lateral septum and dorsal raphe of pubertal rats was observed after the FST. Conclusions Age differences were observed in the SERT-IR of structures related to behavioral despair; SERT expression was modified by the FST in lateral septum and dorsal raphe of pubertal rats. PMID:24490994

Fasudil and DETA NONOate, Loaded in a Peptide-Modified Liposomal Carrier, Slow PAH Progression upon Pulmonary Delivery.

PubMed

Rashid, Jahidur; Nahar, Kamrun; Raut, Snehal; Keshavarz, Ali; Ahsan, Fakhrul

2018-05-07

We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long-acting nitric oxide donor, both loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC), in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified and CAR-modified liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia-induced PAH rats. We also conducted morphometric studies (degree of muscularization, arterial medial wall thickness, and collagen deposition) after treating the PAH rats with test and control formulations. When the rats were treated acutely and chronically, the reduction in mPAP was more pronounced in the liposomal formulation-treated rats than in plain drug-treated rats. CAR-modified liposomes were more selective in reducing mPAP than unmodified liposomes of the drugs. Both drugs, formulated in CAR-modified liposomes, reduced the degree of muscularization, medial arterial wall thickness, and collagen deposition more than the combination of plain drugs did. As seen with the in vivo data, CAR-modified liposomes of fasudil or DN increased the levels of the vasodilatory signaling molecule, cGMP, in the smooth muscle cells of PAH-afflicted human pulmonary arteries. Overall, fasudil and DN, formulated in liposomes, could be used as a combination therapy for a better management of PAH.

Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids

PubMed Central

Song, Byoung-Joon; Moon, Kwan-Hoon; Olsson, Nils U.; Salem, Norman

2008-01-01

Background/Aims We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6, omega-6) and docosahexaenoic (DHA,22:6n3, omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet prevents alcohol-induced fatty liver. Methods Male Long-Evans rats were fed an ethanol or control liquid-diet with or without DHA/AA for 9 weeks. Plasma transaminase levels, liver histology, oxidative/nitrosative stress markers, and activities of oxidatively-modified mitochondrial proteins were evaluated. Results Chronic alcohol administration increased the degree of fatty liver but fatty liver decreased significantly in rats fed the alcohol-DHA/AA-supplemented diet. Alcohol exposure increased oxidative/nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. However, these increments were normalized in rats fed the alcohol-DHA/AA-supplemented diet. The number of oxidatively-modified mitochondrial proteins was markedly increased following alcohol exposure but significantly reduced in rats fed the alcohol-DHA/AA-supplemented diet. The suppressed activities of mitochondrial aldehyde dehydrogenase, ATP synthase, and 3-ketoacyl-CoA thiolase in ethanol-exposed rats were also recovered in animals fed the ethanol-DHA/AA-supplemented diet. Conclusions Addition of DHA/AA prevents alcohol-induced fatty liver and mitochondrial dysfunction in an animal model by protecting various mitochondrial enzymes most likely through reducing oxidative/nitrosative stress. PMID:18571270

Lipoate ameliorates ischemia-reperfusion in animal models.

PubMed

Freisleben, H J

2000-01-01

Ischemia and reperfusion were studied in isolated working rat hearts and in exarticulated rat hind limbs. Free radicals are known to be generated in ischemia/reperfusion and to propagate complications. To reduce reperfusion injury, conditions were ameliorated including the treatment with antioxidants, lipoate or dihydrolipoate. In isolated working rat hearts, cardiac and mitochondrial parameters are impaired during hypoxia and partially recover in reperfusion. Dihydrolipoate, if added into the perfusion buffer at 0.3 microM concentration, keeps the pH higher (7.15) during hypoxia, as compared to controls (6.98). This compound accelerates and stabilizes the recovery of the aortic flow. With dihydrolipoate, ATP synthesis is increased, ATPase activity (ATP hydrolysis) reduced, intracellular creatine kinase activity maintained and thus phosphocreatine contents are higher than in controls. For exarticulated rat hind limbs, the dihydrolipoate group contained 8.3 microM in the modified reperfusate. Recovery of the contractile function was 49% vs. 34% in controls and muscle flexibility was maintained whereas it decreased by 15% in the controls. Release of creatine kinase from cells was significantly lower with dihydrolipoate. Lipoate/dihydrolipoate effectively reduced reperfusion injury in isolated working rat hearts and in exarticulated rat hind limbs after extended ischemia. Finally, the compound was successfully applied in an in vivo pig hind limb model.

Neuropathological Changes in Brain Cortex and Hippocampus in a Rat Model of Alzheimer’s Disease

PubMed Central

Nobakht, Maliheh; Hoseini, Seyed Mohammad; Mortazavi, Pejman; Sohrabi, Iraj; Esmailzade, Banafshe; Roosh, Nahid Rahbar; Omidzahir, Shila

2011-01-01

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. Methods: Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and β-amyloid (Aβ) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 µL of Aβ (1-40) into the hippocampal fissure. Results: In the present study, Aβ (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. Aβ injection CA1 caused Aβ deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. Conclusion: We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group. PMID:21725500

Measuring Attention in Rodents: Comparison of a Modified Signal Detection Task and the 5-Choice Serial Reaction Time Task

PubMed Central

Turner, Karly M.; Peak, James; Burne, Thomas H. J.

2016-01-01

Neuropsychiatric research has utilized cognitive testing in rodents to improve our understanding of cognitive deficits and for preclinical drug development. However, more sophisticated cognitive tasks have not been as widely exploited due to low throughput and the extensive training time required. We developed a modified signal detection task (SDT) based on the growing body of literature aimed at improving cognitive testing in rodents. This study directly compares performance on the modified SDT with a traditional test for measuring attention, the 5-choice serial reaction time task (5CSRTT). Adult male Sprague-Dawley rats were trained on either the 5CSRTT or the SDT. Briefly, the 5CSRTT required rodents to pay attention to a spatial array of five apertures and respond with a nose poke when an aperture was illuminated. The SDT required the rat to attend to a light panel and respond either left or right to indicate the presence of a signal. In addition, modifications were made to the reward delivery, timing, control of body positioning, and the self-initiation of trials. It was found that less training time was required for the SDT, with both sessions to criteria and daily session duration significantly reduced. Rats performed with a high level of accuracy (>87%) on both tasks, however omissions were far more frequent on the 5CSRTT. The signal duration was reduced on both tasks as a manipulation of task difficulty relevant to attention and a similar pattern of decreasing accuracy was observed on both tasks. These results demonstrate some of the advantages of the SDT over the traditional 5CSRTT as being higher throughput with reduced training time, fewer omission responses and their body position was controlled at stimulus onset. In addition, rats performing the SDT had comparable high levels of accuracy. These results highlight the differences and similarities between the 5CSRTT and a modified SDT as tools for assessing attention in preclinical animal models. PMID:26834597

Voluntary ethanol consumption differs in adolescent and adult male rats using a modified sucrose-fading paradigm.

PubMed

Maldonado, Antoniette M; Finkbeiner, Lauren M; Alipour, Kent K; Kirstein, Cheryl L

2008-09-01

Initiation of alcohol consumption during adolescence is high, which usually begins with consumption of highly concentrated sweetened alcoholic beverages in adolescent humans. Enhanced voluntary ethanol (EtOH) intake has been observed previously in adolescent relative to adult rats under continuous access conditions using sweetened EtOH solutions. The present set of experiments investigated patterns of voluntary EtOH intake in adolescent and adult rats using sweetened EtOH solutions in a limited access paradigm. Rats were trained with modified sucrose-substitution protocols that ended at either 5% sucrose-20% EtOH (5S/20E) (Exp. 1) or 5% sucrose-10% EtOH (5S/10E) (Exp. 2). Voluntary EtOH consumption differences between the 2 age groups were apparent at higher (i.e., 10 and 20%), but not lower (i.e., 2 and 5%) EtOH concentrations. Adolescent rats consumed more EtOH on a g/kg basis only at 20% EtOH (Exp. 1). Adolescent rats voluntarily consumed more EtOH than adults when maintained at 5S/10E (Exp. 2). To assess whether these age-related differences in voluntary EtOH intake were concentration dependent, rats were trained with 5S/20E and subsequently trained with decreasing EtOH concentrations (i.e., 5S/10E and 5S/5E). Adolescents consumed more EtOH when initially presented with the 5S/10E and 5S/20E EtOH concentrations, and subsequently at the lower 5S/5E EtOH concentration (Exp. 3). There were no differences in preference for the sucrose-only solution, however adolescents tended to consume more sucrose at the 5S sucrose concentration (Exp. 4). Given that adolescents consumed more EtOH at the 5S/10E and 5S/20E, but not at the 5S/5E EtOH concentrations, preference for sucrose does not solely explain the age differences in voluntary EtOH intake observed. Overall, results replicate previous work, demonstrating adolescent rats consume more EtOH relative to adults. However, the present results were observed using sweetened EtOH solutions in a limited access paradigm. The present modified sucrose-substitution paradigm may serve as a valid model of human adolescent drinking behavior.

Odor Preference Learning and Memory Modify GluA1 Phosphorylation and GluA1 Distribution in the Neonate Rat Olfactory Bulb: Testing the AMPA Receptor Hypothesis in an Appetitive Learning Model

ERIC Educational Resources Information Center

Cui, Wen; Darby-King, Andrea; Grimes, Matthew T.; Howland, John G.; Wang, Yu Tian; McLean, John H.; Harley, Carolyn W.

2011-01-01

An increase in synaptic AMPA receptors is hypothesized to mediate learning and memory. AMPA receptor increases have been reported in aversive learning models, although it is not clear if they are seen with memory maintenance. Here we examine AMPA receptor changes in a cAMP/PKA/CREB-dependent appetitive learning model: odor preference learning in…

Pregabalin reduces acute inflammatory and persistent pain associated with nerve injury and cancer in rat models of orofacial pain.

PubMed

Hummig, Wagner; Kopruszinski, Caroline Machado; Chichorro, Juliana Geremias

2014-01-01

To assess the analgesic effect of pregabalin in orofacial models of acute inflammatory pain and of persistent pain associated with nerve injury and cancer, and so determine its effectiveness in controlling orofacial pains having different underlying mechanisms. Orofacial capsaicin and formalin tests were employed in male Wistar rats to assess the influence of pregabalin (or vehicle) pretreatment in acute pain models, and the results from these experiments were analyzed by one-way analysis of variance (ANOVA) followed by Newman Keuls post-hoc test. Pregabalin (or vehicle) treatment was also tested on the facial heat hyperalgesia that was evaluated in rats receiving injection of the inflammatory irritant carrageenan into the upper lip, as well as after constriction of the infraorbital nerve (a model of trigeminal neuropathic pain), or after inoculation of tumor cells into the facial vibrissal pad; two-way repeated measures ANOVA followed by Newman-Keuls post-hoc test was used to analyze data from these experiments. Facial grooming induced by capsaicin was abolished by pretreatment with pregabalin at 10 and 30 mg/kg. However, pregabalin failed to modify the first phase of the formalin response, but reduced the second phase at both doses (10 and 30 mg/kg). In addition, treatment of rats with pregabalin reduced the heat hyperalgesia induced by carrageenan, as well as by nerve injury and facial cancer. Pregabalin produced a marked antinociceptive effect in rat models of facial inflammatory pain as well as in facial neuropathic and cancer pain models, suggesting that it may represent an important agent for the clinical control of orofacial pain.

Transcriptional alterations in the left ventricle of three hypertensive rat models.

PubMed

Cerutti, Catherine; Kurdi, Mazen; Bricca, Giampiero; Hodroj, Wassim; Paultre, Christian; Randon, Jacques; Gustin, Marie-Paule

2006-11-27

Left ventricular hypertrophy (LVH) is commonly associated with hypertension and represents an independent cardiovascular risk factor. The aim of this study was to test the hypothesis that the cardiac overload related to hypertension is associated to a specific gene expression pattern independently of genetic background. Gene expression levels were obtained with microarrays for 15,866 transcripts from RNA of left ventricles from 12-wk-old rats of three hypertensive models [spontaneously hypertensive rat (SHR), Lyon hypertensive rat (LH), and heterozygous TGR(mRen2)27 rat] and their respective controls. More than 60% of the detected transcripts displayed significant changes between the three groups of normotensive rats, showing large interstrain variability. Expression data were analyzed with respect to hypertension, LVH, and chromosomal distribution. Only four genes had significantly modified expression in the three hypertensive models among which a single gene, coding for sialyltransferase 7A, was consistently overexpressed. Correlation analysis between expression data and left ventricular mass index (LVMI) over all rats identified a larger set of genes whose expression was continuously related with LVMI, including known genes associated with cardiac remodeling. Positioning the detected transcripts along the chromosomes pointed out high-density regions mostly located within blood pressure and cardiac mass quantitative trait loci. Although our study could not detect a unique reprogramming of cardiac cells involving specific genes at early stage of LVH, it allowed the identification of some genes associated with LVH regardless of genetic background. This study thus provides a set of potentially important genes contained within restricted chromosomal regions involved in cardiovascular diseases.

Middle-aged, but not young, rats develop cognitive impairment and cortical neurodegeneration following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion.

PubMed

Ferreira, Emilene D Fiuza; Romanini, Cássia V; Mori, Marco A; de Oliveira, Rúbia M Weffort; Milani, Humberto

2011-10-01

Permanent, stepwise occlusion of the vertebral arteries (VAs) and internal carotid arteries (ICAs) following the sequence VA→ICA→ICA, with an interstage interval (ISI, →) of 7 days, has been investigated as a four-vessel occlusion (4-VO)/ICA model of chronic cerebral hypoperfusion. This model has the advantage of not causing retinal damage. In young rats, however, 4-VO/ICA with an ISI of 7 days fails to cause behavioral sequelae. We hypothesized that such a long ISI would allow the brain to efficiently compensate for cerebral hypoperfusion, preventing the occurrence of cognitive impairment and neurodegeneration. The present study evaluated whether brain neurodegeneration and learning/memory deficits can be expressed by reducing the length of the ISI and whether aging influences the outcome. Young, male Wistar rats were subjected to 4-VO/ICA with different ISIs (5, 4, 3 or 2 days). An ISI of 4 days was used in middle-aged rats. Ninety days after 4-VO/ICA, the rats were tested for learning/memory impairment in a modified radial maze and then examined for neurodegeneration of the hippocampus and cerebral cortex. Regardless of the ISI, young rats were not cognitively impaired, although hippocampal damage was evident. Learning/memory deficits and hippocampal and cortical neurodegeneration occurred in middle-aged rats. The data indicate that 4-VO/ICA has no impact on the capacity of young rats to learn the radial maze task, despite 51% hippocampal cell death. Such resistance is lost in middle-aged animals, for which the most extensive neurodegeneration observed in both the hippocampus and cerebral cortex may be responsible. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Effects of caffeine on locomotor activity in streptozotocin-induced diabetic rats.

PubMed

Bădescu, S V; Tătaru, C P; Kobylinska, L; Georgescu, E L; Zahiu, D M; Zăgrean, A M; Zăgrean, L

2016-01-01

Diabetes mellitus modifies the expression of adenosine receptors in the brain. Caffeine acts as an antagonist of A1 and A2A adenosine receptors and was shown to have a dose-dependent biphasic effect on locomotion in mice. The present study investigated the link between diabetes and locomotor activity in an animal model of streptozotocin-induced diabetes, and the effects of a low-medium dose of caffeine in this relation. The locomotor activity was investigated by using Open Field Test at 6 weeks after diabetes induction and after 2 more weeks of chronic caffeine administration. Diabetes decreased locomotor activity (total distance moved and mobility time). Chronic caffeine exposure impaired the locomotor activity in control rats, but not in diabetic rats. Our data suggested that the medium doses of caffeine might block the A2A receptors, shown to have an increased density in the brain of diabetic rats, and improve or at least maintain the locomotor activity, offering a neuroprotective support in diabetic rats. Abbreviations : STZ = streptozotocin, OFT = Open Field Test.

A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats

PubMed Central

Sun, Chia Chi; Vaja, Valentina; Chen, Shanzhuo; Theurl, Igor; Stepanek, Aaron; Brown, Diane E.; Cappellini, Maria D.; Weiss, Guenter; Hong, Charles C.; Lin, Herbert Y.; Babitt, Jodie L.

2013-01-01

Background Anemia is a common complication of chronic kidney disease (CKD) that negatively impacts the quality of life and is associated with numerous adverse outcomes. Excess levels of the iron regulatory hormone hepcidin are thought to contribute to anemia in CKD patients by decreasing iron availability from the diet and from body stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in human patients. Methods We developed a modified adenine-induced kidney disease model with a higher survival rate than previously reported models, while maintaining persistent kidney disease and anemia. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which was previously shown to lower hepcidin levels in rodents, mobilized iron into the plasma and improved iron-restricted erythropoiesis in this model. Results Adenine-treated rats exhibited increased hepatic hepcidin mRNA, decreased serum iron, increased spleen iron content, low hemoglobin (Hb) and inappropriately low erythropoietin (EPO) levels relative to the degree of anemia. LDN-193189 administration to adenine-treated rats lowered hepatic hepcidin mRNA, mobilized stored iron into plasma and increased Hb content of reticulocytes. Conclusions Our data suggest that hepcidin lowering agents may provide a new therapeutic strategy to improve iron availability for erythropoiesis in CKD. PMID:23345622

Disruption of model-based behavior and learning by cocaine self-administration in rats.

PubMed

Wied, Heather M; Jones, Joshua L; Cooch, Nisha K; Berg, Benjamin A; Schoenbaum, Geoffrey

2013-10-01

Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.

Additive Effects of Rebamipide Plus Proton Pump Inhibitors on the Expression of Tight Junction Proteins in a Rat Model of Gastro-Esophageal Reflux Disease.

PubMed

Gweon, Tae-Geun; Park, Jong-Hyung; Kim, Byung-Wook; Choi, Yang Kyu; Kim, Joon Sung; Park, Sung Min; Kim, Chang Whan; Kim, Hyung-Gil; Chung, Jun-Won

2018-01-15

The aim of this study was to investigate the effects of rebamipide on tight junction proteins in the esophageal mucosa in a rat model of gastroesophageal reflux disease (GERD). GERD was created in rats by tying the proximal stomach. The rats were divided into a control group, a proton pump inhibitor (PPI) group, and a PPI plus rebamipide (PPI+R) group. Pantoprazole (5 mg/kg) was administered intraperitoneally to the PPI and PPI+R groups. An additional dose of rebamipide (100 mg/kg) was administered orally to the PPI+R group. Mucosal erosions, epithelial thickness, and leukocyte infiltration into the esophageal mucosa were measured in isolated esophagi 14 days after the procedure. A Western blot analysis was conducted to measure the expression of claudin-1, -3, and -4. The mean surface area of mucosal erosions, epithelial thickness, and leukocyte infiltration were lower in the PPI group and the PPI+R group than in the control group. Western blot analysis revealed that the expression of claudin-3 and -4 was significantly higher in the PPI+R group than in the control group. Rebamipide may exert an additive effect in combination with PPI to modify the tight junction proteins of the esophageal mucosa in a rat model of GERD. This treatment might be associated with the relief of GERD symptoms.

Cocoa Diet Prevents Antibody Synthesis and Modifies Lymph Node Composition and Functionality in a Rat Oral Sensitization Model.

PubMed

Camps-Bossacoma, Mariona; Abril-Gil, Mar; Saldaña-Ruiz, Sandra; Franch, Àngels; Pérez-Cano, Francisco J; Castell, Margarida

2016-04-23

Cocoa powder, a rich source of polyphenols, has shown immunomodulatory properties in both the intestinal and systemic immune compartments of rats. The aim of the current study was to establish the effect of a cocoa diet in a rat oral sensitization model and also to gain insight into the mesenteric lymph nodes (MLN) activities induced by this diet. To achieve this, three-week-old Lewis rats were fed either a standard diet or a diet with 10% cocoa and were orally sensitized with ovalbumin (OVA) and with cholera toxin as a mucosal adjuvant. Specific antibodies were quantified, and lymphocyte composition, gene expression, and cytokine release were established in MLN. The development of anti-OVA antibodies was almost totally prevented in cocoa-fed rats. In addition, this diet increased the proportion of TCRγδ+ and CD103+CD8+ cells and decreased the proportion of CD62L+CD4+ and CD62L+CD8+ cells in MLN, whereas it upregulated the gene expression of OX40L, CD11c, and IL-1β and downregulated the gene expression of IL-17α. In conclusion, the cocoa diet induced tolerance in an oral sensitization model accompanied by changes in MLN that could contribute to this effect, suggesting its potential implication in the prevention of food allergies.

Cocoa Diet Prevents Antibody Synthesis and Modifies Lymph Node Composition and Functionality in a Rat Oral Sensitization Model

PubMed Central

Camps-Bossacoma, Mariona; Abril-Gil, Mar; Saldaña-Ruiz, Sandra; Franch, Àngels; Pérez-Cano, Francisco J.; Castell, Margarida

2016-01-01

Cocoa powder, a rich source of polyphenols, has shown immunomodulatory properties in both the intestinal and systemic immune compartments of rats. The aim of the current study was to establish the effect of a cocoa diet in a rat oral sensitization model and also to gain insight into the mesenteric lymph nodes (MLN) activities induced by this diet. To achieve this, three-week-old Lewis rats were fed either a standard diet or a diet with 10% cocoa and were orally sensitized with ovalbumin (OVA) and with cholera toxin as a mucosal adjuvant. Specific antibodies were quantified, and lymphocyte composition, gene expression, and cytokine release were established in MLN. The development of anti-OVA antibodies was almost totally prevented in cocoa-fed rats. In addition, this diet increased the proportion of TCRγδ+ and CD103+CD8+ cells and decreased the proportion of CD62L+CD4+ and CD62L+CD8+ cells in MLN, whereas it upregulated the gene expression of OX40L, CD11c, and IL-1β and downregulated the gene expression of IL-17α. In conclusion, the cocoa diet induced tolerance in an oral sensitization model accompanied by changes in MLN that could contribute to this effect, suggesting its potential implication in the prevention of food allergies. PMID:27120615

Development of a Novel Alginate-Based Pleural Sealant

DTIC Science & Technology

2017-09-01

and will be the subject of ongoing studies . Figure 20: Experimental set-up for endobronchial administration of sealants in the ex vivo pig lung...toxicity. In the studies to date, we have done extensive materials characterization not just of modified alginates but now a number of other biologic...pig) ex vivo lung models and have performed initial in vivo evaluations of several compounds in a non-survival surgery rat lung injury model. The

Effect of postnatal low-dose exposure to environmental chemicals on the gut microbiome in a rodent model.

PubMed

Hu, Jianzhong; Raikhel, Vincent; Gopalakrishnan, Kalpana; Fernandez-Hernandez, Heriberto; Lambertini, Luca; Manservisi, Fabiana; Falcioni, Laura; Bua, Luciano; Belpoggi, Fiorella; L Teitelbaum, Susan; Chen, Jia

2016-06-14

This proof-of-principle study examines whether postnatal, low-dose exposure to environmental chemicals modifies the composition of gut microbiome. Three chemicals that are widely used in personal care products-diethyl phthalate (DEP), methylparaben (MPB), triclosan (TCS)-and their mixture (MIX) were administered at doses comparable to human exposure to Sprague-Dawley rats from birth through adulthood. Fecal samples were collected at two time points: postnatal day (PND) 62 (adolescence) and PND 181 (adulthood). The gut microbiome was profiled by 16S ribosomal RNA gene sequencing, taxonomically assigned and assessed for diversity. Metagenomic profiling revealed that the low-dose chemical exposure resulted in significant changes in the overall bacterial composition, but in adolescent rats only. Specifically, the individual taxon relative abundance for Bacteroidetes (Prevotella) was increased while the relative abundance of Firmicutes (Bacilli) was reduced in all treated rats compared to controls. Increased abundance was observed for Elusimicrobia in DEP and MPB groups, Betaproteobacteria in MPB and MIX groups, and Deltaproteobacteria in TCS group. Surprisingly, these differences diminished by adulthood (PND 181) despite continuous exposure, suggesting that exposure to the environmental chemicals produced a more profound effect on the gut microbiome in adolescents. We also observed a small but consistent reduction in the bodyweight of exposed rats in adolescence, especially with DEP and MPB treatment (p < 0.05), which is consistent with our findings of a reduced Firmicutes/Bacteroidetes ratio at PND 62 in exposed rats. This study provides initial evidence that postnatal exposure to commonly used environmental chemicals at doses comparable to human exposure is capable of modifying the gut microbiota in adolescent rats; whether these changes lead to downstream health effects requires further investigation.

Subretinal transplantation of rat MSCs and erythropoietin gene modified rat MSCs for protecting and rescuing degenerative retina in rats.

PubMed

Guan, Y; Cui, L; Qu, Z; Lu, L; Wang, F; Wu, Y; Zhang, J; Gao, F; Tian, H; Xu, L; Xu, G; Li, W; Jin, Y; Xu, G-T

2013-11-01

For degenerative retinal diseases, like the acquired form exemplified by age-related macular degeneration (AMD), there is currently no cure. This study was to explore a stem cell therapy and a stem cell based gene therapy for sodium iodate (SI)-induced retinal degeneration in rats. Three cell types, i.e., rat mesenchymal stem cells (rMSCs) alone, erythropoietin (EPO) gene modified rMSCs (EPO-rMSCs) or doxycycline (DOX) inducible EPO expression rMSCs (Tet-on EPO-rMSCs), were transplanted into the subretinal spaces of SI-treated rats. The rMSCs were prepared for transplantation after 3 to 5 passages or modified with EPO gene. During the 8 weeks after the transplantation, the rats treated with rMSCs alone or with two types of EPO-rMSCs were all monitored with fundus examination, fundus fluorescein angiography (FFA) and electroretinogram. The transplantation efficiency of donor cells was examined for their survival, integration and differentiation. Following the transplantation, labeled donor cells were observed in subretinal space and adopted RPE morphology. EPO concentration in vitreous and retina of SI-treated rats which were transplanted with EPO-rMSCs or Tet-on EPO-rMSCs was markedly increased, in parallel with the improvement of retinal morphology and function. These findings suggest that rMSCs transplantation could be a new therapy for degenerative retinal diseases since it can protect and rescue RPE and retinal neurons, while EPO gene modification to rMSCs could be an even better option.

Stem Cell Therapy with Overexpressed VEGF and PDGF Genes Improves Cardiac Function in a Rat Infarct Model

PubMed Central

Das, Hiranmoy; George, Jon C.; Joseph, Matthew; Das, Manjusri; Abdulhameed, Nasreen; Blitz, Anna; Khan, Mahmood; Sakthivel, Ramasamy; Mao, Hai-Quan; Hoit, Brian D.; Kuppusamy, Periannan; Pompili, Vincent J.

2009-01-01

Background Therapeutic potential was evaluated in a rat model of myocardial infarction using nanofiber-expanded human cord blood derived hematopoietic stem cells (CD133+/CD34+) genetically modified with VEGF plus PDGF genes (VIP). Methods and Findings Myocardial function was monitored every two weeks up to six weeks after therapy. Echocardiography revealed time dependent improvement of left ventricular function evaluated by M-mode, fractional shortening, anterior wall tissue velocity, wall motion score index, strain and strain rate in animals treated with VEGF plus PDGF overexpressed stem cells (VIP) compared to nanofiber expanded cells (Exp), freshly isolated cells (FCB) or media control (Media). Improvement observed was as follows: VIP>Exp> FCB>media. Similar trend was noticed in the exercise capacity of rats on a treadmill. These findings correlated with significantly increased neovascularization in ischemic tissue and markedly reduced infarct area in animals in the VIP group. Stem cells in addition to their usual homing sites such as lung, spleen, bone marrow and liver, also migrated to sites of myocardial ischemia. The improvement of cardiac function correlated with expression of heart tissue connexin 43, a gap junctional protein, and heart tissue angiogenesis related protein molecules like VEGF, pNOS3, NOS2 and GSK3. There was no evidence of upregulation in the molecules of oncogenic potential in genetically modified or other stem cell therapy groups. Conclusion Regenerative therapy using nanofiber-expanded hematopoietic stem cells with overexpression of VEGF and PDGF has a favorable impact on the improvement of rat myocardial function accompanied by upregulation of tissue connexin 43 and pro-angiogenic molecules after infarction. PMID:19809493

Blood pressure, magnesium and other mineral balance in two rat models of salt-sensitive, induced hypertension: effects of a non-peptide angiotensin II receptor type 1 antagonist.

PubMed

Rondón, Lusliany Josefina; Marcano, Eunice; Rodríguez, Fátima; del Castillo, Jesús Rafael

2014-01-01

The renin-angiotensin system is critically involved in regulating arterial blood pressure (BP). Inappropriate angiotensin type-1 receptor activation by angiotensin-II (Ang-II) is related to increased arterial BP. Mg has a role in BP; it can affect cardiac electrical activity, myocardial contractility, and vascular tone. To evaluate the relationship between high BP induced by a high sodium (Na) diet and Mg, and other mineral balances, two experimental rat models of salt-sensitive, induced-hypertension were used: Ang-II infused and Dahl salt-sensitive (SS) rats. We found that: 1) Ang-II infusion progressively increased BP, which was accompanied by hypomagnesuria and signs of secondary hyperaldosteronism; 2) an additive effect between Ang-II and a high Na load may have an effect on strontium (Sr), zinc (Zn) and copper (Cu) balances; 3) Dahl SS rats fed a high Na diet had a slow pressor response, accompanied by altered Mg, Na, potassium (K), and phosphate (P) balances; and 4) losartan prevented BP increases induced by Ang II-NaCl, but did not modify mineral balances. In Dahl SS rats, losartan attenuated high BP and ameliorated magnesemia, Na and K balances. Mg metabolism maybe considered a possible defect in this strain of rat that may contribute to hypertension.

Three-generation reproduction toxicity study of genetically modified rice with insect resistant genes.

PubMed

Hu, Yichun; Zhuo, Qin; Gong, Zhaolong; Piao, Jianhua; Yang, Xiaoguang

2017-01-01

In the present work, we evaluated the three generation reproductive toxicity of the genetically modified rice with insectresistant cry1Ac and sck genes. 120 Sprague-Dawley (SD) rats were divided into three groups which were fed with genetically modified rice diet (GM group), parental control rice diet (PR group) and AIN-93 control diet (both used as negative control) respectively. Bodyweight, food consumption, reproductive data, hematological parameters, serum chemistry, relative organ weights and histopathology for each generation were examined respectively. All the hematology and serum chemistry parameters, organ/body weight indicators were within the normal range or no change to the adverse direction was observed, although several differences in hematology and serum chemistry parameters (WBC, BUN, LDH of male rat, PLT, PCT, MPV of female rats), reproductive data (rate of morphologically abnormal sperm) were observed between GM rice group and two control groups. No macroscopic or histological adverse effects were found or considered as treatment-related, either. Overall, the three generation study of genetically modified rice with cry1Ac and sck genes at a high level showed no unintended adverse effects on rats's reproductive system. Copyright © 2016. Published by Elsevier Ltd.

A Cell Line Producing Recombinant Nerve Growth Factor Evokes Growth Responses in Intrinsic and Grafted Central Cholinergic Neurons

NASA Astrophysics Data System (ADS)

Ernfors, Patrik; Ebendal, Ted; Olson, Lars; Mouton, Peter; Stromberg, Ingrid; Persson, Hakan

1989-06-01

The rat β nerve growth factor (NGF) gene was inserted into a mammalian expression vector and cotransfected with a plasmid conferring resistance to neomycin into mouse 3T3 fibroblasts. From this transfection a stable cell line was selected that contains several hundred copies of the rat NGF gene and produces excess levels of recombinant NGF. Such genetically modified cells were implanted into the rat brain as a probe for in vivo effects of NGF on central nervous system neurons. In a model of the cortical cholinergic deficits in Alzheimer disease, we demonstrate a marked increase in the survival of, and fiber outgrowth from, grafts of fetal basal forebrain cholinergic neurons, as well as stimulation of fiber formation by intact adult intrinsic cholinergic circuits in the cerebral cortex. Adult cholinergic interneurons in intact striatum also sprout vigorously toward implanted fibroblasts. Our results suggest that this model has implications for future treatment of neurodegenerative diseases.

Lentinan: hematopoietic, immunological, and efficacy studies in a syngeneic model of acute myeloid leukemia.

PubMed

McCormack, Emmet; Skavland, Jørn; Mujic, Maja; Bruserud, Øystein; Gjertsen, Bjørn Tore

2010-01-01

Lentinan, a beta-glucan nutritional supplement isolated from the shitake mushroom (Lentula edodes), is a biological response modifier with immunostimulatory properties. Concomitantly, the role of beta-glucans as chemoimmunotherapeutic in a number of solid cancers has been widely documented. We investigated the effects of nutritional grade lentinan upon BN rats and in a preclinical syngeneic model of acute myeloid leukemia. BN rats supplemented daily with lentinan exhibited weight gains, increased white blood cells, monocytes, and circulating cytotoxic T-cells; and had a reduction in anti-inflammatory cytokines IL-4, IL-10, and additionally IL-6. Lentinan treatment of BN rats with BNML leukemia resulted in improved cage-side health and reduced cachexia in the terminal stage of this aggressive disease. Combination of lentinan with standards of care in acute myeloid leukemia, idarubicin, and cytarabine increased average survival compared with monotherapy and reduced cachexia. These results indicate that nutritional supplementation of cancer patients with lentinan should be further investigated.

Morus alba L. Stem Extract Attenuates Pain and Articular Cartilage Damage in the Anterior Cruciate Ligament Transection-Induced Rat Model of Osteoarthritis.

PubMed

Khunakornvichaya, Arada; Lekmeechai, Sujinna; Pham, Phi Phuong; Himakoun, Wanwisa; Pitaksuteepong, Tasana; Morales, Noppawan Phumala; Hemstapat, Warinkarn

2016-01-01

This study was designed to investigate the anti-nociceptive effect of Morus alba stem extract as well as its cartilage protective effect in the anterior cruciate ligament transection (ACLT)-induced rat model of osteoarthritis (OA). The anti-nociceptive effect of this plant extract was determined by measuring hind limb weight bearing, while the severity of cartilage damage to the knee joints was evaluated using the modified Mankin grading system. Oral administration of M. alba stem extract (56 and 560 mg/kg) significantly attenuated joint pain as indicated by a significant (p < 0.05) increase in the values of percent weight borne on the operated hind limb for the OA-induced groups that received M. alba stem extract at 56 and 560 mg/kg when compared to those of the vehicle-treated OA-induced group. In addition, a significant improvement in the Mankin score was also observed in rats treated with 560 mg/kg M. alba stem extract, which was in agreement with its pain-relieving effect. The results showed that M. alba stem extract exhibited an anti-nociceptive effect as well as cartilage protection in the ACLT-induced rat model of OA, supporting its potential use as a therapeutic treatment for OA. © 2016 S. Karger AG, Basel.

Anticonvulsant effects of mefloquine on generalized tonic-clonic seizures induced by two acute models in rats.

PubMed

Franco-Pérez, Javier; Ballesteros-Zebadúa, Paola; Manjarrez-Marmolejo, Joaquín

2015-03-01

Mefloquine can cross the blood-brain barrier and block the gap junction intercellular communication in the brain. Enhanced electrical coupling mediated by gap junctions is an underlying mechanism involved in the generation and maintenance of seizures. For this reason, the aim of this study was to analyze the effects of the systemic administration of mefloquine on tonic-clonic seizures induced by two acute models such as pentylenetetrazole and maximal electroshock. All the control rats presented generalized tonic-clonic seizures after the administration of pentylenetetrazole. However, the incidence of seizures induced by pentylenetetrazole significantly decreased in the groups administered systematically with 40 and 80 mg/kg of mefloquine. In the control group, none of the rats survived after the generalized tonic-clonic seizures induced by pentylenetetrazole, but survival was improved by mefloquine. Besides, mefloquine significantly modified the total spectral power as well as the duration, amplitude and frequency of the epileptiform activity induced by pentylenetetrazole. For the maximal electroshock model, mefloquine did not change the occurrence of tonic hindlimb extension. However, this gap junction blocker significantly decreased the duration of the tonic hindlimb extension induced by the acute electroshock. These data suggest that mefloquine at low doses might be eliciting some anticonvulsant effects when is systemically administered to rats.

Sleep and Behavior in Cross-Fostering Rats: Developmental and Sex Aspects.

PubMed

Santangeli, Olena; Lehtikuja, Henna; Palomäki, Eeva; Wigren, Henna-Kaisa; Paunio, Tiina; Porkka-Heiskanen, Tarja

2016-12-01

Adverse early-life events induce behavioral psychopathologies and sleep changes in adulthood. In order to understand the molecular level mechanisms by which the maltreatment modifies sleep, valid animal models are needed. Changing pups between mothers at early age (cross-fostering) may satisfyingly model adverse events in human childhood. Cross-fostering (CF) was used to model mild early-life stress in male and female Wistar rats. Behavior and BDNF gene expression in the basal forebrain (BF), cortex, and hypothalamus were assessed during adolescence and adulthood. Spontaneous sleep, sleep homeostasis, and BF extracellular adenosine levels were assessed in adulthood. CF rats demonstrated increased number of REM sleep onsets in light and dark periods of the day. Total REM and NREM sleep duration was also increased during the light period. While sleep homeostasis was not severely affected, basal level of adenosine in the BF of both male and female CF rats was lower than in controls. CF did not lead to considerable changes in behavior. Even when the consequences of adverse early-life events are not observed in tests for anxiety and depression, they leave a molecular mark in the brain, which can act as a vulnerability factor for psychopathologies in later life. Sleep is a sensitive indicator for even mild early-life stress. © 2016 Associated Professional Sleep Societies, LLC.

Protein and lipid oxidative damage in streptozotocin-induced diabetic rats submitted to forced swimming test: the insulin and clonazepam effect.

PubMed

Wayhs, Carlos Alberto Yasin; Manfredini, Vanusa; Sitta, Angela; Deon, Marion; Ribas, Graziela; Vanzin, Camila; Biancini, Giovana; Ferri, Marcelo; Nin, Maurício; Barros, Helena Maria Tannhauser; Vargas, Carmen Regla

2010-09-01

Diabetes may modify central nervous system functions and is associated with moderate cognitive deficits and changes in the brain, a condition that may be referred to as diabetic encephalopathy. The prevalence of depression in diabetic patients is higher than in the general population, and clonazepam is being used to treat this complication. Oxidative stress may play a role in the development of diabetes complications. We investigated oxidative stress parameters in streptozotocin-induced diabetic rats submitted to forced swimming test (STZ) and evaluated the effect of insulin (STZ-INS) and/or clonazepam (STZ-CNZ and STZ-INS-CNZ) acute treatment on these animal model. Oxidative damage to proteins measured as carbonyl content in plasma was significantly increased in STZ group compared to STZ treated groups. Malondialdehyde plasma levels were significantly reduced in STZ-INS and STZ-INS-CNZ groups when compared to STZ rats, being significantly reduced in STZ-INS-CNZ than STZ-INS rats. The activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase showed no significant differences among all groups of animals. These findings showed that protein and lipid damage occurs in this diabetes/depression animal model and that the associated treatment of insulin and clonazepam is capable to protect against oxidative damage in this experimental model.

Learned helplessness and social avoidance in the Wistar-Kyoto rat

PubMed Central

Nam, Hyungwoo; Clinton, Sarah M.; Jackson, Nateka L.; Kerman, Ilan A.

2014-01-01

The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague–Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression. PMID:24744709

Learned helplessness and social avoidance in the Wistar-Kyoto rat.

PubMed

Nam, Hyungwoo; Clinton, Sarah M; Jackson, Nateka L; Kerman, Ilan A

2014-01-01

The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague-Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression.

Ethopharmacology of the antidepressant effect of clonazepam in diabetic rats.

PubMed

Gomez, R; Barros, H M

2000-06-01

Diabetes-associated depression may occur due to changes in the quality of life imposed by treatment, or may be a consequence of the biochemical changes accompanying the disease. It was our objective to evaluate the behaviors of diabetic rats through an animal model of depression, and determine if a positive GABA modulator agent, clonazepam, is an effective antidepressant. Wistar male rats were submitted to the forced-swimming test after 26 days of the induction of diabetes with streptozotocin (60 mg/kg). Test and retest days analyzed with an ethological approach. Clonazepam (control, 0.25, 0. 5, and 1.0 mg/kg) was administered IP 24, 5, and 1 h before the retest. Diabetic rats presented longer immobility duration during test and retest of forced swimming. Diabetic rats dived significantly less during the test. Clonazepam 0.25 and 0.5 mg/kg decreased immobility of diabetic rats with no consequences on the behaviors of nondiabetic rats. These results demonstrate that diabetic rats present more intense depressive-like behavior, such as immobility and lack of interest in exploring the environment, when exposed to the forced-swimming test. It is possible that decreased GABA function is involved in depression associated with diabetes, because a benzodiazepine partially counteracts these changes without modifying blood glucose and glycogen parameters.

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

PubMed Central

Bi, Chenchen; Duan, Dongyu; Chu, Liuxiang; Yu, Xin; Wu, Zimei; Wang, Aiping; Sun, Kaoxiang

2018-01-01

Introduction Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson’s disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. Materials and methods The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Results Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference (P<0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf-R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD. Conclusion Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD. PMID:29391788

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects.

PubMed

Yan, Xiuju; Xu, Lixiao; Bi, Chenchen; Duan, Dongyu; Chu, Liuxiang; Yu, Xin; Wu, Zimei; Wang, Aiping; Sun, Kaoxiang

2018-01-01

Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference ( P <0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf-R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD. Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD.

Ketamine facilitates extinction of avoidance behavior and enhances synaptic plasticity in a rat model of anxiety vulnerability: Implications for the pathophysiology and treatment of anxiety disorders.

PubMed

Fortress, Ashley M; Smith, Ian M; Pang, Kevin C H

2018-05-08

Anxiety disorders and posttraumatic stress disorder (PTSD) share a common feature of pathological avoidance behavior. The Wistar Kyoto (WKY) rat has been used as a model of anxiety vulnerability, expressing a behaviorally inhibited temperament, acquiring avoidance behavior more rapidly and displaying extinction-resistant avoidance compared to Sprague Dawley (SD) rats. Subanesthetic levels of ketamine have gained attention as a rapid antidepressant in treatment-resistant depression. While traditional antidepressants are commonly used to treat anxiety disorders and PTSD, the therapeutic utility of ketamine for these disorders is much less understood. The hippocampus is critical for the actions of antidepressants, is a structure of implicated in anxiety disorders and PTSD, and is necessary for extinction of avoidance in SD rats. WKY rats have impaired hippocampal long-term potentiation (LTP), suggesting that persistent avoidance in WKY rats may be due to deficient hippocampal synaptic plasticity. In the present study, we hypothesized that ketamine would facilitate extinction of avoidance learning in WKY rats, and do so by enhancing hippocampal synaptic plasticity. As predicted, ketamine facilitated extinction of avoidance behavior in a subset of WKY rats (responders), with effects lasting at least three weeks. Additionally, LTP in these rats was enhanced by ketamine. Ketamine was not effective in facilitating avoidance extinction or in modifying LTP in WKY non-responders. The results suggest that subanesthetic levels of ketamine may be useful for treating anxiety disorders by reducing avoidance behaviors when combined with extinction conditions. Moreover, ketamine may have its long-lasting behavioral effects through enhancing hippocampal synaptic plasticity. Copyright © 2018. Published by Elsevier Ltd.

Rat behavior in maze after flight aboard Kosmos-690 biosatellite. [Effects of space flight factors (acceleration, vibration, and weightlessness) on. gamma. -radioinduced behavioral changes in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Livshits, N.N.; Apanasenko, Z.I.; Kuznetsova, M.A.

1978-10-26

It was previously demonstrated that radiobiological effects can change appreciably in space flights. However, there is no information in the known literature concerning the effects of inflight radiation on higher nervous activity (HNA). Yet this is an important question, since mental efficiency depends largely on the state of HNA. It was established in model laboratory experiments that dynamic factors (acceleration and vibration) modify the effect of radiation on HNA. For this reason, it was necessary to investigate the effect on HNA of radiation combined with the factors occurring in space flights.

Alterations of reward mechanisms in bulbectomised rats.

PubMed

Grecksch, Gisela; Becker, Axel

2015-06-01

The positive association between alcoholism and depression is a common clinical observation. We investigated the relationship between depression and reward mechanisms using a validated animal model for depressive-like behaviour, the olfactory bulbectomy in rats. The effects of bilateral olfactory bulbectomy on reward mechanisms were studied in two different experimental paradigms - the voluntary self-administration of ethanol and the conditioned place preference to alcohol injection and compared to the effects of ethanol on locomotor activity and body core temperature. The voluntary ethanol intake was increased significantly in bulbectomised rats in a drinking experiment and also after a period of abstinence. Conditioned place preference (CPP) was induced in all animals. However, bulbectomised rats needed a higher dose of alcohol to produce CPP. The sedative effect of ethanol on locomotor activity was reduced in bulbectomised animals. Measurement of body temperature revealed a dose-dependent hypothermic effect of ethanol in both groups. These results suggest that the reward mechanisms may be altered in this animal model as a common phenomenon associated with depression. Furthermore, they support the hypothesis that the addictive and/or rewarding properties of some drugs of abuse may be modified in depression. Copyright © 2015 Elsevier B.V. All rights reserved.

Body weight loss, effective satiation and absence of homeostatic neuropeptide compensation in male Sprague Dawley rats schedule fed a protein crosslinked diet.

PubMed

Cassie, Nikki; Anderson, Richard L; Wilson, Dana; Pawsey, Anne; Mercer, Julian G; Barrett, Perry

2017-10-01

Food structure contributes to the induction of satiation and the maintenance of satiety following intake of a meal. There is evidence from human studies that protein-crosslinking of a milk-protein based meal may enhance satiety, but the mechanism underpinning this effect is unknown. We investigated whether a rat model would respond in a similar manner and might provide mechanistic insight into enhanced satiety by structural modification of a food source. Rats were schedule fed a modified AIN-93M based diet in a liquid form or protein-crosslinked to produce a soft-solid form. This was compared to a modified AIN-93M solid diet. Average daily caloric intake was in the order solid > liquid > crosslinked. Body composition was unaltered in the solid group, but there was a loss of fat in the liquid group and a loss of lean and fat tissue in the crosslinked group. Compared to rats fed a solid diet, acute responses in circulating GLP-1, leptin and insulin were eliminated or attenuated in rats fed a liquid or crosslinked diet. Quantification of homeostatic neuropeptide expression in the hypothalamus showed elevated levels of Npy and Agrp in rats fed the liquid diet. Measurement of food intake after a scheduled meal indicated that reduced energy intake of liquid and crosslinked diets is not due to enhancement of satiety. When continuously available ad-libitum, rats fed a liquid diet showed reduced weight gain despite greater 24 h caloric intake. During the dark phase, caloric intake was reduced, but compensated for during the light phase. We conclude that structural modification from a liquid to a solidified state is beneficial for satiation, with less of a detrimental effect on metabolic parameters and homeostatic neuropeptides. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

PubMed Central

Amchova, Petra; Kucerova, Jana; Giugliano, Valentina; Babinska, Zuzana; Zanda, Mary T.; Scherma, Maria; Dusek, Ladislav; Fadda, Paola; Micale, Vincenzo; Sulcova, Alexandra; Fratta, Walter; Fattore, Liana

2013-01-01

Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behavior after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5–10 mg/kg), did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg) did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2) reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens (NAc) of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive-like state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats. PMID:24688470

Additive Effects of Rebamipide Plus Proton Pump Inhibitors on the Expression of Tight Junction Proteins in a Rat Model of Gastro-Esophageal Reflux Disease

PubMed Central

Gweon, Tae-Geun; Park, Jong-Hyung; Kim, Byung-Wook; Choi, Yang Kyu; Kim, Joon Sung; Park, Sung Min; Kim, Chang Whan; Kim, Hyung-Gil; Chung, Jun-Won; Incheon

2018-01-01

Background/Aims The aim of this study was to investigate the effects of rebamipide on tight junction proteins in the esophageal mucosa in a rat model of gastroesophageal reflux disease (GERD). Methods GERD was created in rats by tying the proximal stomach. The rats were divided into a control group, a proton pump inhibitor (PPI) group, and a PPI plus rebamipide (PPI+R) group. Pantoprazole (5 mg/kg) was administered intraperitoneally to the PPI and PPI+R groups. An additional dose of rebamipide (100 mg/kg) was administered orally to the PPI+R group. Mucosal erosions, epithelial thickness, and leukocyte infiltration into the esophageal mucosa were measured in isolated esophagi 14 days after the procedure. A Western blot analysis was conducted to measure the expression of claudin-1, -3, and -4. Results The mean surface area of mucosal erosions, epithelial thickness, and leukocyte infiltration were lower in the PPI group and the PPI+R group than in the control group. Western blot analysis revealed that the expression of claudin-3 and -4 was significantly higher in the PPI+R group than in the control group. Conclusions Rebamipide may exert an additive effect in combination with PPI to modify the tight junction proteins of the esophageal mucosa in a rat model of GERD. This treatment might be associated with the relief of GERD symptoms. PMID:29069891

Biocompatibility and tissue integration of a novel shape memory surgical mesh for ventral hernia: In vivo animal studies

PubMed Central

Zimkowski, Michael M.; Rentschler, Mark E.; Schoen, Jonathan A.; Mandava, Nageswara; Shandas, Robin

2014-01-01

Approximately 400,000 ventral hernia repair surgeries are performed each year in the United States. Many of these procedures are performed using laparoscopic minimally invasive techniques and employ the use of surgical mesh. The use of surgical mesh has been shown to reduce recurrence rates compared to standard suture repairs. The placement of surgical mesh in a ventral hernia repair procedure can be challenging, and may even complicate the procedure. Others have attempted to provide commercial solutions to the problems of mesh placement, but these have not been well accepted by the clinical community. In this article, two versions of shape memory polymer (SMP)-modified surgical mesh, and unmodified surgical mesh, were compared by performing laparoscopic manipulation in an acute porcine model. Also, SMP-integrated polyester surgical meshes were implanted in four rats for 30–33 days to evaluate chronic biocompatibility and capacity for tissue integration. Porcine results show that the modified mesh provides a controlled, temperature-activated, automated deployment when compared to an unmodified mesh. In rats, results indicate that implanted SMP-modified meshes exhibit exceptional biocompatibility and excellent integration with surrounding tissue with no noticeable differences from the unmodified counterpart. This article provides further evidence that an SMP-modified surgical mesh promises reduction in surgical placement time and that such a mesh is not substantially different from unmodified meshes in chronic biocompatibility. PMID:24327401

Effects of caffeine on locomotor activity in streptozotocin-induced diabetic rats

PubMed Central

Bădescu, SV; Tătaru, CP; Kobylinska, L; Georgescu, EL; Zahiu, DM; Zăgrean, AM; Zăgrean, L

2016-01-01

Diabetes mellitus modifies the expression of adenosine receptors in the brain. Caffeine acts as an antagonist of A1 and A2A adenosine receptors and was shown to have a dose-dependent biphasic effect on locomotion in mice. The present study investigated the link between diabetes and locomotor activity in an animal model of streptozotocin-induced diabetes, and the effects of a low-medium dose of caffeine in this relation. The locomotor activity was investigated by using Open Field Test at 6 weeks after diabetes induction and after 2 more weeks of chronic caffeine administration. Diabetes decreased locomotor activity (total distance moved and mobility time). Chronic caffeine exposure impaired the locomotor activity in control rats, but not in diabetic rats. Our data suggested that the medium doses of caffeine might block the A2A receptors, shown to have an increased density in the brain of diabetic rats, and improve or at least maintain the locomotor activity, offering a neuroprotective support in diabetic rats. Abbreviations: STZ = streptozotocin, OFT = Open Field Test PMID:27974933

Housing environment influences stress-related hippocampal substrates and depression-like behavior.

PubMed

Ashokan, Archana; Hegde, Akshaya; Balasingham, Anushanthy; Mitra, Rupshi

2018-03-15

Rats are widely used animal models for biological psychiatry and neuroscience. Laboratory rats are typically housed in impoverished sensory environments. The lack of species-typical sensory environment might radically change the response of individual animals to stressful and/or threatening episodes. In this report, we demonstrate that behavioral and neural sequelae of chronic stress were modified by sensory environment of adult male rats. This includes effects of stress on the density of spines on CA3 hippocampal neurons, hippocampal neurogenesis and abundance of glucocorticoid or mineralocorticoid receptors. Enrichment also reduced depression-like behavior in a forced swim task. Stress and sensory enrichment evoked opposing effects on all the above endpoints. The sensory enrichment used in this report is of a relatively short duration provided during adulthood. This period excludes critical windows of greater plasticity during pre- and peripubertal stages. Our results suggest that standard housing practices for laboratory rats remain austere concerning sensory requirements of this species. Thus, even a moderate sensory enrichment is capable of reducing high stress-sensitivity and depressive-like behavior in standard laboratory rats. Copyright © 2018. Published by Elsevier B.V.

Modelling individual differences in the form of Pavlovian conditioned approach responses: a dual learning systems approach with factored representations.

PubMed

Lesaint, Florian; Sigaud, Olivier; Flagel, Shelly B; Robinson, Terry E; Khamassi, Mehdi

2014-02-01

Reinforcement Learning has greatly influenced models of conditioning, providing powerful explanations of acquired behaviour and underlying physiological observations. However, in recent autoshaping experiments in rats, variation in the form of Pavlovian conditioned responses (CRs) and associated dopamine activity, have questioned the classical hypothesis that phasic dopamine activity corresponds to a reward prediction error-like signal arising from a classical Model-Free system, necessary for Pavlovian conditioning. Over the course of Pavlovian conditioning using food as the unconditioned stimulus (US), some rats (sign-trackers) come to approach and engage the conditioned stimulus (CS) itself - a lever - more and more avidly, whereas other rats (goal-trackers) learn to approach the location of food delivery upon CS presentation. Importantly, although both sign-trackers and goal-trackers learn the CS-US association equally well, only in sign-trackers does phasic dopamine activity show classical reward prediction error-like bursts. Furthermore, neither the acquisition nor the expression of a goal-tracking CR is dopamine-dependent. Here we present a computational model that can account for such individual variations. We show that a combination of a Model-Based system and a revised Model-Free system can account for the development of distinct CRs in rats. Moreover, we show that revising a classical Model-Free system to individually process stimuli by using factored representations can explain why classical dopaminergic patterns may be observed for some rats and not for others depending on the CR they develop. In addition, the model can account for other behavioural and pharmacological results obtained using the same, or similar, autoshaping procedures. Finally, the model makes it possible to draw a set of experimental predictions that may be verified in a modified experimental protocol. We suggest that further investigation of factored representations in computational neuroscience studies may be useful.

Modelling Individual Differences in the Form of Pavlovian Conditioned Approach Responses: A Dual Learning Systems Approach with Factored Representations

PubMed Central

Lesaint, Florian; Sigaud, Olivier; Flagel, Shelly B.; Robinson, Terry E.; Khamassi, Mehdi

2014-01-01

Reinforcement Learning has greatly influenced models of conditioning, providing powerful explanations of acquired behaviour and underlying physiological observations. However, in recent autoshaping experiments in rats, variation in the form of Pavlovian conditioned responses (CRs) and associated dopamine activity, have questioned the classical hypothesis that phasic dopamine activity corresponds to a reward prediction error-like signal arising from a classical Model-Free system, necessary for Pavlovian conditioning. Over the course of Pavlovian conditioning using food as the unconditioned stimulus (US), some rats (sign-trackers) come to approach and engage the conditioned stimulus (CS) itself – a lever – more and more avidly, whereas other rats (goal-trackers) learn to approach the location of food delivery upon CS presentation. Importantly, although both sign-trackers and goal-trackers learn the CS-US association equally well, only in sign-trackers does phasic dopamine activity show classical reward prediction error-like bursts. Furthermore, neither the acquisition nor the expression of a goal-tracking CR is dopamine-dependent. Here we present a computational model that can account for such individual variations. We show that a combination of a Model-Based system and a revised Model-Free system can account for the development of distinct CRs in rats. Moreover, we show that revising a classical Model-Free system to individually process stimuli by using factored representations can explain why classical dopaminergic patterns may be observed for some rats and not for others depending on the CR they develop. In addition, the model can account for other behavioural and pharmacological results obtained using the same, or similar, autoshaping procedures. Finally, the model makes it possible to draw a set of experimental predictions that may be verified in a modified experimental protocol. We suggest that further investigation of factored representations in computational neuroscience studies may be useful. PMID:24550719

Modified Multivisceral Transplantation with Native Spleen Removal in Rats.

PubMed

Stringa, Pablo; Arreola, Nidia Monserrat; Moreno, Ane M Andres; Largo, Carlota; Rumbo, Martín; Hernandez, Francisco

2018-02-23

 Modified multivisceral transplantation (MMVTx) refers to the use of a graft that includes all abdominal organs except the liver. The use of this type of transplant in children and adults expanded over the last years with good results. However, long-term survival in experimental models has not been reported. Our aim is to describe in detail some technical modifications of MMVTx to obtain long-term survival.  Syngeneic (Lewis-Lewis) heterotopic MMVTx was performed in 16 male rats (180-250 g). All procedures were performed under isoflurane anesthesia. The graft consisted of stomach, duodenopancreatic axis, spleen, and small bowel. The vascular pedicle consisted of a conduit of aorta, including the celiac trunk and the superior mesenteric artery (SMA), and the portal vein (PV). The engraftment was performed by end-to-side anastomosis to the infra-renal cava vein and aorta. After reperfusion, the graft was accommodated in the right side of the abdomen, and a terminal ileostomy performed. The native spleen was removed.  Donor and recipient time was 39 ± 4.4 minutes and 69 ± 7 minutes, respectively; venous and arterial anastomosis time was 14 ± 1 minutes and 12.3 ± 1 minutes, respectively. Total ischemia time was 77.2 ± 7.9 minutes. Survival was 75% (12/16), six were sacrificed after 2 hours, and six were kept alive for long-term evaluation (more than 1 week).  Long-term survival is reported after heterotopic MMVTx in rats. The heterotopic MMVTx with native spleen removal would potentially improve the existent models for transplant research. The usefulness of this model warrants further confirmation in allogeneic experiments. Georg Thieme Verlag KG Stuttgart · New York.

Immunomodulating and antioxidant effects of polysaccharide conjugates from the fruits of Ziziphus Jujube on Chronic Fatigue Syndrome rats.

PubMed

Chi, Aiping; Kang, Chenzhe; Zhang, Yan; Tang, Liang; Guo, Huanhuan; Li, Hong; Zhang, Kunru

2015-05-20

To detect the treatment effect of the fruits of Ziziphus Jujube in Chronic Fatigue Syndrome (CFS). Jujube polysaccharide conjugates (JPC) were isolated from the fruits of Z. Jujube. General physicochemical properties of JPC were analyzed. A four-week rats CFS model was established and JPC were orally administrated, the behavior experiments were conducted after CFS. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the levels of malondialdehyde (MDA) in serum were elevated and T lymphocyte proliferation, CD4(+)/CD8(+) ratio and natural killer (NK) cells activity were analyzed. JPC markedly improved behaviors of CFS rats, also decreased MDA levels in serum, and elevated T lymphocyte proliferation, CD4(+)/CD8(+) ratio and natural killer (NK) cells activities. This suggests that JPC can improve the immune system and antioxidant activity of CFS rats and might be regarded as a biological response modifier. Copyright © 2015 Elsevier Ltd. All rights reserved.

New insights into the effects of onion consumption on lipid mediators using a diet-induced model of hypercholesterolemia.

PubMed

González-Peña, Diana; Checa, Antonio; de Ancos, Begoña; Wheelock, Craig E; Sánchez-Moreno, Concepción

2017-04-01

The levels and roles of lipid mediators can be modified in response to nutritional stimuli. The aim of this study was to investigate shifts in oxylipin and sphingolipid profiles stimulated by a hypercholesterolemic (HC) diet along with the modulating effects of onion introduced as an antioxidant functional ingredient characterized in the diet (HCO). Oxylipin and sphingolipid profiles were determined in plasma and tissues from Wistar rats using LC-MS/MS. Plasma ω-3 and ω-6 PUFA-derived oxylipins decreased in rats after 7 weeks of HC feeding, but did not evidence a further shift with HCO diet. Onion ingredient supplementation modulated the hepatic concentrations of prostaglandins and enhanced ω-3 oxylipins in the liver of HCO-fed rats relative to the HC group. The HC diet induced shifts in plasma sphingolipids, increasing sphingoid bases, dihydroceramides and ceramides, whilst the sphingomyelin, hexosylceramide and lactosylceramide families decreased. The HCO diet modified some HC diet-induced changes in sphingolipids in liver and spleen tissue. Onion supplementation effected changes in lipid mediator levels in diet-induced hypercholesterolemic Wistar rats. The potential of onion as regulator of pro-inflammatory mediators, and possible enhancer of pro-resolution pathways, warrants further study of the interaction of functional ingredients with bioactive lipid mediators and their potential impact on inflammation, oxidative stress and organ dysfunction. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Inhibition of Comt with tolcapone slows progression of polycystic kidney disease in the more severely affected PKD/Mhm (cy/+) substrain of the Hannover Sprague-Dawley rat

PubMed Central

Boehn, Susanne N.E.; Spahn, Sonja; Neudecker, Sabine; Keppler, Andrea; Bihoreau, Marie-Thérèse; Kränzlin, Bettina; Pandey, Priyanka; Hoffmann, Sigrid C.; Li, Li; Torres, Vicente E.; Gröne, Hermann-Josef; Gretz, Norbert

2013-01-01

Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human inherited diseases. Modifier genes seem to modulate the disease progression and might therefore be promising drug targets. Although a number of modifier loci have been already identified, no modifier gene has been proven to be a real modifier yet. Methods Gene expression profiling of two substrains of the Han:SPRD rat, namely PKD/Mhm and PKD/US, both harboring the same mutation, was conducted in 36-day-old animals. Catechol-O-methyltransferase (Comt) was identified as a potential modifier gene. A 3-month treatment with tolcapone, a selective inhibitor of Comt, was carried out in PKD/Mhm and PKD/US (cy/+) animals. Results Comt is localized within a known modifier locus of PKD (MOP2). The enzyme encoding gene was found upregulated in the more severely affected PKD/Mhm substrain and was hence presumed to be a putative modifier gene of PKD. The treatment with tolcapone markedly attenuated the loss of renal function, inhibited renal enlargement, shifted the size distribution of renal cysts and retarded cell proliferation, apoptosis, inflammation and fibrosis development in affected (cy/+) male and female PKD/Mhm and PKD/US rats. Conclusions Comt has been confirmed to be the first reported modifier gene for PKD and tolcapone offers a promising drug for treating PKD. PMID:23543593

Influence of simulated microgravity on the VO2 max of nontrained and trained rats

NASA Technical Reports Server (NTRS)

Woodman, C. R.; Monnin, K. A.; Sebastian, L. A.; Tipton, C. M.

1993-01-01

Head-down suspension (HDS) of rats has evolved as a useful model for the simulation of a microgravity environment. Previous HDS experiments with rats have shown an impaired capacity to perform aerobic exercise as demonstrated by reductions in maximum oxygen consumption (VO2 max), treadmill run time (RT), and mechanical efficiency (ME) of treadmill running at submaximal conditions. To determine whether endurance training (TR) before HDS would modify exercise performance, male Sprague-Dawley rats were assigned to nontrained (NT) or TR groups for 6 wk and exposed to HDS or cage control (CC) conditions for 29 days. The rats were tested for VO2 max, RT, and ME before treatment and on days 7, 14, 21, and 28. In addition, water and electrolyte excretion was measured on days 1 and 21 of the experimental period. Before HDS, the TR rats had significantly higher measures of VO2 max (15%) and RT (22%) than the NT rats. On day 28, HDS was associated with significant reductions in absolute VO2 max (ml/min) in TR (-30%) and NT (-14%) rats. Relative VO2 max (ml.min-1.kg-1) was significantly reduced in TR (-15%) but not NT rats. Similar reductions in RT occurred in TR (-37%) and NT (-35%) rats by day 28. ME was reduced 22% in both TR and NT rats after 28 days of suspension. HDS elicited diuresis, natriuresis, and kaliuresis in TR rats after 21 days but not after 24 h. In contrast, HDS-NT rats exhibited no diuretic, natriuretic, or kaliuretic responses.(ABSTRACT TRUNCATED AT 250 WORDS).

Lewis and Fischer 344 rats as a model for genetic differences in spatial learning and memory: Cocaine effects.

PubMed

Fole, Alberto; Miguéns, Miguel; Morales, Lidia; González-Martín, Carmen; Ambrosio, Emilio; Del Olmo, Nuria

2017-06-02

Lewis (LEW) and Fischer 344 (F344) rats are considered a model of genetic vulnerability to drug addiction. We previously showed important differences in spatial learning and memory between them, but in contrast with previous experiments demonstrating cocaine-induced enhanced learning in Morris water maze (MWM) highly demanding tasks, the eight-arm radial maze (RAM) performance was not modified either in LEW or F344 rats after chronic cocaine treatment. In the present work, chronically cocaine-treated LEW and F344 adult rats have been evaluated in learning and memory performance using the Y-maze, two RAM protocols that differ in difficulty, and a reversal protocol that tests cognitive flexibility. After one of the RAM protocols, we quantified dendritic spine density in hippocampal CA1 neurons and compared it to animals treated with cocaine but not submitted to RAM. LEW cocaine treated rats showed a better performance in the Y maze than their saline counterparts, an effect that was not evident in the F344 strain. F344 rats significantly took more time to learn the RAM task and made a greater number of errors than LEW animals in both protocols tested, whereas cocaine treatment induced deleterious effects in learning and memory in the highly difficult protocol. Moreover, hippocampal spine density was cocaine-modulated in LEW animals whereas no effects were found in F344 rats. We propose that differences in addictive-like behavior between LEW and F344 rats could be related to differences in hippocampal learning and memory processes that could be on the basis of individual vulnerability to cocaine addiction. Copyright © 2017 Elsevier Inc. All rights reserved.

Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats.

PubMed

Eagle, Andrew L; Singh, Robby; Kohler, Robert J; Friedman, Amy L; Liebowitz, Chelsea P; Galloway, Matthew P; Enman, Nicole M; Jutkiewicz, Emily M; Perrine, Shane A

2015-05-01

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20 mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. Copyright © 2015. Published by Elsevier B.V.

Maternal separation in early life modifies anxious behavior and Fos and glucocorticoid receptor expression in limbic neurons after chronic stress in rats: effects of tianeptine.

PubMed

Trujillo, Verónica; Durando, Patricia E; Suárez, Marta M

2016-01-01

Early-life adversity can lead to long-term consequence persisting into adulthood. Here, we assess the implications of an adverse early environment on vulnerability to stress during adulthood. We hypothesized that the interplay between early and late stress would result in a differential phenotype regarding the number of neurons immunoreactive for glucocorticoid receptor (GR-ir) and neuronal activity as assessed by Fos immunoreactivity (Fos-ir) in brain areas related to stress responses and anxiety-like behavior. We also expected that the antidepressant tianeptine could correct some of the alterations induced in our model. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h during the first 3 weeks of life. As adults, the rats were exposed to chronic stress for 24 d and they were treated daily with tianeptine (10 mg/kg intraperitoneal) or vehicle (isotonic saline). Fos-ir was increased by MS in all structures analyzed. Chronic stress reduced Fos-ir in the hippocampus, but increased it in the paraventricular nucleus. Furthermore, chronic stress increased GR-ir in hippocampus (CA1) and amygdala in control non-MS rats. By contrast, when MS and chronic stress were combined, GR-ir was decreased in these structures. Additionally, whereas tianeptine did not affect Fos-ir, it regulated GR-ir in a region-dependent manner, in hippocampus and amygdala opposing in some cases the stress or MS effects. Furthermore, tianeptine reversed the MS- or stress-induced anxious behavior. The interplay between MS and chronic stress observed indicates that MS rats have a modified phenotype, which is expressed when they are challenged by stress in later life.

Restorative and synergistic efficacy of Kalpaamruthaa, a modified Siddha preparation, on an altered antioxidant status in adjuvant induced arthritic rat model.

PubMed

Mythilypriya, Rajendran; Shanthi, Palanivelu; Sachdanandam, Panchanatham

2007-07-20

Rheumatoid arthritis (RA) is a prevalent and debilitating disease that affects the joints. Infiltration of blood-derived cells in the affected joints upon activation generate reactive oxygen/nitrogen species, resulting in an oxidative stress. One approach to counteract this oxidative stress is the use of antioxidants as therapeutic agents. Kalpaamruthaa (KA), a modified indigenous Siddha preparation constituting Semecarpus anacardium nut milk extract (SA), Emblica officinalis (EO) and honey was evaluated for its synergistic antioxidant potential in adjuvant induced arthritic rats than sole SA treatment. Levels/activities of reactive oxygen species (ROS)/reactive nitrogen species (RNS), myeloperoxidase, lipid peroxide and enzymic and non-enzymic antioxidants were determined in control, arthritis induced, SA and KA treated (150 mg/kg b.wt.) animals. The levels/activities of ROS/RNS, myeloperoxidase and lipid peroxide were increased significantly (p<0.05) and the activities of enzymic and non-enzymic antioxidants were in turn decreased in arthritic rats, whereas these changes were reverted to near normal levels upon SA and KA treatment. KA showed an enhanced antioxidant potential than sole treatment of SA in adjuvant induced arthritic rats. KA via enhancing the antioxidant status in adjuvant induced arthritic rats than sole SA treatment proves to be an important therapeutic modality in the management of RA and thereby instituting the role of oxidative stress in the clinical manifestation of the disease RA. The profound antioxidant efficacy of KA than SA alone might be due to the synergistic action of the polyphenols such as flavonoids, tannins and other compounds such as vitamin C and hydroxycinnamates present in KA.

A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions.

PubMed

Ewart, Lorna; Milne, Aileen; Adkins, Debbie; Benjamin, Amanda; Bialecki, Russell; Chen, Yafei; Ericsson, Ann-Christin; Gardner, Stacey; Grant, Claire; Lengel, David; Lindgren, Silvana; Lowing, Sarah; Marks, Louise; Moors, Jackie; Oldman, Karen; Pietras, Mark; Prior, Helen; Punton, James; Redfern, Will S; Salmond, Ross; Skinner, Matt; Some, Margareta; Stanton, Andrea; Swedberg, Michael; Finch, John; Valentin, Jean-Pierre

2013-01-01

Parts A and B of the ICH S7 guidelines on safety pharmacology describe the in vivo studies that must be conducted prior to first time in man administration of any new pharmaceutical. ICH S7A requires a consideration of the sensitivity and reproducibility of the test systems used. This could encompass maintaining a dataset of historical pre-dose values, power analyses, as well as a demonstration of acceptable model sensitivity and robust pharmacological validation. During the process of outsourcing safety pharmacology studies to Charles River Laboratories, AstraZeneca set out to ensure that models were performed identically in each facility and saw this as an opportunity to review the inter-laboratory variability of these essential models. The five in vivo studies outsourced were the conscious dog telemetry model for cardiovascular assessment, the rat whole body plethysmography model for respiratory assessment, the rat modified Irwin screen for central nervous system assessment, the rat charcoal meal study for gastrointestinal assessment and the rat metabolic cage study for assessment of renal function. Each study was validated with known reference compounds and data were compared across facilities. Statistical power was also calculated for each model. The results obtained indicated that each of the studies could be performed with comparable statistical power and could achieve a similar outcome, independent of facility. The consistency of results obtained from these models across multiple facilities was high thus providing confidence that the models can be run in different facilities and maintain compliance with ICH S7A and B. Copyright © 2013 Elsevier Inc. All rights reserved.

Gut Microbiota in a Rat Oral Sensitization Model: Effect of a Cocoa-Enriched Diet

PubMed Central

Camps-Bossacoma, Mariona; Pérez-Cano, Francisco J.; Franch, Àngels

2017-01-01

Increasing evidence is emerging suggesting a relation between dietary compounds, microbiota, and the susceptibility to allergic diseases, particularly food allergy. Cocoa, a source of antioxidant polyphenols, has shown effects on gut microbiota and the ability to promote tolerance in an oral sensitization model. Taking these facts into consideration, the aim of the present study was to establish the influence of an oral sensitization model, both alone and together with a cocoa-enriched diet, on gut microbiota. Lewis rats were orally sensitized and fed with either a standard or 10% cocoa diet. Faecal microbiota was analysed through metagenomics study. Intestinal IgA concentration was also determined. Oral sensitization produced few changes in intestinal microbiota, but in those rats fed a cocoa diet significant modifications appeared. Decreased bacteria from the Firmicutes and Proteobacteria phyla and a higher percentage of bacteria belonging to the Tenericutes and Cyanobacteria phyla were observed. In conclusion, a cocoa diet is able to modify the microbiota bacterial pattern in orally sensitized animals. As cocoa inhibits the synthesis of specific antibodies and also intestinal IgA, those changes in microbiota pattern, particularly those of the Proteobacteria phylum, might be partially responsible for the tolerogenic effect of cocoa. PMID:28239436

Gut Microbiota in a Rat Oral Sensitization Model: Effect of a Cocoa-Enriched Diet.

PubMed

Camps-Bossacoma, Mariona; Pérez-Cano, Francisco J; Franch, Àngels; Castell, Margarida

2017-01-01

Increasing evidence is emerging suggesting a relation between dietary compounds, microbiota, and the susceptibility to allergic diseases, particularly food allergy. Cocoa, a source of antioxidant polyphenols, has shown effects on gut microbiota and the ability to promote tolerance in an oral sensitization model. Taking these facts into consideration, the aim of the present study was to establish the influence of an oral sensitization model, both alone and together with a cocoa-enriched diet, on gut microbiota. Lewis rats were orally sensitized and fed with either a standard or 10% cocoa diet. Faecal microbiota was analysed through metagenomics study. Intestinal IgA concentration was also determined. Oral sensitization produced few changes in intestinal microbiota, but in those rats fed a cocoa diet significant modifications appeared. Decreased bacteria from the Firmicutes and Proteobacteria phyla and a higher percentage of bacteria belonging to the Tenericutes and Cyanobacteria phyla were observed. In conclusion, a cocoa diet is able to modify the microbiota bacterial pattern in orally sensitized animals. As cocoa inhibits the synthesis of specific antibodies and also intestinal IgA, those changes in microbiota pattern, particularly those of the Proteobacteria phylum, might be partially responsible for the tolerogenic effect of cocoa.

An animal model of intrinsic dental erosion caused by gastro-oesophageal reflux disease.

PubMed

Higo, T; Mukaisho, K; Ling, Z-Q; Oue, K; Chen, K-H; Araki, Y; Sugihara, H; Yamamoto, G; Hattori, T

2009-07-01

To explore the association between dental erosion and gastro-oesophageal reflux disease (GORD), we used an animal model of GORD. We performed an operation to force gastro-duodenal contents reflux in male Wistar rats, and examined the teeth in the reflux rats at 15 or 30 weeks postoperatively. Dental erosion was evaluated based on a slightly modified index from a previous report. Estimation of pH was employed in the oesophageal and gastric contents. Macroscopically, dental erosion was only detected in the reflux rats. Histopathologically, dentin exposure was detected in three of the seven cases after 30 weeks. Alveolar bone destruction and osteomyelitis were also noted in severe cases. The pH of the oesophageal and stomach contents was 6.93 +/- 0.15 and 3.7 +/- 0.39, respectively. We confirmed the relationship between dental erosion and GORD. First step of dental erosion caused by GORD is the loss of surface enamel induced by regurgitation of an acidic liquid and acidic gas. Subsequently, further destruction of dental hard tissues and tooth supporting structure is accelerated by mixed juice with gastric and duodenal contents. The reflux animal model is a useful tool to examine the mechanism of dental erosion in GORD.

A metabolic cage for the hindlimb suspended rat

NASA Technical Reports Server (NTRS)

Evans, J.; Mulenburg, G. M.; Harper, J. S.; Skundberg, T. L.; Navidi, M.; Arnaud, S. B.

1994-01-01

Hindlimb suspension has been successfully used to simulate the effects of microgravity in rats. The cage and suspension system developed by E. R. Holton is designed to produce a headward shift of fluid and unload the hindlimbs in rodents, causing changes in bone and muscle similar to those in animals and humans exposed to spaceflight. While the Holton suspension system simulates many of the conditions observed in the spaceflight animal, it does not provide for the collection of urine and feces needed to monitor some metabolic activities. As a result, only limited information has been gathered on the nutritional status, and the gastrointestinal and renal function of animals using that model. Although commercial metabolic cages are available, they are usually cylindrical and require a centrally located suspension system and thus, do not readily permit movement of the rats. The limited floor space of commercial cages may affect comparisons with studies using the Holton model which has more than twice the living space of most commercially available cages. To take advantage of the extra living space and extensive data base that has been developed with the Holton model, Holton's cage was modified to make urine and fecal collections possible.

Efficient, Glucose Responsive, and Islet-Specific Transgene Expression by a Modified Rat Insulin Promoter

PubMed Central

Chai, Renjie; Chen, Shuyuan; Ding, Jiahuan; Grayburn, Paul A

2009-01-01

This study was done to improve efficiency and islet specificity of the rat insulin promoter (RIP). Various rat insulin promoter lengths were prepared and tested in vitro to drive luciferase reporter gene expression in INS1-cells, alpha-cells, acinar cells, ductal cells, and fibroblasts. The CMV promoter was used as a positive control. In addition, the DsRed reporter gene was administered in vivo to rat pancreas by ultrasound-targeted microbubble destruction (UTMD). Confocal microscopy was used to detect the presence and distribution of DsRed within the pancreas after UTMD. A modified RIP3.1 promoter, which includes portions of the insulin gene after its transcription start site is 5-fold more active in INS-1 cells than the full length RIP promoter or the CMV promoter. RIP3.1 is regulated by glucose level and various islet transcription factors in vitro, and exhibits activity in alpha-cells, but not exocrine cells. In vivo delivery of RIP3.1-DsRed resulted in expression of DsRed protein in beta-cells, and to a lesser extent alpha cells under normal glucose conditions. No DsRed signal was present in exocrine pancreas under RIP3.1. A modified rat insulin promoter, RIP3.1, efficiently and specifically directs gene expression to endocrine pancreas. PMID:19727136

Effect of gangliosides in the autoimmune response induced by liposome-associated antigens.

PubMed

Correa, S G; Rivero, V E; Yranzo-Volonté, N; Romero-Piffiguer, M; Ferro, M E; Riera, C M

1993-01-01

A model of autoimmunity to rat male accessory glands (RAG) was recently developed by intraperitoneal administration of three doses of native RAG associated with liposomes. In this work we analysed the effects of gangliosides in the cellular response to RAG when they were intraperitoneally administrated prior to the second dose of liposome-associated RAG. Results show that the ganglioside treatment could modify an established DTH response. Also, gangliosides markedly reduced the number of Ia antigen-positive peritoneal exudated cells (PEC). However, they modified neither the processing of liposomes through PEC nor their viability. Moreover, we obtained cellular response by transferring PEC from immunized donors into naive receptors.

Evaluation of disease modifying activity of Coriandrum sativum in experimental models

PubMed Central

Nair, Vinod; Singh, Surender; Gupta, Y.K.

2012-01-01

Background & objectives: Coriandrum sativum (CS), has been widely used in traditional systems of medicine for treatment of rheumatoid arthritis. However, the mechanism of action for its antiarthritic effects is not clearly known. Therefore, the present study was carried out to evaluate the antiarthritic activity of CS in rats in two experimental models. Methods: The antiarthritic activity of CS seed hydroalcoholic extract (CSHE) was evaluated in adult Wistar rats by using two experimental models, viz. formaldehyde and Complete Freund's adjuvant (CFA) induced arthritis. The expression of pro-inflammatory cytokines (predominantly contributed by macrophages) was also evaluated. TNF-α level was estimated in serum by ELISA method. TNF-R1, IL-1 β and IL-6 expression in the synovium was analysed by immunohistochemistry. Results: CSHE produced a dose dependent inhibition of joint swelling as compared to control animals in both, formaldehyde and CFA induced arthritis. Although there was a dose dependent increase in serum TNF-α levels in the CSHE treated groups as compared to control, the synovial expression of macrophage derived pro-inflammatory cytokines/cytokine receptor was found to be lower in the CSHE treated groups as compared to control. Interpretation & conclusions: Our results demonstrate that the antiarthritic activity of CSHE may be attributed to the modulation of pro-inflammatory cytokines in the synovium. In further studies CSHE could be explored to be developed as a disease modifying agent in the treatment of RA. PMID:22446868

A novel model approach for esophageal burns in rats: A comparison of three methods.

PubMed

Kalkan, Yildiray; Tumkaya, Levent; Akdogan, Remzi Adnan; Yucel, Ahmet Fikret; Tomak, Yakup; Sehitoglu, İbrahim; Pergel, Ahmet; Kurt, Aysel

2015-07-01

Corrosive esophageal injury causes serious clinical problems. We aimed to create a new experimental esophageal burn model using a single catheter without a surgical procedure. We conducted the study with two groups of 12 male rats that fasted for 12 h before application. A modified Foley balloon catheter was inserted into the esophageal lumen. The control group was given 0.9% sodium chloride, while the experimental group was given 37.5% sodium hydroxide with the other part of the catheter. After 60s, esophagus was washed with distilled water. The killed rats were examined using histopathological methods after 28 days. In comparison with the histopathological changes experienced by the study groups, the control groups were observed to have no pathological changes. Basal cell degeneration, dermal edema, and a slight increase in the keratin layer and collagen density of submucosa due to stenosis were all observed in the group subjected to esophageal corrosion. A new burn model can thus, we believe, be created without the involvement of invasive laparoscopic surgery and general anesthesia. The burn in our experiment was formed in both the distal and proximal esophagus, as in other models; it can also be formed optionally in the entire esophagus. © The Author(s) 2013.

Anti-diabetic effect of pyroglutamic acid in type 2 diabetic Goto-Kakizaki rats and KK-Ay mice.

PubMed

Yoshinari, Orie; Igarashi, Kiharu

2011-10-01

With the rapidly increasing prevalence of type 2 diabetes mellitus (T2DM), specific dietary components with anti-diabetic efficacy could be one strategy with therapeutic potential. In the present study, the anti-diabetic effects of an amino acid, pyroglutamic acid (PA), found in vegetables and fruits were investigated in T2DM models using Goto-Kakizaki (GK) rats and KK-Ay mice by measuring glucose tolerance and other markers of diabetes. Moreover, the effect of PA on gene expression in GK rats was measured by DNA microarray analysis. Oral glucose tolerance and serum insulin levels were reduced by PA in both animal models. Serum and liver total cholesterol levels were also improved by PA. Expression of genes involved with gluconeogenesis and those involved with its related transcription factor were down-regulated by feeding PA. In KK-Ay mice, the glucokinase:glucose-6-phosphatase (G6Pase) activity ratio increased. From these results, it is suggested that dietary PA beneficially modifies glucose and lipid metabolism in diabetic animals, and can potentially contribute to the mitigation of T2DM.

Biodegradable Magnesium Stent Treatment of Saccular Aneurysms in a Rat Model - Introduction of the Surgical Technique.

PubMed

Nevzati, Edin; Rey, Jeannine; Coluccia, Daniel; D'Alonzo, Donato; Grüter, Basil; Remonda, Luca; Fandino, Javier; Marbacher, Serge

2017-10-01

The steady progess in the armamentarium of techniques available for endovascular treatment of intracranial aneurysms requires affordable and reproducable experimental animal models to test novel embolization materials such as stents and flow diverters. The aim of the present project was to design a safe, fast, and standardized surgical technique for stent assisted embolization of saccular aneurysms in a rat animal model. Saccular aneurysms were created from an arterial graft from the descending aorta.The aneurysms were microsurgically transplanted through end-to-side anastomosis to the infrarenal abdominal aorta of a syngenic male Wistar rat weighing >500 g. Following aneurysm anastomosis, aneurysm embolization was performed using balloon expandable magnesium stents (2.5 mm x 6 mm). The stent system was retrograde introduced from the lower abdominal aorta using a modified Seldinger technique. Following a pilot series of 6 animals, a total of 67 rats were operated according to established standard operating procedures. Mean surgery time, mean anastomosis time, and mean suturing time of the artery puncture site were 167 ± 22 min, 26 ± 6 min and 11 ± 5 min, respectively. The mortality rate was 6% (n=4). The morbidity rate was 7.5% (n=5), and in-stent thrombosis was found in 4 cases (n=2 early, n=2 late in stent thrombosis). The results demonstrate the feasibility of standardized stent occlusion of saccular sidewall aneurysms in rats - with low rates of morbidity and mortality. This stent embolization procedure combines the opportunity to study novel concepts of stent or flow diverter based devices as well as the molecular aspects of healing.

Evaluation of the safety of a genetically modified DAS-444Ø6-6 soybean meal and hulls in a 90-day dietary toxicity study in rats.

PubMed

Papineni, Sabitha; Murray, Jennifer A; Ricardo, Ekmay; Dunville, Christina M; Sura, Radha Krishna; Thomas, Johnson

2017-11-01

A 90-day sub chronic toxicity study was conducted in rats to evaluate the safety of genetically modified DAS-444Ø6-6 soybeans expressing herbicide tolerant proteins when compared with its conventional comparators (non-transgenic near isoline control soybean and three commercially available non-transgenic line control soybeans). Rats were given diets formulated with either 10% or 20% w/w of soybean meal and 1% or 2% hulls of DAS-444Ø6-6 soybean with an equivalent amount of hulls from an isoline non-transgenic control soybean for at least 90 days. In addition, three separate 20% w/w non-transgenic commercially available soybean varieties were also given to groups of rats to serve as reference controls. Animals were evaluated by cage-side and hand-held detailed clinical observations, ophthalmic examinations, body weights/body weight gains, feed consumption, hematology, prothrombin time, urinalysis, clinical chemistry, selected organ weights, and gross and histopathologic examinations. Under the conditions of this study, the genetically modified DAS-444Ø6-6 diets did not cause any treatment-related effects in rats following 90 days of dietary administration as compared with rats fed diets with soybean of isoline control or commercial reference controls and are considered equivalent to the diets prepared from conventional comparators. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Stereotactic Administration of Edaravone Ameliorates Collagenase-Induced Intracerebral Hemorrhage in Rat.

PubMed

Zhang, Yan; Yang, Yang; Zhang, Guang-Zhu; Gao, Mou; Ge, Guang-Zhi; Wang, Qin-Qin; Ji, Xin-Chao; Sun, Yi-Lin; Zhang, Hong-Tian; Xu, Ru-Xiang

2016-10-01

Edaravone is widely used for treating ischemic stroke, but it is not still confirmed in intracerebral hemorrhage (ICH) as an ideal medication targeting the brain parenchyma. We aimed to investigate the neuroprotective effects of stereotactic administration of edaravone (SI) into the brain parenchyma. Intracerebral hemorrhage rat models were established by infusion of collagenase into the caudate nucleus. Neural functional recovery was assessed using modified neurological severity scores (mNSS). A comparative study of therapeutic effects between SI and intraperitoneal injection of edaravone (IP) involved in cerebral edema, blood-brain barrier (BBB) permeability, hematoma absorption, inflammatory response and neuronal apoptosis. Compared with IP, the mNSS was significantly (P < 0.05) improved by SI; cerebral edema and BBB permeability were dramatically ameliorated (P < 0.05); IL-4 and IL-10 levels increased, but IL-1β and TNF-α levels significantly decreased; neuron apoptosis decreased markedly (P < 0.05); and caspase-3 and Bax expression significantly dropped, but Bcl-2 increased in SI group (P < 0.05). SI markedly improved neurological deficits in ICH rat models via antiinflammatory and antiapoptosis mechanisms and promoted M2-type microglia differentiation. SI was effective in rats with collagenase-induced ICH. © 2016 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

The anticonvulsant action of nafimidone on kindled amygdaloid seizures in rats.

PubMed

Albertson, T E; Walby, W F

1988-01-01

The anticonvulsant effectiveness of nafimidone (1-[2-naphthoylmethyl]imidazole hydrochloride) was evaluated in the kindled amygdaloid seizure model in rats. Nafimidone (3.1-120 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and supranthreshold (400 microA) paradigms. Nafimidone (25-50 mg/kg) significantly reduced supranthreshold elicited afterdischarge length and seizure severity only at doses with some prestimulation toxicity. The maximum anticonvulsant effectiveness for the 25 mg/kg i.p. dose of nafimidone was seen between 15 and 30 min utilizing a suprathreshold kindling paradigm. Nafimidone did not significantly elevate seizure thresholds at the doses tested; however, nafimidone (3.1-50 mg/kg) reduced the severity and afterdischarge duration of threshold elicited seizures in a non-dose response manner. Drug-induced electroencephalographic spikes were seen in both cortex and amygdala in most kindled rats receiving 100-120 mg/kg i.p. within 30 min of dosing before electrical stimulation. The frequency of spike and wave complexes increased in most of these animals leading to drug-induced spontaneous seizures and death in approximately 25% before electrical stimulation. This study has demonstrated that although nafimidone can modify both threshold and suprathreshold elicited kindled amygdaloid seizures, it lacks significant specificity in this model of epilepsy.

Liposomal Aerosols of Nitric Oxide (NO) Donor as a Long-Acting Substitute for the Ultra-Short-Acting Inhaled NO in the Treatment of PAH.

PubMed

Nahar, Kamrun; Rashid, Jahidur; Absar, Shahriar; Al-Saikhan, Fahad I; Ahsan, Fakhrul

2016-07-01

This study seeks to develop a liposomal formulation of diethylenetriamine NONOate (DN), a long acting nitric oxide (NO) donor, with a goal to replace inhaled NO (iNO) in the treatment of pulmonary arterial hypertension (PAH). Liposomal formulations were prepared by a lipid film hydration method and modified with a cell penetrating peptide, CAR. The particles were characterized for size, polydispersity index (PDI), zeta potential, entrapment efficiency, storage and nebulization stability, and in-vitro release profiles. The cellular uptake and transport were assessed in rat alveolar macrophages (NR8383) and transforming growth factor β (TGF-β) activated rat pulmonary arterial smooth muscle cells (PASMCs). The fraction of the formulation that enters the systemic circulation, after intratracheal administration, was determined in an Isolated Perfused Rat Lung (IPRL) model. The safety of the formulations were assessed using an MTT assay and by measuring injury markers in the bronchoalveolar lavage (BAL) fluid; the pharmacological efficacy was evaluated by monitoring the changes in the mean pulmonary arterial (mPAP) and systemic pressure (mSAP) in a monocrotaline (MCT) induced-PAH rat model Liposome size, zeta potential, and entrapment efficiency were 171 ± 4 nm, -37 ± 3 mV, and 46 ± 5%, respectively. The liposomes released 70 ± 5% of the drug in 8 h and were stable when stored at 4°C. CAR-conjugated-liposomes were taken up more efficiently by PASMCs than liposomes-without-CAR; the uptake of the formulations by rat alveolar macrophages was minimal. DN-liposomes did not increase lung weight, protein quantity, and levels of injury markers in the BAL fluid. Intratracheal CAR-liposomes reduced the entry of liposomes from the lung to blood; the formulations produced a 40% reduction in mPAP for 180 minutes. This study establishes the proof-of-concept that peptide modified liposomal formulations of long-acting NO donor can be an alternative to short-acting iNO.

Increased trabecular bone and improved biomechanics in an osteocalcin-null rat model created by CRISPR/Cas9 technology.

PubMed

Lambert, Laura J; Challa, Anil K; Niu, Aidi; Zhou, Lihua; Tucholski, Janusz; Johnson, Maria S; Nagy, Tim R; Eberhardt, Alan W; Estep, Patrick N; Kesterson, Robert A; Grams, Jayleen M

2016-10-01

Osteocalcin, also known as bone γ-carboxyglutamate protein (Bglap), is expressed by osteoblasts and is commonly used as a clinical marker of bone turnover. A mouse model of osteocalcin deficiency has implicated osteocalcin as a mediator of changes to the skeleton, endocrine system, reproductive organs and central nervous system. However, differences between mouse and human osteocalcin at both the genome and protein levels have challenged the validity of extrapolating findings from the osteocalcin-deficient mouse model to human disease. The rat osteocalcin (Bglap) gene locus shares greater synteny with that of humans. To further examine the role of osteocalcin in disease, we created a rat model with complete loss of osteocalcin using the CRISPR/Cas9 system. Rat osteocalcin was modified by injection of CRISPR/Cas9 mRNA into the pronuclei of fertilized single cell Sprague-Dawley embryos, and animals were bred to homozygosity and compound heterozygosity for the mutant alleles. Dual-energy X-ray absorptiometry (DXA), glucose tolerance testing (GTT), insulin tolerance testing (ITT), microcomputed tomography (µCT), and a three-point break biomechanical assay were performed on the excised femurs at 5 months of age. Complete loss of osteocalcin resulted in bones with significantly increased trabecular thickness, density and volume. Cortical bone volume and density were not increased in null animals. The bones had improved functional quality as evidenced by an increase in failure load during the biomechanical stress assay. Differences in glucose homeostasis were observed between groups, but there were no differences in body weight or composition. This rat model of complete loss of osteocalcin provides a platform for further understanding the role of osteocalcin in disease, and it is a novel model of increased bone formation with potential utility in osteoporosis and osteoarthritis research. © 2016. Published by The Company of Biologists Ltd.

Synthesis and physico-chemical characterization of modified starches from banana (Musa AAB) and its biological activities in diabetic rats.

PubMed

Reddy, Chagam Koteswara; Suriya, M; Vidya, P V; Haripriya, Sundaramoorthy

2017-01-01

This study describes a simple method of preparation and physico-chemical properties of modified starches (type-3 resistant starches) from banana (Musa AAB), and the modified starches investigated as functional food with a beneficial effect on type-2 diabetes. RS3 was prepared using a method combined with debranching modification and physical modification; native and modifies starches were characterized by scanning electron microscope (SEM), powder X-ray diffraction (XRD), differential scanning calorimetry (DSC) and rapid visco analyzer (RVA). Use of the enzymatic and physical modification methodology, improved the yield of RS (26.62%) from Musa AAB. A reduced viscosity and swelling power; increased transition temperatures, water absorption capacity and solubility index with B-type crystalline pattern and loss of granular appearance were observed during the debranching modification and physical modification. The modified starches exhibited beneficial health effects in diabetic and HFD rats who consumed it. These results recommend that dietary feeding of RS3 was effective in the regulation of glucose and lipid profile in serum and suppressing the oxidative stress in rats under diabetic and HFD condition. This current study provides new bioactive starches, with potential applications in the food and non-food industries. Copyright © 2016 Elsevier B.V. All rights reserved.

Age-dependent salt hypertension in Dahl rats: fifty years of research.

PubMed

Zicha, J; Dobešová, Z; Vokurková, M; Rauchová, H; Hojná, S; Kadlecová, M; Behuliak, M; Vaněčková, I; Kuneš, J

2012-01-01

Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension - salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of renin-angiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the salt-sensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake. On the contrary, moderate salt hypertension in adult Dahl rats is attenuated by superoxide scavenging or endothelin-A receptor blockade which do not affect salt hypertension development in young animals.

Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats

PubMed Central

Eagle, Andrew L.; Singh, Robby; Kohler, Robert J.; Friedman, Amy L.; Liebowitz, Chelsea P.; Galloway, Matthew P.; Enman, Nicole M.; Jutkiewicz, Emily M.; Perrine, Shane A.

2017-01-01

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague–Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0,10 or 20mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, asexpected. However, compared to control ratson Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. PMID:25712697

Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease.

PubMed

Farrand, Ariana Q; Helke, Kristi L; Gregory, Rebecca A; Gooz, Monika; Hinson, Vanessa K; Boger, Heather A

Parkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. To assess therapeutic potential of VNS in a PD model. To mimic the progression of PD degeneration, rats received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1). VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN α-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. Our findings of increased locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased α-synuclein density in SN TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic. Copyright © 2017 Elsevier Inc. All rights reserved.

Fluorescein transport properties across artificial lipid membranes, Caco-2 cell monolayers and rat jejunum.

PubMed

Berginc, Katja; Zakelj, Simon; Levstik, Lea; Ursic, Darko; Kristl, Albin

2007-05-01

Membrane transport characteristics of a paracellular permeability marker fluorescein were evaluated using artificial membrane, Caco-2 cell monolayers and rat jejunum, all mounted in side-by-side diffusion cells. Modified Ringer buffers with varied pH values were applied as incubation salines on both sides of artificial membrane, cell culture monolayers or rat jejunum. Passive transport according to pH partition theory was determined using all three permeability models. In addition to that, active transport of fluorescein in the M-S (mucosal-to-serosal) direction through rat jejunum was observed. The highest M-S P(app) values regarding the active transport through the rat jejunum were observed in incubation saline with pH 6.5. Fluorescein transport through the rat jejunum was inhibited by DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) and alpha-CHC (alpha-cyano-4-hydroxycinnamic acid). Thus, we assume that two pH-dependent influx transporters could be involved in the fluorescein membrane transport through the intestinal (jejunal) epithelium. One is very likely an MCT (monocarboxylic acid cotransporter) isoform, inhibited by specific MCT inhibitor alpha-CHC, while the involvement of the second one with overlapping substrate/inhibitor specificities (most probably a member of the organic anion-transporting polypeptide family, inhibited at least partially by DIDS) could not be excluded.

Beneficial Effects of Galectin-3 Blockade in Vascular and Aortic Valve Alterations in an Experimental Pressure Overload Model

PubMed Central

Ibarrola, Jaime; Martínez-Martínez, Ernesto; Sádaba, J. Rafael; Arrieta, Vanessa; García-Peña, Amaia; Álvarez, Virginia; Fernández-Celis, Amaya; Gainza, Alicia; Rossignol, Patrick; Cachofeiro Ramos, Victoria; López-Andrés, Natalia

2017-01-01

Galectin-3 (Gal-3) is involved in cardiovascular fibrosis and aortic valve (AV) calcification. We hypothesized that Gal-3 pharmacological inhibition with modified citrus pectin (MCP) could reduce aortic and AV remodeling in normotensive rats with pressure overload (PO). Six weeks after aortic constriction, vascular Gal-3 expression was up-regulated in male Wistar rats. Gal-3 overexpression was accompanied by an increase in the aortic media layer thickness, enhanced total collagen, and augmented expression of fibrotic mediators. Further, vascular inflammatory markers as well as inflammatory cells content were greater in aorta from PO rats. MCP treatment (100 mg/kg/day) prevented the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of PO rats. Gal-3 levels were higher in AVs from PO rats. This paralleled enhanced AV fibrosis, inflammation, as well as greater expression of calcification markers. MCP treatment prevented the increase in Gal-3 as well as fibrosis, inflammation, and calcification in AVs. Overall, Gal-3 is overexpressed in aorta and AVs from PO rats. Gal-3 pharmacological inhibition blocks aortic and AV remodeling in experimental PO. Gal-3 could be a new therapeutic approach to delay the progression and the development of aortic remodeling and AV calcification in PO. PMID:28758988

Effects of varenicline on operant self-administration of alcohol and/or nicotine in a rat model of co-abuse.

PubMed

Funk, D; Lo, S; Coen, K; Lê, A D

2016-01-01

Alcohol and nicotine (in the form of tobacco) are often taken together, with increased negative health consequences. Co-use may modify intake of one or both of the drugs, or the effects of drugs used to treat nicotine or alcohol addiction. Varenicline is commonly prescribed as an aid to enhance quitting smoking. More recently it has been shown to reduce alcohol intake in humans and laboratory animals. There is little work investigating the role of co-exposure to alcohol and nicotine in the effects of varenicline. In pilot clinical studies, it has been reported that smoking enhances varenicline's effectiveness as a treatment for alcohol misuse, but this relationship has not been systematically investigated. To help resolve this, we examined if the effects of varenicline on alcohol and nicotine self-administration (SA) in rats are modified when the two drugs are taken together. Rats were trained on alcohol SA, and some were implanted with i.v. catheters for nicotine SA. Groups of animals then lever pressed for alcohol or nicotine alone, and another group lever pressed for alcohol and nicotine, using a two lever choice procedure. Varenicline did not affect alcohol SA. Varenicline reduced nicotine SA modestly. Access to both alcohol and nicotine reduced self-administration of either drug, but did not change the effects of varenicline. We found that in rats with a history of alcohol SA, varenicline reduced reinstatement of extinguished alcohol seeking induced by exposure to an alcohol prime combined with cues previously associated with alcohol. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of removal of dietary polyunsaturated fatty acids on plasma extravasation and mechanical allodynia in a trigeminal neuropathic pain model

PubMed Central

Martin, Yasmina B; Avendaño, Carlos

2009-01-01

Background Neuropathic pain (NP) is partially mediated by neuroinflammatory mechanisms, and also modulates local neurogenic inflammation. Dietary lipids, in particular the total amount and relative proportions of polyunsaturated fatty acids (PUFAs) of the ω-3 and ω-6 families, have been reported to modify the threshold for thermal and mechanical allodynia in the partial sciatic nerve ligation model of NP in rats. The effects of dietary lipids on other popular NP models, such as the chronic constriction injury (CCI), have not yet been examined. It is also unknown whether dietary PUFAs exert any effect on the capsaicin (CAP)-induced neurogenic inflammation under control or NP conditions. In this study we investigated these interrelated phenomena in the trigeminal territory, which has been much less explored, and for which not all data derived from limb nerves can be directly applied. Results We studied the effects of a CCI of the infraorbital nerve (IoN) on the development of mechanical allodynia and CAP-induced plasma extravasation in rats fed either a regular diet (RD), or a modified diet (MD) with much lower total content and ω-3:ω-6 ratio of PUFAs. In rats kept on MD, mechanical allodynia following CCI-IoN was more pronounced and developed earlier. Extravasation was substantially increased in naive rats fed MD, and displayed differential diet-depending changes one and four weeks after CCI-IoN. When compared with basal levels (in naive and/or sham cases), the net effect of CCI-IoN on ipsilateral extravasation was a reduction in the MD group, but an increase in the RD group, effectively neutralizing the original intergroup differences. Conclusion In summary, PUFA intake reduces CAP-induced neurogenic plasma extravasation in the trigeminal territory, and their removal significantly alters the mechanical allodynia and the plasma extravasation that result from a unilateral CCI-IoN. It is likely that this "protective" effect of dietary lipids is temporary. Also, the presence of contralateral effects of CCI-IoN precludes using the contralateral side as control. PMID:19243598

Evaluation of right heart function in a rat model using modified echocardiographic views.

PubMed

Bernardo, Ivan; Wong, James; Wlodek, Mary E; Vlahos, Ross; Soeding, Paul

2017-01-01

Echocardiography plays a major role in assessing cardiac function in animal models. We investigated use of a modified parasternal mid right-ventricular (MRV) and right ventricle (RV) outflow (RVOT) view, in assessing RV size and function, and the suitability of advanced 2D-strain analysis. 15 WKY rats were examined using transthoracic echocardiography. The left heart was assessed using standard short and long axis views. For the right ventricle a MRV and RVOT view were used to measure RV chamber and free wall area. 2D-strain analysis was applied to both ventricles using off-line analysis. RV chamber volume was determined by injection of 2% agarose gel, and RV free wall dissected and weighed. Echocardiography measurement was correlated with necropsy findings. The RV mid-ventricular dimension (R1) was 0.42±0.07cm and the right ventricular outflow tract dimension (R2) was 0.34±0.06cm, chamber end-diastolic area measurements were 0.38±0.09cm2 and 0.29±0.08cm2 for MRV and RVOT views respectively. RVOT and MRV chamber area correlated with gel mass. Doppler RV stroke volume was 0.32±0.08ml, cardiac output (CO) 110±27 ml.min-1 and RV free wall contractility assessed using 2D-strain analysis was demonstrated. We have shown that modified MRV and RVOT views can provide detailed assessment of the RV in rodents, with 2D-strain analysis of the RV free wall potentially feasible.

Paroxetine-induced reduction of sexual incentive motivation in female rats is not modified by 5-HT1B or 5-HT2C antagonists.

PubMed

Kaspersen, Helge; Agmo, Anders

2012-03-01

Clinical data show that paroxetine causes sexual dysfunction in a substantial proportion of women taking this compound. This work was conducted to determine whether chronic paroxetine reduces sexual incentive motivation in female rats and whether this compound can modify any aspect of paced mating. The role of the 5-HT(1B) and 5-HT(2C) receptors in any potential effects was also evaluated. Ovariectomized female rats were implanted with osmotic minipumps releasing 10 mg/kg per day of paroxetine or vehicle for 28 days. Tests for sexual incentive motivation and paced mating were performed just before implantation and at regular intervals thereafter. The females were primed with estradiol benzoate (25 μg/rat) and progesterone (1 mg/rat) before each of these tests. On days 25-27 of treatment, the females were injected with the 5-HT(1B) antagonist GR125,743 (5 mg/kg), the 5-HT(2C) antagonist SB206,553 (5 mg/kg) and vehicle in counterbalanced order. Preinjection time was 30 min. Paroxetine reduced sexual incentive motivation on day 20 of treatment without affecting any aspect of paced mating. None of the antagonists modified the inhibitory effect of paroxetine on sexual incentive motivation. In the group chronically treated with vehicle, SB206,553 reduced proceptive behaviors in the paced mating test. No other effect was obtained. The effects of paroxetine seen in female rats are similar to those observed in women, suggesting that disturbances of sexual incentive motivation in rats are predictive of sexual dysfunction in women. The 5-HT(1B) and 5-HT(2C) receptors do not seem to be of any importance for paroxetine's inhibitory effect.

Hepatocyte transplants improve liver function and encephalopathy in portacaval shunted rats.

PubMed

Fogel, Wieslawa Agnieszka; Stasiak, Anna; Maksymowicz, Michał; Kobos, Jozef; Unzeta, Mercedes; Mussur, Miroslaw

2014-07-01

Rats with portacaval shunt (PCS) are useful experimental models of human hepatic encephalopathy in chronic liver dysfunction. We have previously shown that PCS modifies amine neurotransmitter systems in the CNS and increases voluntary alcohol intake by rats. Hepatocyte transplantation, used in acute liver failure, has recently also been applied to chronic liver diseases, which prompted us to investigate whether the altered brain amine system and the drinking behavior in long-term shunted rats could be normalized by hepatocyte transplants. Hepatocytes, isolated from syngeneic donors by collagenase digestion, were injected (3 × 10(6) cells/rat) into the pancreatic tail region, 6 months after PCS. Hepatic function was evaluated by measuring urine urea and plasma L-histidine concentrations. A free choice test with two bottles (tap water and 10% ethyl alcohol) was performed for 3 days to assess the rats' preference for alcohol. The rats were euthanized 2 months posttransplantation. Brain histamine and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured by radioenzymatic assay and by HPLC-EC, respectively, N-tele-methylhistamine by GC/MS while MAOA and MAOB activities by isotopic procedures. Portacaval shunt rats with hepatocyte transplants gave more urea than before transplantation, with lower plasma L-His levels and higher body weight versus the PCS counterparts. Also, those rats consumed less alcohol. The CNS amines and 5-HIAA concentrations, as well as MAO-B activity, being abnormally high in untreated PCS rats, significantly reduced after PCS hepatocyte treatment. The results support the therapeutic values of hepatocyte transplants in chronic liver diseases and the temporary character of PCS-exerted CNS dysfunctions. © 2014 John Wiley & Sons Ltd.

Pharmacological interference with tissue hypercatabolism in tumour-bearing rats.

PubMed Central

Tessitore, L; Costelli, P; Baccino, F M

1994-01-01

Marked loss of body weight and profound waste of both skeletal muscle and white adipose tissue occur in rats into which the ascites hepatoma Yoshida AH-130 has been transplanted, associated with marked perturbations in the hormonal homoeostasis and the presence of circulating tumour necrosis factor and high plasma levels of prostaglandin E2 [Tessitore, Costelli and Baccino (1993) Br. J. Cancer 67, 15-23]. On the basis of previous findings, the present study examined whether the development of cachexia in this model system could be significantly affected by adrenalectomy or by pharmacological treatments that may interfere with proximal or distal mediators of tissue hypercatabolism. In no instance was tumour growth modified. Medroxyprogesterone acetate, an anabolic-hormone-like drug, was completely ineffective. In adrenalectomized animals, although changes such as the elevation of plasma triacylglycerols and corticosterone were corrected, the general course of cachexia was not modified. A partial prevention of muscle waste was observed with acetylsalicylic acid, a non-steroidal anti-inflammatory drug, or with leupeptin, a proteinase inhibitor. Insulin afforded the most significant preservation of muscle protein and adipose-tissue mass, which were maintained close to control values even 10 days after transplantation. The effects of insulin on gastrocnemius muscle and liver protein content were exerted by slowing down protein turnover, mainly enhancing synthesis. Consistently, the total free amino acid concentration in the gastrocnemius of insulin-treated rats 10 days after tumour transplantation was close to that of controls. Although treatment with insulin decreased plasma corticosterone to normal values, it did not modify the circulating level of tumour necrosis factor. On the whole these data show that it seems possible to prevent, at least in part, the tissue waste that characterizes cancer cachexia by purely pharmacological means. PMID:8166661

Matching- and Nonmatching-to-Sample Concept Learning in Rats Using Olfactory Stimuli

ERIC Educational Resources Information Center

April, L. Brooke; Bruce, Katherine; Galizio, Mark

2011-01-01

Previous research has shown that rats can learn matching-to-sample relations with olfactory stimuli; however, the specific characteristics of this relational control are unclear. In Experiment 1, 6 rats were trained to either match or nonmatch to sample in a modified operant chamber using common household spices as olfactory stimuli. After…

Prebiotic Fibre Supplementation In Combination With Metformin Modifies Appetite, Energy Metabolism, And Gut Satiety Hormones In Obese Rats

NASA Astrophysics Data System (ADS)

Pyra, Kim Alicia

The prebiotic fibre, oligofructose (OFS), reduces energy intake and improves glycemic control in rodents and man. Metformin (MT) is a commonly used insulin-sensitizing agent that may limit weight gain in individuals with type 2 diabetes. Our objective was to determine if using OFS as an adjunct to MT therapy (AD) modifies satiety hormone production and metabolism in obese rats. Independently, OFS and MT decreased energy intake, body fat, hepatic triglyceride content, plasma leptin and glucose-dependent insulinotropic peptide (GIP) levels. OFS and AD but not MT rats showed superior glycemic control during an oral glucose tolerance test (OGTT) compared to C. Area under the curve for GIP was lowest in ADThe prebiotic fibre, oligofructose (OFS), reduces energy intake and improves glycemic control in rodents and man. Metformin (MT) is a commonly used insulin-sensitizing agent that may limit weight gain in individuals with type 2 diabetes. Our objective was to determine if using OFS as an adjunct to MT therapy (AD) modifies satiety hormone production and metabolism in obese rats. Independently, OFS and MT decreased energy intake, body fat, hepatic triglyceride content, plasma leptin and glucose-dependent insulinotropic peptide (GIP) levels. OFS and AD but not MT rats showed superior glycemic control during an oral glucose tolerance test (OGTT) compared to C. Area under the curve for GIP was lowest in AD

PGE1, dexamethasone, U-74389G, or Bt2-cAMP as an additive to promote protection by UW solution in I/R injury.

PubMed

Chiang, C H; Hsu, K; Yan, H C; Harn, H J; Chang, D M

1997-08-01

A method to reduce ischemia-reperfusion (I/R) injury can be an important criterion to improve the preservation solution. Although University of Wisconsin solution (UW) works as a lung preservation solution, its attenuation effect on I/R injury has not been investigated. We attempted to determine whether, by adding various protective agents, modified UW solutions will enhance the I/R attenuation by UW. We examined the I/R injury in an isolated rat lung model. Various solutions, e.g., physiological salt solution (PSS), UW, and modified UW solutions containing various protective agents such as prostaglandin E1, dexamethasone, U-74389G, or dibutyryl adenosine 3',5'-cyclic monophosphate were perfused individually to evaluate the I/R injury. Isolated rat lung experiments, with ischemia for 45 min, then reperfusion for 60 min, were conducted in a closed circulating system. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (Kfc), protein content of lavage fluid, concentration of cytokines, and lung histopathology were analyzed. Results showed that the acute I/R lung injury with immediate permeability pulmonary edema was associated with an increase in tumor necrosis factor-alpha (TNF-alpha) production. A significant correlation existed between TNF-alpha and Kfc (r = 0.8, P < 0.0001) and TNF-alpha and LWG (r = 0. 9, P < 0.0001), indicating that TNF-alpha is an important cytokine modulating early I/R injury. Significantly lower levels of Kfc, LWG, TNF-alpha, and protein concentration of lung lavage (P < 0.05) were found in the UW-perfused group than in the control group perfused with PSS. Modified UW promoted the protective effect of UW to further decrease Kfc, LWG, and TNF-alpha (P < 0.05). Histopathological observations also substantiated this evidence. In the UW+U-74389G group, bronchial alveolar lavage fluid contained lowest protein concentration. We conclude that the UW solution attenuates I/R injury of rat lung and that the modified UW solutions further enhance the effect of UW in reducing I/R injury. Among modified solutions, UW+U-74389G is the best. Further investigation of the improved effects of the modified UW solutions would be beneficial in lung transplantation.

A novel chemically modified curcumin reduces inflammation-mediated connective tissue breakdown in a rat model of diabetes: periodontal and systemic effects.

PubMed

Elburki, M S; Moore, D D; Terezakis, N G; Zhang, Y; Lee, H-M; Johnson, F; Golub, L M

2017-04-01

Periodontal disease is the most common chronic inflammatory disease known to mankind (and the major cause of tooth loss in the adult population) and has also been linked to various systemic diseases, particularly diabetes mellitus. Based on the literature linking periodontal disease with diabetes in a "bidirectional manner", the objectives of the current study were to determine: (i) the effect of a model of periodontitis, complicated by diabetes, on mechanisms of tissue breakdown including bone loss; and (ii) the response of the combination of this local and systemic phenotype to a novel pleiotropic matrix metalloproteinase inhibitor, chemically modified curcumin (CMC) 2.24. Diabetes was induced in adult male rats by intravenous injection of streptozotocin (nondiabetic rats served as controls), and Escherichia coli endotoxin (lipopolysaccharide) was repeatedly injected into the gingiva to induce periodontitis. CMC 2.24 was administered by oral gavage (30 mg/kg) daily; untreated diabetic rats received vehicle alone. After 3 wk of treatment, the rats were killed, and gingiva, jaws, tibia and skin were collected. The maxillary jaws and tibia were dissected and radiographed. The gingival tissues of each experimental group (n = 6 rats/group) were pooled, extracted, partially purified and, together with individual skin samples, analyzed for matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography; MMP-8 was analyzed in gingival and skin tissue extracts, and in serum, by western blotting. The levels of three bone-resorptive cytokines [interleukin (IL)-1β, IL-6 and tumor necrosis factor-α], were measured in gingival tissue extracts and serum by ELISA. Systemic administration of CMC 2.24 to diabetic rats with endotoxin-induced periodontitis significantly inhibited alveolar bone loss and attenuated the severity of local and systemic inflammation. Moreover, this novel tri-ketonic phenylaminocarbonyl curcumin (CMC 2.24) appeared to reduce the pathologically excessive levels of inducible MMPs to near-normal levels, but appeared to have no significant effect on the constitutive MMPs required for physiologic connective tissue turnover. In addition to the beneficial effects on periodontal disease, induced both locally and systemically, CMC 2.24 also favorably affected extra-oral connective tissues, skin and skeletal bone. This study supports our hypothesis that CMC 2.24 is a potential therapeutic pleiotropic MMP inhibitor, with both intracellular and extracellular effects, which reduces local and systemic inflammation and prevents hyperglycemia- and bacteria-induced connective tissue destruction. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Tocotrienol-Enriched Formulation Protects against Radiation-Induced Changes in Cardiac Mitochondria without Modifying Late Cardiac Function or Structure

PubMed Central

Sridharan, Vijayalakshmi; Tripathi, Preeti; Aykin-Burns, Nukhet; Krager, Kimberly J; Sharma, Sunil K.; Moros, Eduardo G.; Melnyk, Stepan B.; Pavliv, Oleksandra; Hauer-Jensen, Martin; Boerma, Marjan

2015-01-01

Radiation-induced heart disease (RIHD) is a common and sometimes severe late side effect of radiation therapy for intrathoracic and chest wall tumors. We have previously shown that local heart irradiation in a rat model caused prolonged changes in mitochondrial respiration and increased susceptibility to mitochondrial permeability transition pore (mPTP) opening. Because tocotrienols are known to protect against oxidative stress-induced mitochondrial dysfunction, in this study, we examined the effects of tocotrienols on radiation-induced alterations in mitochondria, and structural and functional manifestations of RIHD. Male Sprague-Dawley rats received image-guided localized X irradiation to the heart to a total dose of 21 Gy. Twenty-four hours before irradiation, rats received a tocotrienol-enriched formulation or vehicle by oral gavage. Mitochondrial function and mitochondrial membrane parameters were studied at 2 weeks and 28 weeks after irradiation. In addition, cardiac function and histology were examined at 28 weeks. A single oral dose of the tocotrienol-enriched formulation preserved Bax/Bcl2 ratios and prevented mPTP opening and radiation-induced alterations in succinate-driven mitochondrial respiration. Nevertheless, the late effects of local heart irradiation pertaining to myocardial function and structure were not modified. Our studies suggest that a single dose of tocotrienols protects against radiation-induced mitochondrial changes, but these effects are not sufficient against long-term alterations in cardiac function or remodeling. PMID:25710576

A tocotrienol-enriched formulation protects against radiation-induced changes in cardiac mitochondria without modifying late cardiac function or structure.

PubMed

Sridharan, Vijayalakshmi; Tripathi, Preeti; Aykin-Burns, Nukhet; Krager, Kimberly J; Sharma, Sunil K; Moros, Eduardo G; Melnyk, Stepan B; Pavliv, Oleksandra; Hauer-Jensen, Martin; Boerma, Marjan

2015-03-01

Radiation-induced heart disease (RIHD) is a common and sometimes severe late side effect of radiation therapy for intrathoracic and chest wall tumors. We have previously shown that local heart irradiation in a rat model caused prolonged changes in mitochondrial respiration and increased susceptibility to mitochondrial permeability transition pore (mPTP) opening. Because tocotrienols are known to protect against oxidative stress-induced mitochondrial dysfunction, in this study, we examined the effects of tocotrienols on radiation-induced alterations in mitochondria, and structural and functional manifestations of RIHD. Male Sprague-Dawley rats received image-guided localized X irradiation to the heart to a total dose of 21 Gy. Twenty-four hours before irradiation, rats received a tocotrienol-enriched formulation or vehicle by oral gavage. Mitochondrial function and mitochondrial membrane parameters were studied at 2 weeks and 28 weeks after irradiation. In addition, cardiac function and histology were examined at 28 weeks. A single oral dose of the tocotrienol-enriched formulation preserved Bax/Bcl2 ratios and prevented mPTP opening and radiation-induced alterations in succinate-driven mitochondrial respiration. Nevertheless, the late effects of local heart irradiation pertaining to myocardial function and structure were not modified. Our studies suggest that a single dose of tocotrienols protects against radiation-induced mitochondrial changes, but these effects are not sufficient against long-term alterations in cardiac function or remodeling.

Role of female sex hormones in neuronal nitric oxide release and metabolism in rat mesenteric arteries.

PubMed

Minoves, Nuria; Balfagón, Gloria; Ferrer, Mercedes

2002-09-01

This study examines the effects of female sex hormones on the vasoconstrictor response to electrical field stimulation (EFS), as well as the modulation of this response by neuronal NO. For this purpose, segments of denuded superior mesenteric artery from ovariectomized (OvX) female Sprague-Dawley rats and from control rats (in oestrus phase) were used. EFS induced frequency-dependent contractions, which were greater in segments from OvX rats than in those from control rats. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester strengthened EFS-elicited contractions to a greater extent in arteries from OvX rats than in those from control rats. Similar results were observed with the preferential neuronal NO synthase inhibitor 7-nitroindazole. The sensorial neurotoxin capsaicin did not modify EFS-induced contractions in segments from either group. In noradrenaline-precontracted segments, sodium nitroprusside (SNP) induced concentration-dependent relaxation, which was greater in segments from control rats than in those from OvX rats. 8-Bromo-cGMP induced similar concentration-dependent relaxation in noradrenaline-precontracted segments from both OvX and control rats. Diethyldithiocarbamate, a superoxide dismutase (SOD) inhibitor, reduced the relaxation induced by SNP in segments from both groups of rats. SOD, a superoxide anion scavenger, enhanced the relaxation induced by SNP in segments from OvX rats, but did not modify it in segments from control rats. EFS induced NO(-)(2) formation, which was greater in segments from OvX than in those from control rats, and pretreatment with tetrodotoxin, a blocker of nerve impulse propagation, abolished release in both cases. These results suggest that EFS induces greater neuronal NO release in mesenteric segments from OvX rats than in those from control rats and, although NO metabolism is also higher, the contribution of net neuronal NO in the vasomotor response to EFS is greater in segments from OvX rats than in those from control rats.

Chronic uremia induces permeability changes, increased nitric oxide synthase expression, and structural modifications in the peritoneum.

PubMed

Combet, S; Ferrier, M L; Van Landschoot, M; Stoenoiu, M; Moulin, P; Miyata, T; Lameire, N; Devuyst, O

2001-10-01

Advanced glycation end products (AGE), growth factors, and nitric oxide contribute to alterations of the peritoneum during peritoneal dialysis (PD). These mediators are also involved in chronic uremia, a condition associated with increased permeability of serosal membranes. It is unknown whether chronic uremia per se modifies the peritoneum before PD initiation. A rat model of subtotal nephrectomy was used to measure peritoneal permeability after 3, 6, and 9 wk, in parallel with peritoneal nitric oxide synthase (NOS) isoform expression and activity and structural changes. Uremic rats were characterized by a higher peritoneal permeability for small solutes and an increased NOS activity due to the up-regulation of endothelial and neuronal NOS. The permeability changes and increased NOS activities correlated with the degree of renal failure. Focal areas of vascular proliferation and fibrosis were detected in uremic rats, in relation with a transient up-regulation of vascular endothelial growth factor and basic fibroblast growth factor, as well as vascular deposits of the AGE carboxymethyllysine and pentosidine. Correction of anemia with erythropoietin did not prevent the permeability or structural changes in uremic rats. Thus, in this rat model, uremia induces permeability and structural changes in the peritoneum, in parallel with AGE deposits and up-regulation of specific NOS isoforms and growth factors. These data suggest an independent contribution of uremia in the peritoneal changes during PD and offer a paradigm to better understand the modifications of serosal membranes in uremia.

The Nile Rat (Arvicanthis niloticus) as a Superior Carbohydrate-Sensitive Model for Type 2 Diabetes Mellitus (T2DM)

PubMed Central

Landstrom, Michelle; Luu, Alice; Hayes, K. C.

2018-01-01

Type II diabetes mellitus (T2DM) is a multifactorial disease involving complex genetic and environmental interactions. No single animal model has so far mirrored all the characteristics or complications of diabetes in humans. Since this disease represents a chronic nutritional insult based on a diet bearing a high glycemic load, the ideal model should recapitulate the underlying dietary issues. Most rodent models have three shortcomings: (1) they are genetically or chemically modified to produce diabetes; (2) unlike humans, most require high-fat feeding; (3) and they take too long to develop diabetes. By contrast, Nile rats develop diabetes rapidly (8–10 weeks) with high-carbohydrate (hiCHO) diets, similar to humans, and are protected by high fat (with low glycemic load) intake. This review describes diabetes progression in the Nile rat, including various aspects of breeding, feeding, and handling for best experimental outcomes. The diabetes is characterized by a striking genetic permissiveness influencing hyperphagia and hyperinsulinemia; random blood glucose is the best index of disease progression; and kidney failure with chronic morbidity and death are outcomes, all of which mimic uncontrolled T2DM in humans. Non-alcoholic fatty liver disease (NAFLD), also described in diabetic humans, results from hepatic triglyceride and cholesterol accumulation associated with rising blood glucose. Protection is afforded by low glycemic load diets rich in certain fibers or polyphenols. Accordingly, the Nile rat provides a unique opportunity to identify the nutritional factors and underlying genetic and molecular mechanisms that characterize human T2DM. PMID:29463026

Modeling Combined Immunosuppressive and Anti-inflammatory Effects of Dexamethasone and Naproxen in Rats Predicts the Steroid-Sparing Potential of Naproxen.

PubMed

Li, Xiaonan; DuBois, Debra C; Song, Dawei; Almon, Richard R; Jusko, William J; Chen, Xijing

2017-07-01

Dexamethasone (DEX), a widely prescribed corticosteroid, has long been the cornerstone of the treatment of inflammation and immunologic dysfunctions in rheumatoid arthritis. Corticosteroids are frequently used in combination with other antirheumatic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs to mitigate disease symptoms and minimize unwanted effects. We explored the steroid dose-sparing potential of the NSAID naproxen (NPX) with in vitro and in vivo studies. The single and joint suppressive effects of DEX and NPX on the in vitro mitogen-induced proliferation of T lymphocytes in blood and their anti-inflammatory actions on paw edema were investigated in female and male Lewis rats with collagen-induced arthritis (CIA). As expected, DEX was far more potent than NPX in these systems. Mathematical models incorporating an interaction term ψ were applied to quantitatively assess the nature and intensity of pharmacodynamic interactions between DEX and NPX. Modest synergistic effects of the two drugs were found in suppressing the mitogenic response of T lymphocytes. A pharmacokinetic/pharmacodynamic/disease progression model integrating dual drug inhibition quantitatively described the pharmacokinetics, time-course of single and joint anti-inflammatory effects (paw edema), and sex differences in CIA rats, and indicated additive effects of DEX and NPX. Further model simulations demonstrated the promising steroid-sparing potential of NPX in CIA rats, with the beneficial effects of the combination therapy more likely in males than females. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Effect of modified alkaline supplementation on bone metabolic turnover in rats.

PubMed

Chui, D H; Marotta, F; Liu, T; Minelli, E; Yadav, H; Signorelli, P; Lorenzetti, A; Jain, S

2008-01-01

This study aims to determine the effects of a high protein diet and alkaline supplementation on bone metabolic turnover in rats. Eight-week-old male Sprague-Dawley rats were investigated by bone status, including bone mineral density (BMD) and biomechanical markers from blood and urine. Thirty rats were randomly divided into three groups and treated for 8 weeks as follows: baseline control group (n. 10, C), high-protein supplemented diet group (n. 10, chronic acidosis, CA group) and supplemented chronic acidosis (n.10, SCA). Diet-treated rats were fed an acidic high-protein diet and the supplementation consisted in a modified alkaline formula (Basenpulver, NaMed, Italy). At the end of the experimental period, the rats were sacrificed, blood samples were drawn and femur and tibia were removed for analysis of bone mineral density (BMD) by dual energy X-ray absorptiometry (DEXA). In the CA group, 24-hour urinary calcium (Ca) and phosphorus (P) excretion were increased 2.1-fold (p<0.05 vs normal diet controls) as well as kidney weight. However, serum Ca and P concentration, as well as urinary Dpd excretion were not significantly changed. Femural and tibial BMD was significantly decreased in the CA group (p<0.05), but alkaline supplementation prevented such phenomenon (p<0.05 vs CA). These results suggest that blood Ca and P concentrations in chronic acidosis condition during the 12-week supplementation might be maintained by hypercalciuria and hyperphosphaturia at the expenses of bone structure. However, modified alkaline supplementation is able to prevent such derangements.

Age-dependent effects of topiramate on the acquisition and the retention of rapid kindling.

PubMed

Mazarati, Andréy; Shin, Don; Auvin, Stéphane; Sankar, Raman

2007-04-01

To examine antiepileptogenic, disease modifying, and anticonvulsant effects of topiramate under conditions of rapid kindling at different stages of development. Afterdischarge threshold (ADT) and duration (ADD) were examined in 2-, 3-, and 5-week-old Wistar rats before and after administration of topiramate (200 mg/kg). Animals underwent a rapid kindling protocol (sixty 10-s trains, bipolar 20 Hz square wave pulses delivered every 5 min). The progression of behavioral and electrographic seizures, and responses to test stimulations 24 h after the protocol were compared between topiramate and vehicle-treated control rats. In addition, rats that were previously given vehicle only prior to kindling, were then given topiramate to examine the effect on established kindled seizures. In 2-week-old animals, topiramate affected neither the baseline afterdischarge, nor the progression of kindled seizures. In 3-week-old rats, topiramate did not modify the baseline afterdischarge, but significantly delayed the occurrence of full motor seizures in response to repeated stimulations. Topiramate treatment of 5-week-old rats increased baseline ADT, shortened ADD, and delayed the progression of kindled seizures. Twenty-four h after the last kindling stimulation, animals of all ages exhibited a decreased ADT, an increase ADD, and developed behavioral seizures in response to threshold stimulation. Vehicle-treated kindled rats that were then given topiramate displayed significantly attenuated behavioral seizures induced by the threshold stimulation. Topiramate exhibited age-dependent disease-modifying effects under conditions of rapid kindling, but failed to block epileptogenesis. Topiramate also inhibited kindled seizures with equal efficacy across the three ages.

Age-Dependent Effects of Topiramate on the Acquisition and the Retention of Rapid Kindling

PubMed Central

Mazarati, Andréy; Shin, Don; Auvin, Stéphane; Sankar, Raman

2008-01-01

Summary Purpose To examine antiepileptogenic, disease-modifying, and anticonvulsant effects of topiramate under conditions of rapid kindling at different stages of development. Methods Afterdischarge threshold (ADT) and duration (ADD) were examined in two-, three-, and five-week old Wistar rats before and after administration of topiramate (200 mg/kg). Animals underwent a rapid kindling protocol (sixty 10 second trains, bipolar 20 Hz square wave pulses delivered every five minutes). The progression of behavioral and electrographic seizures, and responses to test stimulations 24 hours after the protocol were compared between topiramate and vehicle treated control rats. In addition, rats that were previously given vehicle only prior to kindling, were then given topiramate to examine the effect on established kindled seizures. Results In two-week old animals, topiramate affected neither the baseline afterdischarge, nor the progression of kindled seizures. In three-week old rats, topiramate did not modify the baseline afterdischarge, but significantly delayed the occurrence of full motor seizures in response to repeated stimulations. Topiramate treatment of five-week old rats increased baseline ADT, shortened ADD, and delayed the progression of kindled seizures. Twenty four hours after the last kindling stimulation, animals of all ages exhibited a decreased ADT, an increase ADD, and developed behavioral seizures in response to threshold stimulation. Vehicle treated kindled rats that were then given topiramate displayed significantly attenuated behavioral seizures induced by the threshold stimulation. Conclusions Topiramate exhibited age-dependent disease-modifying effects under conditions of rapid kindling, but failed to block epileptogenesis. Topiramate also inhibited kindled seizures with equal efficacy across the three ages. PMID:17319916

Impairments of spatial learning and memory following intrahippocampal injection in rats of 3-mercaptopropionic acid-modified CdTe quantum dots and molecular mechanisms.

PubMed

Wu, Tianshu; He, Keyu; Ang, Shengjun; Ying, Jiali; Zhang, Shihan; Zhang, Ting; Xue, Yuying; Tang, Meng

2016-01-01

With the rapid development of nanotechnology, quantum dots (QDs) as advanced nanotechnology products have been widely used in neuroscience, including basic neurological studies and diagnosis or therapy for neurological disorders, due to their superior optical properties. In recent years, there has been intense concern regarding the toxicity of QDs, with a growing number of studies. However, knowledge of neurotoxic consequences of QDs applied in living organisms is lagging behind their development, even if several studies have attempted to evaluate the toxicity of QDs on neural cells. The aim of this study was to evaluate the adverse effects of intrahippocampal injection in rats of 3-mercaptopropionic acid (MPA)-modified CdTe QDs and underlying mechanisms. First of all, we observed impairments in learning efficiency and spatial memory in the MPA-modified CdTe QD-treated rats by using open-field and Y-maze tests, which could be attributed to pathological changes and disruption of ultrastructure of neurons and synapses in the hippocampus. In order to find the mechanisms causing these effects, transcriptome sequencing (RNA-seq), an advanced technology, was used to gain the potentially molecular targets of MPA-modified CdTe QDs. According to ample data from RNA-seq, we chose the signaling pathways of PI3K-Akt and MPAK-ERK to do a thorough investigation, because they play important roles in synaptic plasticity, long-term potentiation, and spatial memory. The data demonstrated that phosphorylated Akt (p-Akt), p-ERK1/2, and c-FOS signal transductions in the hippocampus of rats were involved in the mechanism underlying spatial learning and memory impairments caused by 3.5 nm MPA-modified CdTe QDs.

FOOD-INTAKE DYSREGULATION IN TYPE 2 DIABETIC GOTO-KAKIZAKI RATS: HYPOTHESIZED ROLE OF DYSFUNCTIONAL BRAINSTEM THYROTROPIN-RELEASING HORMONE AND IMPAIRED VAGAL OUTPUT

PubMed Central

Zhao, K.; Ao, Y.; Harper, R.M.; Go, V. L.W.; Yang, H.

2013-01-01

Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56–81% in GK rats. Fasting (48 h) and refeeding (2 h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity. PMID:23701881

Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output.

PubMed

Zhao, K; Ao, Y; Harper, R M; Go, V L W; Yang, H

2013-09-05

Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity. Published by Elsevier Ltd.

The effect of resuscitation in 100% oxygen on brain injury in a newborn rat model of severe hypoxic-ischaemic encephalopathy.

PubMed

Smit, Elisa; Liu, Xun; Gill, Hannah; Jary, Sally; Wood, Thomas; Thoresen, Marianne

2015-11-01

Infants with birth asphyxia frequently require resuscitation. Current guidance is to start newborn resuscitation in 21% oxygen. However, infants with severe hypoxia-ischaemia may require prolonged resuscitation with oxygen. To date, no study has looked at the effect of resuscitation in 100% oxygen following a severe hypoxic-ischaemic insult. Postnatal day 7 Wistar rats underwent a severe hypoxic-ischaemic insult (modified Vannucci unilateral brain injury model) followed by immediate resuscitation in either 21% or 100% oxygen for 30 min. Seven days following the insult, negative geotaxis testing was performed in survivors, and the brains were harvested. Relative ipsilateral cortical and hippocampal area loss was assessed histologically. Total area loss in the affected hemisphere and area loss within the hippocampus did not significantly differ between the two groups. The same results were seen for short-term neurological assessment. No difference was seen in weight gain between pups resuscitated in 21% and 100% oxygen. Resuscitation in 100% oxygen does not cause a deleterious effect on brain injury following a severe hypoxic-ischaemic insult in a rat model of hypoxia-ischaemia. Further work investigating the effects of resuscitation in 100% oxygen is warranted, especially for newborn infants with severe hypoxic-ischaemic encephalopathy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[The effects of nicergoline on the heart rate in the normotensive or spontaneously hypertensive rat. Possible participation of central alpha-1 receptors].

PubMed

Huchet, A M; Schmitt, H

1986-01-01

The cardiovascular effects of nicergoline, a preferential alpha 1-adrenoceptor blocking drug, were studied in anaesthetized normotensive or spontaneously hypertensive (SH) rats. Nicergoline (300 micrograms/kg, i.v.) significantly reduced blood pressure and heart rate in control, bivagotomized or beta-blocked normotensive or SH rats. In bilaterally vagotomized and beta-blocked rats, nicergoline reduced mean blood pressure but did no longer modify heart rate. Thus, it is postulated that nicergoline could reduce the sympathetic tone and increase the vagal nerve activity, possibly by inhibiting central alpha 1-adrenoceptors. The nicergoline--induced bradycardia was greater in bivagotomized SHR than in normotensive ones. Intracerebroventricular injections of nicergoline (30 micrograms/kg) did not modify heart rate in normotensive control, bivagotomized or beta-blocked rats. On the contrary, nicergoline (30 micrograms/kg) injected into the cisterna magna induced a significant bradycardia in the three groups of normotensive rats. Blood pressure was reduced in the same way in all groups centrally treated by nicergoline. In conclusion, it seems that nicergoline reduces blood pressure by peripheral alpha-adrenoceptor blockade and modulates the autonomic nervous activity by inhibiting alpha 1-adrenoceptors mainly localized in the brainstem.

Effects of sleeve gastrectomy surgery with modified jejunoileal bypass on body weight, food intake and metabolic hormone levels of rats.

PubMed

Yan, Lingling; Zhu, Zhanyong; Wu, Dan; Zhou, Qixing; Wu, Yiping

2011-12-01

This study examined the effects of a combined surgery of sleeve gastrectomy (SG) and modified jejunoileal bypass (JIB) on the body weight, food intake, and the plasma levels of active glucagon-like peptide-1 (GLP-1) and total ghrelin of rats. Rats were divided into 3 groups in terms of different surgical protocol: SG-JIB (n=12), SG (n=12), JIB (n=12) and sham surgery groups (n=10). In SG-JIB group, rats was subjected to sleeve gastrectomy and end to side anastomosis of part of the jejunum (25 cm from the ligament of Treitz) to the ileum 25 cm proximal to the cecum. The body weight and food intake were evaluated during 10 consecutive weeks postoperatively. The levels of active GLP-1 and total ghrelin in the plasma of the rats were measured by ELISA assay. The results showed that the SG-JIB treated rats relative to SG- or JIB-treated ones produced a sustained reduction in food intake and weight gain. The level of active GLP-1 was elevated and total ghrelin level decreased in SG-JIB-treated rats as compared with SG- or JIB-treated ones. It was concluded that SG-JIB could efficiently reduce the body weight and food intake, alter obesity-related hormone levels of the rats, indicating that SG-JIB may be potentially used for the treatment of obesity.

Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight.

PubMed

Morey-Holton, E R; Globus, R K

1998-05-01

A model that uses hindlimb unloading of rats was developed to study the consequences of skeletal unloading and reloading as occurs during and following space flight. Studies using the model were initiated two decades ago and further developed at National Aeronautics and Space Administration (NASA)-Ames Research Center. The model mimics some aspects of exposure to microgravity by removing weightbearing loads from the hindquarters and producing a cephalic fluid shift. Unlike space flight, the forelimbs remain loaded in the model, providing a useful internal control to distinguish between the local and systemic effects of hindlimb unloading. Rats that are hindlimb unloaded by tail traction gain weight at the same rate as pairfed controls, and glucocorticoid levels are not different from controls, suggesting that systemic stress is minimal. Unloaded bones display reductions in cancellous osteoblast number, cancellous mineral apposition rate, trabecular bone volume, cortical periosteal mineralization rate, total bone mass, calcium content, and maturation of bone mineral relative to controls. Subsequent studies reveal that these changes also occur in rats exposed to space flight. In hindlimb unloaded rats, bone formation rates and masses of unloaded bones decline relative to controls, while loaded bones do not change despite a transient reduction in serum 1,25-dihydroxyvitamin D (1,25D) concentrations. Studies using the model to evaluate potential countermeasures show that 1,25D, growth hormone, dietary calcium, alendronate, and muscle stimulation modify, but do not completely correct, the suppression of bone growth caused by unloading, whereas continuous infusion of transforming growth factor-beta2 or insulin-like growth factor-1 appears to protect against some of the bone changes caused by unloading. These results emphasize the importance of local as opposed to systemic factors in the skeletal response to unloading, and reveal the pivotal role that osteoblasts play in the response to gravitational loading. The hindlimb unloading model provides a unique opportunity to evaluate in detail the physiological and cellular mechanisms of the skeletal response to weightbearing loads, and has proven to be an effective model for space flight.

Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight

NASA Technical Reports Server (NTRS)

Morey-Holton, E. R.; Globus, R. K.

1998-01-01

A model that uses hindlimb unloading of rats was developed to study the consequences of skeletal unloading and reloading as occurs during and following space flight. Studies using the model were initiated two decades ago and further developed at National Aeronautics and Space Administration (NASA)-Ames Research Center. The model mimics some aspects of exposure to microgravity by removing weightbearing loads from the hindquarters and producing a cephalic fluid shift. Unlike space flight, the forelimbs remain loaded in the model, providing a useful internal control to distinguish between the local and systemic effects of hindlimb unloading. Rats that are hindlimb unloaded by tail traction gain weight at the same rate as pairfed controls, and glucocorticoid levels are not different from controls, suggesting that systemic stress is minimal. Unloaded bones display reductions in cancellous osteoblast number, cancellous mineral apposition rate, trabecular bone volume, cortical periosteal mineralization rate, total bone mass, calcium content, and maturation of bone mineral relative to controls. Subsequent studies reveal that these changes also occur in rats exposed to space flight. In hindlimb unloaded rats, bone formation rates and masses of unloaded bones decline relative to controls, while loaded bones do not change despite a transient reduction in serum 1,25-dihydroxyvitamin D (1,25D) concentrations. Studies using the model to evaluate potential countermeasures show that 1,25D, growth hormone, dietary calcium, alendronate, and muscle stimulation modify, but do not completely correct, the suppression of bone growth caused by unloading, whereas continuous infusion of transforming growth factor-beta2 or insulin-like growth factor-1 appears to protect against some of the bone changes caused by unloading. These results emphasize the importance of local as opposed to systemic factors in the skeletal response to unloading, and reveal the pivotal role that osteoblasts play in the response to gravitational loading. The hindlimb unloading model provides a unique opportunity to evaluate in detail the physiological and cellular mechanisms of the skeletal response to weightbearing loads, and has proven to be an effective model for space flight.

Mandibular Repair in Rats with Premineralized Silk Scaffolds and BMP-2-modified bMSCs

PubMed Central

Jiang, Xinquan; Zhao, Jun; Wang, Shaoyi; Sun, Xiaojuan; Zhang, Xiuli; Chen, Jake; Kaplan, David L.; Zhang, Zhiyuan

2010-01-01

Premineralized silk fibroin protein scaffolds (mSS) were prepared to combine the osteoconductive properties of biological apatite with aqueous-derived silk scaffold (SS) as a composite scaffold for bone regeneration. The aim of present study was to evaluate the effect of premineralized silk scaffolds combined with bone morphogenetic protein-2 (BMP-2) modified bone marrow stromal cells (bMSCs) to repair mandibular bony defects in a rat model. bMSCs were expanded and transduced with adenovirus AdBMP-2, AdLacZ gene in vitro. These genetically modified bMSCs were then combined with premineralized silk scaffolds to form tissue engineered bone. Mandibular repairs with AdBMP-2 transduced bMSCs/mSS constructs were compared with those treated with AdLacZ transduced bMSCs/mSS constructs, native (nontransduced) bMSCs/mSS constructs and mSS alone. Eight weeks post-operation, the mandibles were explanted and evaluated by radiographic observation, micro-CT, histological analysis and immunohistochemistry. The presence of BMP-2 gene enhanced tissue engineered bone in terms of the most new bone formed and the highest local bone mineral densities (BMD) found. These results demonstrated that premineralized silk scaffold could serve as a potential substrate for bMSCs to construct tissue engineered bone for mandibular bony defects. BMP-2 gene therapy and tissue engineering techniques could be used in mandibular repair and bone regeneration. PMID:19501905

A modified fluid percussion device.

PubMed

Yamaki, T; Murakami, N; Iwamoto, Y; Yoshino, E; Nakagawa, Y; Ueda, S; Horikawa, J; Tsujii, T

1994-10-01

This report examines a modified fluid percussion device with specific improvements made to address deficiencies found in previously reported devices. These improvements include the use of a cylindrical saline reservoir made of stainless steel, placement of the reservoir in a 15-degree head-up position for the easy release of air bubbles, placement of the fluid flushing outlet and the pressure transducer close to the piston on the same plane, with both perpendicular to the direction of the piston, and adjustable reservoir volume to vary the waveform of the pressure pulse, and a metallic central injury screw secured to the animal's skull over the exposed dura. Using this device, midline fluid percussion (MFP) and lateral fluid percussion (LFP) injuries were performed in 70 rats. Histopathologic findings included diffuse axonal injury in the MFP model and cortical contusion in the LFP model. Survival rate was 41.4% in MFP animals and 100% in LFM animals when the device settings were 178 mm3 of the cylindrical reservoir and 50 degrees-60 degrees in height of the pendulum. Our results suggest that this modified fluid percussion device may offer significant improvements over previously reported fluid percussion models for use in experimental head injury.

Fetal Alcohol Exposure Reduces Dopamine Receptor D2 and Increases Pituitary Weight and Prolactin Production via Epigenetic Mechanisms

PubMed Central

Gangisetty, Omkaram; Wynne, Olivia; Jabbar, Shaima; Nasello, Cara; Sarkar, Dipak K.

2015-01-01

Recent evidence indicated that alcohol exposure during the fetal period increases the susceptibility to tumor development in mammary and prostate tissues. Whether fetal alcohol exposure increases the susceptibility to prolactin-producing tumor (prolactinoma) development in the pituitary was studied by employing the animal model of estradiol-induced prolactinomas in Fischer 344 female rats. We employed an animal model of fetal alcohol exposure that simulates binge alcohol drinking during the first two trimesters of human pregnancy and involves feeding pregnant rats with a liquid diet containing 6.7% alcohol during gestational day 7 to day 21. Control rats were pair-fed with isocaloric liquid diet or fed ad libitum with rat chow diet. Adult alcohol exposed and control female offspring rats were used in this study on the day of estrus or after estrogen treatment. Results show that fetal alcohol-exposed rats had increased levels of pituitary weight, pituitary prolactin (PRL) protein and mRNA, and plasma PRL. However, these rats show decreased pituitary levels of dopamine D2 receptor (D2R) mRNA and protein and increased pituitary levels of D2R promoter methylation. Also, they show elevated pituitary mRNA levels of DNA methylating genes (DNMT1, DNMT3b, MeCP2) and histone modifying genes (HDAC2, HDAC4, G9a). When fetal alcohol exposed rats were treated neonatally with a DNA methylation inhibitor 5-Aza deoxycytidine and/or a HDAC inhibitor trichostatin-A their pituitary D2R mRNA, pituitary weights and plasma PRL levels were normalized. These data suggest that fetal alcohol exposure programs the pituitary to increase the susceptibility to the development of prolactinomas possibly by enhancing the methylation of the D2R gene promoter and repressing the synthesis and control of D2R on PRL-producing cells. PMID:26509893

Evaluating Intra-Articular Drug Delivery for the Treatment of Osteoarthritis in a Rat Model

PubMed Central

Allen, Kyle D.; Adams, Samuel B.

2010-01-01

Osteoarthritis (OA) is a degenerative joint disease that can result in joint pain, loss of joint function, and deleterious effects on activity levels and lifestyle habits. Current therapies for OA are largely aimed at symptomatic relief and may have limited effects on the underlying cascade of joint degradation. Local drug delivery strategies may provide for the development of more successful OA treatment outcomes that have potential to reduce local joint inflammation, reduce joint destruction, offer pain relief, and restore patient activity levels and joint function. As increasing interest turns toward intra-articular drug delivery routes, parallel interest has emerged in evaluating drug biodistribution, safety, and efficacy in preclinical models. Rodent models provide major advantages for the development of drug delivery strategies, chiefly because of lower cost, successful replication of human OA-like characteristics, rapid disease development, and small joint volumes that enable use of lower total drug amounts during protocol development. These models, however, also offer the potential to investigate the therapeutic effects of local drug therapy on animal behavior, including pain sensitivity thresholds and locomotion characteristics. Herein, we describe a translational paradigm for the evaluation of an intra-articular drug delivery strategy in a rat OA model. This model, a rat interleukin-1β overexpression model, offers the ability to evaluate anti-interleukin-1 therapeutics for drug biodistribution, activity, and safety as well as the therapeutic relief of disease symptoms. Once the action against interleukin-1 is confirmed in vivo, the newly developed anti-inflammatory drug can be evaluated for evidence of disease-modifying effects in more complex preclinical models. PMID:19943805

Improved Butanol-Methanol (BUME) Method by Replacing Acetic Acid for Lipid Extraction of Biological Samples.

PubMed

Cruz, Mutya; Wang, Miao; Frisch-Daiello, Jessica; Han, Xianlin

2016-07-01

Extraction of lipids from biological samples is a critical step in lipidomics, especially for shotgun lipidomics where lipid extracts are directly infused into a mass spectrometer. The butanol-methanol (BUME) extraction method was originally developed to extract lipids from plasma samples with 1 % acetic acid. Considering some lipids are sensitive to acidic environments, we modified this protocol by replacing acetic acid with lithium chloride solution and extended the modified extraction to tissue samples. Although no significant reduction of plasmalogen levels in the acidic BUME extracts of rat heart samples was found, the modified method was established to extract various tissue samples, including rat liver, heart, and plasma. Essentially identical profiles of the majority of lipid classes were obtained from the extracts of the modified BUME and traditional Bligh-Dyer methods. However, it was found that neither the original, nor the modified BUME method was suitable for 4-hydroxyalkenal species measurement in biological samples.

Improved Butanol-Methanol (BUME) Method by Replacing Acetic Acid for Lipid Extraction of Biological Samples

PubMed Central

Cruz, Mutya; Wang, Miao; Frisch-Daiello, Jessica; Han, Xianlin

2016-01-01

Extraction of lipids from biological samples is a critical step in lipidomics, especially for shotgun lipidomics where lipid extracts are directly infused into a mass spectrometer. The butanol-methanol (BUME) extraction method was originally developed to extract lipids from plasma samples with 1% acetic acid. Considering some lipids are sensitive to acidic environments, we modified this protocol by replacing acetic acid with lithium chloride solution and extended the modified extraction to tissue samples. Although no significant reduction of plasmalogen levels in the acidic BUME extracts of rat heart samples was found, the modified method was established to extract various tissue samples, including rat liver, heart, and plasma. Essentially identical profiles of the majority of lipid classes were obtained from the extracts of the modified BUME and traditional Bligh-Dyer methods. However, it was found that neither the original, nor the modified BUME method was suitable for 4-hydroxyalkenal species measurement in biological samples. PMID:27245345

HEMORHEOLOGY INDEX CHANGES IN A RAT ACUTE BLOOD STASIS MODEL: A SYSTEMATIC REVIEW AND META-ANALYSIS

PubMed Central

Zhang, Jun-Xiu; Feng, Yu; Zhang, Yin; Liu, Yi; Li, Shao-Dan; Yang, Ming-Hui

2017-01-01

Background: Blood stasis has received increasing attention in research related to traditional Chinese medicine (TCM) and integrative Chinese and Western medicine. More than 90% of research studies use hemorheology indexes to evaluate the establishment of animal blood stasis models rather than pathological methods, as hemorheology index evaluations of blood stasis were short of the consolidated standard. The aim of this study was to evaluate the accuracy of hemorheology indexes in rat models of acute blood stasis (ABS) based on studies in which the ABS model had been confirmed by pathological methods. Materials and Methods: We searched the Chinese National Knowledge Infrastructure database (CNKI), Chinese Medical Journal Database (CMJD), Chinese Biology Medicine disc (CBM), Wanfang database, and PubMed for studies of rat blood stasis models; the search identified 18 studies of rat ABS models induced by subcutaneous injection of epinephrine combined with an ice bath. Each included study received a modified Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) score list and methodological quality assessment, then data related to whole blood viscosity, plasma viscosity, platelet aggregation rate, erythrocyte aggregation index, and fibrinogen concentration were extracted. Extracted data were analyzed using Revman 5.3; heterogeneity was tested using Egger’s test. Results: A total of 343 studies of rat blood stasis were reviewed. Eighteen studies were included in this meta-analysis; the mean CAMARADES score was 3.5. The rat ABS model revealed a significant increase in whole blood viscosity (medium shear rate), whole blood viscosity (high shear rate), plasma viscosity, platelet aggregation rate, erythrocyte aggregation index, and fibrinogen concentration compared to controls, with weighted mean differences (WMD) of 2.42 mPa/s (95% confidence interval (CI) = 1.73 - 3.10); 1.76 mPa/s (95% CI = 1.28 - 2.24); 0.39 mPa/s (95% CI = 0.24 - 0.55); 13.66% (95% CI = 9.78 - 17.55); 0.84 (95% CI = 0.53 - 1.16); and 1.22 g/L (95% CI = 0.76 - 1.67), respectively. Subgroup analysis showed that whole blood viscosity, plasma viscosity, and the platelet aggregation rate test methods were more sensitive when measured at 0-24 h than at 24-72 h after induction of blood stasis. Conclusions: Rat blood stasis studies have incomplete experimental design and quality controls, and thus need an integrated improvement. Meta-analysis of included studies indicated that the unified hemorheology index of whole blood viscosity (medium and high shear rate), platelet aggregation rate, erythrocyte aggregation rate, and fibrinogen concentration might be used for assessment of rat ABS models independent of pathology methods. PMID:28638872

Medical ozone therapy reduces oxidative stress and testicular damage in an experimental model of testicular torsion in rats.

PubMed

Tusat, Mustafa; Mentese, Ahmet; Demir, Selim; Alver, Ahmet; Imamoglu, Mustafa

2017-01-01

Testicular torsion (TT) refers to rotation of the testis and twisting of the spermatic cord. TT results in ischemia-reperfusion (I/R) injury involving increased oxidative stress, inflammation and apoptosis, and can even lead to infertility. The aim of this study was to investigate the effect of ozone therapy on testicular damage due to I/R injury in an experimental torsion model. 24 male Sprague-Dawley rats were divided into 3 groups; sham-operated, torsion/detorsion (T/D), and T/D+ozone. Ozone (1mg/kg) was injected intraperi-toneally 120 minutes before detorsion and for the following 24h. Blood and tissue samples were collected at the end of 24h. Johnsen score, ischemia modified albumin (IMA), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels were determined. Levels of IMA, TOS, OSI, and histopathological scores increased in the serum/tissue of the rats in the experimental T/D group. Serum IMA, TOS, and OSI levels and tissue histo-pathological scores were lower in the rats treated with ozone compared with the T/D group. Our study results suggest that ozone therapy may exhibit beneficial effects on both biochemical and histopathological findings. Clinical trials are now necessary to confirm this. Copyright® by the International Brazilian Journal of Urology.

Site-dependent modulating effects of conjugated fatty acids from safflower oil in a rat two-stage carcinogenesis model in female Sprague-Dawley rats.

PubMed

Kimoto, N; Hirose, M; Futakuchi, M; Iwata, T; Kasai, M; Shirai, T

2001-07-10

Modifying effects of dietary administration of conjugated fatty acids from safflower oil (CFA-S), rich in conjugated linoleic acid, on major organs were examined in the post-initiation stage of a two-stage carcinogenesis model in female rats. Groups of 21 or 22 F344 female rats were treated sequentially with 2,2'-dihydroxy-di-n-propylnitosamine (intragastrically, i.g.), 7,12-dimethylbenz[a]anthracene (i.g.), 1,2-dimethylhydrazine (subcutaneously) and N-butyl-N-(4-hydroxybutyl)nitrosamine (in drinking water) during the first 3 weeks for initiation, and then administered diet containing 1 or 0.1% CFA-S for 33 weeks. Further groups of animals were treated with carcinogens or 1% CFA-S alone, or maintained as non-treated controls. All surviving animals were killed at week 36, and major organs were examined histopathologically for development of pre-neoplastic and neoplastic lesions. The 1 and 0.1% CFA-S treatment significantly decreased the incidence and multiplicity of mammary carcinomas, though a clear dose response was not observed. In the urinary bladder, the incidence of papillary or nodular hyperplasia but not tumors was significantly increased in the 1% CFA-S-treated group. The results indicate that low dose CFA-S may find application as a potent chemopreventor of mammary carcinogenesis.

Amelioration of collagen-induced arthritis using antigen-loaded dendritic cells modified with NF-κB decoy oligodeoxynucleotides

PubMed Central

Jiang, Hongmei; Hu, Henggui; Zhang, Yali; Yue, Ping; Ning, Lichang; Zhou, Yan; Shi, Ping; Yuan, Rui

2017-01-01

Dendritic cells (DCs) play an important role in the initiation of autoimmunity in rheumatoid arthritis (RA); therefore, the use of DCs needs to be explored to develop new therapeutic approaches for RA. Here, we investigated the therapeutic effect of bovine type II collagen (BIIC)-loaded DCs modified with NF-κB decoy oligodeoxynucleotides (ODNs) on collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms. DCs treated with BIIC and NF-κB decoy ODNs exhibited features of immature DCs with low levels of costimulatory molecule (CD80 and CD86) expression. The development of arthritis in rats with CIA injected with BIIC + NF-κB decoy ODN-propagated DCs (BIIC–decoy DCs) was significantly ameliorated compared to that in rats injected with BIIC-propagated DCs or phosphate-buffered saline. We also found that the BIIC–decoy DCs exerted antiarthritis effects by inhibiting self-lymphocyte proliferative response and suppressing IFN-γ and anti-BIIC antibody production and inducing IL-10 antibody production. Additionally, antihuman serum antibodies were successfully produced in the rats treated with BIIC–decoy DCs but not in those treated with NF-κB decoy ODN-propagated DCs; moreover, the BIIC–decoy DCs did not affect immune function in the normal rats. These findings suggested that NF-κB decoy ODN-modified DCs loaded with a specific antigen might offer a practical method for the treatment of human RA. PMID:29075103

Association of brominated proteins and changes in protein expression in the rat kidney with subcarcinogenic to carcinogenic doses of bromate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kolisetty, Narendrababu; Bull, Richard J.; Muralidhara, Srinivasa

2013-10-15

The water disinfection byproduct bromate (BrO{sub 3}{sup −}) produces cytotoxic and carcinogenic effects in rat kidneys. Our previous studies demonstrated that BrO{sub 3}{sup −} caused sex-dependent differences in renal gene and protein expression in rats and the elimination of brominated organic carbon in their urine. The present study examined changes in renal cell apoptosis and protein expression in male and female F344 rats treated with BrO{sub 3}{sup −} and associated these changes with accumulation of 3-bromotyrosine (3-BT)-modified proteins. Rats were treated with 0, 11.5, 46 and 308 mg/L BrO{sub 3}{sup −} in drinking water for 28 days and renal sectionsmore » were prepared and examined for apoptosis (TUNEL-staining), 8-oxo-deoxyguanosine (8-oxoG), 3-BT, osteopontin, Kim-1, clusterin, and p-21 expression. TUNEL-staining in renal proximal tubules increased in a dose-related manner beginning at 11.5 mg BrO{sub 3}{sup −}/L in female rats and 46 mg/L in males. Increased 8-oxoG staining was observed at doses as low as 46 mg/L. Osteopontin expression also increased in a dose-related manner after treatment with 46 mg/L, in males only. In contrast, Kim-1 expression increased in a dose-related manner in both sexes, although to a greater extent in females at the highest dose. Clusterin and p21 expression also increased in a dose-related manner in both sexes. The expression of 3-BT-modified proteins only increased in male rats, following a pattern previously reported for accumulation of α-2{sub u}-globulin. Increases in apoptosis in renal proximal tubules of male and female rats at the lowest doses suggest a common mode of action for renal carcinogenesis for the two sexes that is independent of α-2{sub u}-globulin nephropathy. - Highlights: • Bromate induced nephrotoxicity in both male and female rats by similar mechanisms. • Apoptosis was seen in both male and female rats at the lowest doses tested. • Bromate-induced apoptosis correlated to 8-oxo-deoxyguanosine formation. • Bromate increased the level of 3-bromotyrosine-modified proteins in male rats only. • These data identify possible novel mechanisms for bromate-induced nephrotoxicity.« less

Prenatal stress increases the obesogenic effects of a high-fat-sucrose diet in adult rats in a sex-specific manner.

PubMed

Paternain, L; de la Garza, A L; Batlle, M A; Milagro, F I; Martínez, J A; Campión, J

2013-03-01

Stress during pregnancy can induce metabolic disorders in adult offspring. To analyze the possible differential response to a high-fat-sucrose (HFS) diet in offspring affected by prenatal stress (PNS) or not, pregnant Wistar rats (n = 11) were exposed to a chronic mild stress during the third week of gestation. The aim of this study was to model a chronic depressive-like state that develops over time in response to exposure of rats to a series of mild and unpredictable stressors. Control dams (n = 11) remained undisturbed. Adult offspring were fed chow or HFS diet (20% protein, 35% carbohydrate, 45% fat) for 10 weeks. Changes in adiposity, biochemical profile, and retroperitoneal adipose tissue gene expression by real-time polymerase chain reaction were analyzed. An interaction was observed between HFS and PNS concerning visceral adiposity, with higher fat mass in HFS-fed stressed rats, statistically significant only in females. HFS modified lipid profile and increased insulin resistance biomarkers, while PNS reduced insulin concentrations and the homeostasis model assessment index. HFS diet increased gene (mRNA) expression for leptin and apelin and decreased cyclin-dependent kinase inhibitor 1A and fatty acid synthase (Fasn), whereas PNS increased Fasn and stearoyl-CoA desaturase1. An interaction between diet and PNS was observed for adiponutrin (Adpn) and peroxisome proliferator-activated receptor-γ coactivator1-α (Ppargc1a) gene expression: Adpn was increased by the PNS only in HFS-fed rats, whereas Ppargc1a was increased by the PNS only in chow-fed rats. From these results, it can be concluded that experience of maternal stress during intrauterine development can enhance predisposition to obesity induced by a HFS diet intake.

Very-early-strength latex-modified concrete overlay.

DOT National Transportation Integrated Search

1998-12-01

This paper describes the installation and condition of the first two very-early-strength latex modified concrete (LMC-VE) overlays constructed for the Virginia Department of Transportation. The overlays were prepared with a special blended cement rat...

Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.

PubMed

Das, Melanie M; Avalos, Pablo; Suezaki, Patrick; Godoy, Marlesa; Garcia, Leslie; Chang, Christine D; Vit, Jean-Philippe; Shelley, Brandon; Gowing, Genevieve; Svendsen, Clive N

2016-06-01

Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population. Copyright © 2016 Elsevier Inc. All rights reserved.

Transplantation of dedifferentiated fat cell-derived micromass pellets contributed to cartilage repair in the rat osteochondral defect model.

PubMed

Shimizu, Manabu; Matsumoto, Taro; Kikuta, Shinsuke; Ohtaki, Munenori; Kano, Koichiro; Taniguchi, Hiroaki; Saito, Shu; Nagaoka, Masahiro; Tokuhashi, Yasuaki

2018-03-20

Mature adipocyte-derived dedifferentiated fat (DFAT) cells possesses the ability to proliferate effectively and the potential to differentiate into multiple linages of mesenchymal tissue; similar to adipose-derived stem cells (ASCs). The purpose of this study is to examine the effects of DFAT cell transplantation on cartilage repair in a rat model of osteochondral defects. Full-thickness osteochondral defects were created in the knees of Sprague-Dawley rats bilaterally. Cartilage-like micromass pellets were prepared from green fluorescent protein (GFP)-labeled rat DFAT cells and subsequently transplanted into the affected right knee of these rats. Defects in the left knee were used as a control. Macroscopic and microscopic changes of treated and control defects were evaluated up to 12 weeks post-treatment with DFAT cells. To observe the transplanted cells, sectioned femurs were immunostained for GFP and type II collagen. DFAT cells formed micromass pellets expressing characteristics of immature cartilage in vitro. In the DFAT cell-transplanted limbs, the defects were completely filled with white micromass pellets as early as 2 weeks post-treatment. These limbs became smooth at 4 weeks. Conversely, the defects in the control limbs were still not repaired by 4 weeks. Macroscopic ICRS scores at 2 and 4 weeks were significantly higher in the DFAT cells-transplanted limbs compared to those of the control limbs. The modified O'Driscol histological scores for the DFAT cell-transplanted limbs were significantly higher than those of the control limbs at corresponding time points. GFP-positive DAFT cells were detected in the transplanted area at 2 weeks but hardly visible at 12 weeks post-operation. Transplantation of DFAT cell-derived micromass pellets contribute to cartilage repair in a rat osteochondral defect model. DFAT cell transplantation may be a viable therapeutic strategy for the repair of osteochondral injuries. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Human Hepatocyte Growth Factor (hHGF)-Modified Hepatic Oval Cells Improve Liver Transplant Survival

PubMed Central

Li, Li; Ran, Jiang-Hua; Li, Xue-Hua; Liu, Zhi-Heng; Liu, Gui-Jie; Gao, Yan-Chao; Zhang, Xue-Li; Sun, Hiu-Dong

2012-01-01

Despite progress in the field of immunosuppression, acute rejection is still a common postoperative complication following liver transplantation. This study aims to investigate the capacity of the human hepatocyte growth factor (hHGF) in modifying hepatic oval cells (HOCs) administered simultaneously with orthotopic liver transplantation as a means of improving graft survival. HOCs were activated and isolated using a modified 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model in male Lewis rats. A HOC line stably expressing the HGF gene was established following stable transfection of the pBLAST2-hHGF plasmid. Our results demonstrated that hHGF-modified HOCs could efficiently differentiate into hepatocytes and bile duct epithelial cells in vitro. Administration of HOCs at the time of liver transplantation induced a wider distribution of SRY-positive donor cells in liver tissues. Administration of hHGF-HOC at the time of transplantation remarkably prolonged the median survival time and improved liver function for recipients compared to these parameters in the other treatment groups (P<0.05). Moreover, hHGF-HOC administration at the time of liver transplantation significantly suppressed elevation of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) levels while increasing the production of IL-10 and TGF-β1 (P<0.05). HOC or hHGF-HOC administration promoted cell proliferation, reduced cell apoptosis, and decreased liver allograft rejection rates. Furthermore, hHGF-modified HOCs more efficiently reduced acute allograft rejection (P<0.05 versus HOC transplantation only). Our results indicate that the combination of hHGF-modified HOCs with liver transplantation decreased host anti-graft immune responses resulting in a reduction of allograft rejection rates and prolonging graft survival in recipient rats. This suggests that HOC-based cell transplantation therapies can be developed as a means of treating severe liver injuries. PMID:23028627

Brain maps 4.0—Structure of the rat brain: An open access atlas with global nervous system nomenclature ontology and flatmaps

PubMed Central

2018-01-01

Abstract The fourth edition (following editions in 1992, 1998, 2004) of Brain maps: structure of the rat brain is presented here as an open access internet resource for the neuroscience community. One new feature is a set of 10 hierarchical nomenclature tables that define and describe all parts of the rat nervous system within the framework of a strictly topographic system devised previously for the human nervous system. These tables constitute a global ontology for knowledge management systems dealing with neural circuitry. A second new feature is an aligned atlas of bilateral flatmaps illustrating rat nervous system development from the neural plate stage to the adult stage, where most gray matter regions, white matter tracts, ganglia, and nerves listed in the nomenclature tables are illustrated schematically. These flatmaps are convenient for future development of online applications analogous to “Google Maps” for systems neuroscience. The third new feature is a completely revised Atlas of the rat brain in spatially aligned transverse sections that can serve as a framework for 3‐D modeling. Atlas parcellation is little changed from the preceding edition, but the nomenclature for rat is now aligned with an emerging panmammalian neuroanatomical nomenclature. All figures are presented in Adobe Illustrator vector graphics format that can be manipulated, modified, and resized as desired, and freely used with a Creative Commons license. PMID:29277900

Flavanol plasma bioavailability is affected by metabolic syndrome in rats.

PubMed

Margalef, Maria; Pons, Zara; Iglesias-Carres, Lisard; Bravo, Francisca Isabel; Muguerza, Begoña; Arola-Arnal, Anna

2017-09-15

Flavanols, which exert several health benefits, are metabolized after ingestion. Factors such as the host physiological condition could affect the metabolism and bioavailability of flavanols, influencing their bioactivities. This study aimed to qualitatively evaluate whether a pathological state influenced flavanol plasma bioavailability. Standard and cafeteria (CAF) diet fed rats, a robust model of metabolic syndrome (MeS), were administered 1000mg/kg of flavanol enriched grape seed polyphenol extract (GSPE). Flavanols and their metabolites were quantified by HPLC-MS/MS in plasma before and at 2, 4, 7, 24, and 48h after GSPE ingestion. Results showed that in CAF administered rats the maximum time of plasma flavanol concentration was delayed and these animals presented higher levels of plasma phase-II metabolites as well as altered microbial metabolites. In conclusion, this study demonstrated that MeS pathological state modified flavanol bioavailability, supporting the hypothesis that flavanol metabolism, and therefore flavanol functionality, depend on the organism's state of health. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of a Theoretical Model to Assess the Hepatocarcinogenic Potential of Chemicals Using Structure-Activity Relationships and the Rat Hepatocyte Assay

DTIC Science & Technology

1985-11-01

Kappus ,19a5; Tyson and Green, in press). When ethane evolution was quantitated, the experimental conditions were modified to maximize sensitivity, as...commonly used and convenient technique for tVat purpose ( Kappus , 1985). Since MDA, the lipid breakdown product that the TBA reaction primarily...cytcchrome P-450(c) reductase. Mol. Pharmacol. 20, 669-673 (1981). Kappus , H. (1985). Lipid peroxidatioa: mechanisms, analysis, enzymology and

Estrous cycle and ovarian changes in a rat mammary carcinogenesis model after irradiation, tamoxifen chemoprevention, and aging.

PubMed

Karim, Baktiar O; Landolfi, Jennifer A; Christian, Archie; Ricart-Arbona, Rodolfo; Qiu, Weiping; McAlonis, Melissa; Eyabi, Paul O; Khan, Khalid A; Dicello, John F; Mann, Jill F; Huso, David L

2003-10-01

Variation in the effects of selective estrogen receptor modulators (SERMs) on the estrous cycle and reproductive organs during aging could play an important role in the observed heterogeneity of tamoxifen chemoprevention efficacy against breast cancer. Of the 1,022 female Sprague Dawley rats enrolled in a long-term tamoxifen chemoprevention study, 87 were randomly chosen from four groups (irradiated, irradiated and tamoxifen treated, tamoxifen treated, and control). Vaginal smears were evaluated for determination of cycle stage, and vaginal pathologic changes. Correlation with the histologic features of reproductive tissues in 43 animals was made. More tamoxifen-treated (21.9%; 7/32) rats had irregular cycling than did control (9%; 3/23) rats. Ovarian granulosa cell hyperplasia was present in 50% (3/6) of tamoxifen-treated rats, and 20% (2/10) of control rats. Endometrial-type cells (ETCs) were present only in tamoxifen-treated (tamoxifen alone 6.25% [2/32]) and tamoxifen/ radiation-treated (28.6% [4/14]) rats. The modified Papanicolaou stain used here provided excellent morphologic detail for evaluating the estrous cycle in rodents. Tamoxifen altered vaginal cytologic and ovarian histologic features during aging. Results indicated that tamoxifen had direct and indirect effects on the reproductive tract, causing disturbance of the estrous cycle, shedding of ETCs, and promoting granulosa cell hyperplasia. Understanding of the heterogeneous response to tamoxifen chemoprevention during aging in rodents may provide important insights into the basis for tamoxifen chemoprevention failures in humans.

Studies on the role of serotonin receptor subtypes in the effect of sibutramine in various feeding paradigms in rats

PubMed Central

Grignaschi, G; Fanelli, E; Scagnol, I; Samanin, R

1999-01-01

The effect of the 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake inhibitor sibutramine was studied in food deprived, neuropeptide Y (NPY)- or muscimol-injected rats. Sibutramine dose-dependently reduced feeding caused by food-deprivation (ED50=5.1±0.8 mg kg−1) or by NPY injection into the paraventricular nucleus of the hypothalamus (ED50=6.0±0.5 mg kg−1). The increase in food intake caused by muscimol injected into the dorsal raphe was not modified by sibutramine (1–10 mg kg−1). The hypophagic effect of 5.1 mg kg−1 sibutramine in food-deprived rats was studied in rats pretreated with different serotonin receptor antagonists. Metergoline (non-selective, 0.3 and 1.0 mg kg−1), ritanserin (5-HT2A/2C, 0.5 and 1.0 mg kg−1) and GR127935 (5-HT1B/1D, 0.5 and 1.0 mg kg−1) did not modify the hypophagic effect of sibutramine, while SB206553 (5-HT2B/2C, 5 and 10 mg kg−1) slightly but significantly reduced it (Fint(2.53)=3.4; P<0.05). The reduction in food intake caused by 6.0 mg kg−1 sibutramine in NPY-injected rats was not modified by GR127935 (1.0 mg kg−1). The results suggest that, with the possible exception of a partial involvement of 5-HT2B/2C receptors in sibutramine's hypophagia in food-deprived rats, 5-HT1 and 5-HT2 receptor subtypes do not play an important role in the hypophagic effect of sibutramine, at least in the first 2 h after injection. PMID:10455265

Rapeseed oil-rich diet alters in vitro menadione and nimesulide hepatic mitochondrial toxicity.

PubMed

Monteiro, João P; Silva, Ana M; Jurado, Amália S; Oliveira, Paulo J

2013-10-01

Diet-induced changes in the lipid composition of mitochondrial membranes have been shown to influence physiological processes. However, the modulation effect of diet on mitochondrially-active drugs has not yet received the deserved attention. Our hypothesis is that modulation of membrane dynamics by diet impacts drug-effects on liver mitochondrial functioning. In a previous work, we have shown that a diet rich in rapeseed oil altered mitochondrial membrane composition and bioenergetics in Wistar rats. In the present work, we investigated the influence of the modified diet on hepatic mitochondrial activity of two drugs, menadione and nimesulide, and FCCP, a classic protonophore, was used for comparison. The results showed that the effects of menadione and nimesulide were less severe on liver mitochondria for rats fed the modified diet than on rats fed the control diet. A specific effect on complex I seemed to be involved in drug-induced mitochondria dysfunction. Liver mitochondria from the modified diet group were more susceptible to nimesulide effects on MPT induction. The present work demonstrates that diet manipulation aimed at modifying mitochondrial membrane properties alters the toxicity of mitochondria active agents. This work highlights that diet may potentiate mitochondrial pharmacologic effects or increase drug-induced liabilities. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nopal (Opuntia ficus indica) protects from metabolic endotoxemia by modifying gut microbiota in obese rats fed high fat/sucrose diet.

PubMed

Sánchez-Tapia, Mónica; Aguilar-López, Miriam; Pérez-Cruz, Claudia; Pichardo-Ontiveros, Edgar; Wang, Mei; Donovan, Sharon M; Tovar, Armando R; Torres, Nimbe

2017-07-05

Current efforts are directed to reducing the gut dysbiosis and inflammation produced by obesity. The purpose of this study was to investigate whether consuming nopal, a vegetable rich in dietary fibre, vitamin C, and polyphenols can reduce the metabolic consequences of obesity by modifying the gut microbiota and preventing metabolic endotoxemia in rats fed a high fat and sucrose diet. With this aim, rats were fed a high fat diet with 5% sucrose in the drinking water (HFS) for 7 months and then were fed for 1 month with HFS + 5% nopal (HFS + N). The composition of gut microbiota was assessed by sequencing the 16S rRNA gene. Nopal modified gut microbiota and increased intestinal occludin-1 in the HFS + N group. This was associated with a decrease in metabolic endotoxemia, glucose insulinotropic peptide, glucose intolerance, lipogenesis, and metabolic inflexibility. These changes were accompanied by reduced hepatic steatosis and oxidative stress in adipose tissue and brain, and improved cognitive function, associated with an increase in B. fragilis. This study supports the use of nopal as a functional food and prebiotic for its ability to modify gut microbiota and to reduce metabolic endotoxemia and other obesity-related biochemical abnormalities.

Improved outcome of Trypanosoma cruzi infection in rats following treatment in early life with suspensions of heat-killed environmental Actinomycetales.

PubMed

Fontanella, G H; Pascutti, M F; Daurelio, L; Perez, A R; Nocito, A L; Wojdyla, D; Bottasso, O; Revelli, S S; Stanford, J L

2007-04-30

The well-established model of Chagas' disease in "l" rats was used to evaluate the effects of three injections of heat-killed Gordonia bronchialis, Rhodococcus coprophilus or saline on Trypanosoma cruzi parasitaemia and acute and chronic myocarditis, sequelae of the infection. Two vaccinating injections were given prior to challenge with T. cruzi, and the third, immunotherapeutic, injection was given 7 days after challenge. Treatment with either actinomycete significantly reduced acute parasitaemia (p<0.04), modified cellular infiltration during acute myocarditis and limited chronic myocarditis (p<0.03) in comparison with the saline-treated control animals. Immunological investigations showed that both bacterial preparations achieved their results through different mechanisms. The relevance of our findings to human Chagas' disease is discussed.

Prophylactic effects of swimming exercise on autophagy-induced muscle atrophy in diabetic rats

PubMed Central

Lee, Youngjeon; Kim, Joo-Heon; Hong, Yunkyung; Lee, Sang-Rae; Chang, Kyu-Tae

2012-01-01

Diabetes decreases skeletal muscle mass and induces atrophy. However, the mechanisms by which hyperglycemia and insulin deficiency modify muscle mass are not well defined. In this study, we evaluated the effects of swimming exercise on muscle mass and intracellular protein degradation in diabetic rats, and proposed that autophagy inhibition induced by swimming exercise serves as a hypercatabolic mechanism in the skeletal muscles of diabetic rats, supporting a notion that swimming exercise could efficiently reverse the reduced skeletal muscle mass caused by diabetes. Adult male Sprague-Dawley rats were injected intraperitoneally with streptozotocin (60 mg/kg body weight) to induce diabetes and then submitted to 1 hr per day of forced swimming exercise, 5 days per week for 4 weeks. We conducted an intraperitoneal glucose tolerance test on the animals and measured body weight, skeletal muscle mass, and protein degradation and examined the level of autophagy in the isolated extensor digitorum longus, plantaris, and soleus muscles. Body weight and muscle tissue mass were higher in the exercising diabetic rats than in control diabetic rats that remained sedentary. Compared to control rats, exercising diabetic rats had lower blood glucose levels, increased intracellular contractile protein expression, and decreased autophagic protein expression. We conclude that swimming exercise improves muscle mass in diabetes-induced skeletal muscle atrophy, suggesting the activation of autophagy in diabetes contributes to muscle atrophy through hypercatabolic metabolism and that aerobic exercise, by suppressing autophagy, may modify or reverse skeletal muscle wasting in diabetic patients. PMID:23091517

Antagonism of specific corticotropin-releasing factor receptor subtypes selectively modifies weight loss in restrained rats.

PubMed

Chotiwat, Christina; Harris, Ruth B S

2008-12-01

Rats exposed to 3 h of restraint stress on each of 3 days (RRS) lose weight on the days of RRS and gain weight at the same rate as controls after stress ends, but do not return to the weight of controls. RRS rats also show an exaggerated endocrine response to subsequent novel stressors. Studies described here tested the effects of corticotropin-releasing factor receptor (CRFR) antagonism on RRS-induced weight loss, hypophagia, and corticosterone release during mild stress in the postrestraint period. Weight loss was not prevented by either peripheral or third-ventricle administration of a CRFR1 antagonist, antalarmin, before each restraint. Antalarmin did, however, allow recovery of body weight in the poststress period. Third-ventricle administration of a CRFR2 antagonist, antisauvagine 30, had no effect in RRS rats but caused sustained weight loss in control animals. Surprisingly, third-ventricle administration of the nonselective CRFR antagonist, astressin, caused hypophagia and reversible weight loss in control rats. It had no effect in RRS rats. None of the antagonists modified the corticosterone response to RRS or to mild stress in the post-RRS period, but antalarmin suppressed corticosterone during the period of restraint in Control rats. These results suggest that CRFR1 activation is required for the initiation of events that lead to a prolonged down-regulation of body weight in RRS rats. The sustained reduction in body weight is independent of the severity of hypophagia on the days of restraint and of RRS-induced corticosterone release.

Behavioral and neurophysiological correlates of regret in rat decision-making on a neuroeconomic task

PubMed Central

Steiner, Adam P.; Redish, A. David

2014-01-01

Summary Disappointment entails the recognition that one did not get the value one expected. In contrast, regret entails the recognition that an alternate (counterfactual) action would have produced a more valued outcome. Thus, the key to identifying regret is the representation of that counterfactual option in situations in which a mistake has been made. In humans, the orbitofrontal cortex is active during expressions of regret, and humans with damage to the orbitofrontal cortex do not express regret. In rats and non-human primates, both the orbitofrontal cortex and the ventral striatum have been implicated in decision-making, particularly in representations of expectations of reward. In order to examine representations of regretful situations, we recorded neural ensembles from orbitofrontal cortex and ventral striatum in rats encountering a spatial sequence of wait/skip choices for delayed delivery of different food flavors. We were able to measure preferences using an economic framework. Rats occasionally skipped low-cost choices and then encountered a high-cost choice. This sequence economically defines a potential regret-inducing instance. In these situations, rats looked backwards towards the lost option, the cells within the orbitofrontal cortex and ventral striatum represented that missed action, rats were more likely to wait for the long delay, and rats rushed through eating the food after that delay. That these situations drove rats to modify their behavior suggests that regret-like processes modify decision-making in non-human mammals. PMID:24908102

The Effects of Cache Modification on Food Caching and Retrieval Behavior by Rats

ERIC Educational Resources Information Center

McKenzie, T.L.B.; Bird, L.R.; Roberts, W.A.

2005-01-01

Rats cached pieces of cheese on four different arms of an eight-arm radial maze. On a retrieval test given 45min later, rats learned to return to arms where food was cached before arms where food had not been cached. Tests were then performed in which cache sites on one side of the maze were always modified (pilfered or degraded), but cache sites…

Doxorubicin coupled to lactosaminated albumin: Effects on rats with liver fibrosis and cirrhosis.

PubMed

Di Stefano, G; Fiume, L; Domenicali, M; Busi, C; Chieco, P; Kratz, F; Lanza, M; Mattioli, A; Pariali, M; Bernardi, M

2006-06-01

The conjugate of doxorubicin with lactosaminated human albumin has the potential of increasing the doxorubicin efficacy in the treatment of hepatocellular carcinomas expressing the asialoglycoprotein receptor. However, coupled doxorubicin also accumulates in the liver, which might damage hepatocytes. To verify whether coupled doxorubicin impairs liver function in rats with liver fibrosis and cirrhosis. Coupled doxorubicin was administered using the same schedule which exerted an antineoplastic effect on rat hepatocellular carcinomas (4-weekly injections of doxorubicin at 1 microg/g). Liver fibrosis/cirrhosis was produced by carbon tetrachloride (CCl4) poisoning. Liver samples were studied histologically. Serum parameters of liver function and viability were determined. In normal rats, administration of coupled doxorubicin neither caused microscopic changes of hepatocytes nor modified serum liver parameters. In rats with fibrosis/cirrhosis, although a selective doxorubicin accumulation within the liver followed coupled doxorubicin administration, the drug did not have a detrimental effect on the histology of the liver and, among serum liver tests, only alanine aminotransferase and aspartate aminotransferase levels were moderately modified. Coupled doxorubicin can be administered to rats with liver fibrosis/cirrhosis without inducing a severe liver damage. If further studies will confirm the efficacy and safety of this compound, coupled doxorubicin therapy may open a new perspective in the treatment of hepatocellular carcinoma.

[Effect of Electroacupuncture on Expression of Cortical srGAP 1 and Cdc 42 in Rats with Focal Cerebral Infarction].

PubMed

Dai, En-ze; Long, Fei; Gong, Biao; Guo, Quan-hu; Wang, Ying; Zeng, Zhi-hua

2015-06-01

To observe the effect of electroacupuncture (EA) intervention on the neurological function and the expression change of Slit-Robo GTPase-activating protein-1 (srGAP 1) and cell division-cycle 42 (Cdc 42) in the cortex of rats with cerebral ischemic injury (CIRI) , so as to explore the mechanism of EA in the management of cerebral infarction. A total of 48 male Sprague Dawley (SD) rats were randomly and equally divided into control, model, non-acupoint EA and EA groups (n = 12/group). The CIRI model was established based on the modified Zea Longa method. EA intervention was applied for 30 min, once a day for 14 days. Modified neurologic severity scores (mNSS) were assessed on day 1,3,7 and 14 after mode- ling. Immunofluorescence assay was used to detect the immunoactivity and distribution of srGAP 1 and Cdc 42 in the cortical ischemic region. Western blot was employed to detect the expression of srGAP 1 and Cdc 42 in the affected cortex. The mNSS displayed that the neurological score in the EA group was significantly lower than that in the model group and non-acupoint EA group at the 7th d and 14th d (P<0. 01). Immunofluorescence results showed that cerebral srGAP 1 and Cdc 42 were ex- pressed mainly in the cytoplasm. The fluorescence intensity of srGAP 1 of the EA group was significantly lower than that of the model group and non-acupoint EA group(P<0. 01). Meanwhile the fluorescence intensity of Cdc 42 of the EA group was markedly higher than that in the model group and non-acupoint EA group(P<0. 01). Western blot assay indicated that the expression level of srGAP 1 in the model group was significantly higher than that of the control group( P<0. 01) ,and that of the EA group was much lower than those of the model group and non-acupoint EA group(P<0. 01). There was no significant difference of srGAP 1 expression levels between the non-acupoint EA group and the model group(P>0. 05). Additionally, the protein expression of Cdc 42 in the model group was slightly higher than that of the control group(P>0. 05), and that of the EA group was significantly higher than those of the model group and non-acupoint EA group(P<0. 01). There was no significant difference of Cdc 42 expression levels between the non-acupoint EA group and the model group(P>0. 05). Cerebral infarction induced increase of cerebral srGAP 1 and decrease of Cdc 42 can be reversed by acupoint EA intervention in CIRI rats, which may be responsible for its effect in improving impaired neurological function after cerebral infarction.

[Operational mechanism modification of bone mechanostat in an animal model of nutritional stress: effect of propranolol].

PubMed

Pintos, Patricia Mabel; Lezón, Christian Esteban; Bozzini, Clarisa; Friedman, Silvia María; Boyer, Patricia Mónica

2013-01-01

Propranolol (P) treatment exerts a preventive effect against the detrimental consequences to bone status in mildly chronically food-restricted growing rats (NGR) by an increment in cortical bone and by improving its spatial distribution. To study the effect of beta-blocker on operational mechanism of bone mechanostat in an animal model of nutritional stress. Weanling male Wistar rats were randomly assigned to four groups: control (C), C + P (CP), NGR and NGR + P (NGRP). C and CP rats were fed freely with the standard diet. NGR and NGRP rats received, for 4 weeks, 80% of the amount of food consumed by C and CP respectively, the previous day, corrected by body weight. Propranolol (7 mg/kg/day) was injected ip 5 days per week, for four weeks in CP and NGRP rats. C and NGR received saline injections at an identical dosage regimen. Body weight and length were determined during the experimental period. Dietary intake was registered daily. Animals were sacrificed after 4 weeks of food restriction. Immediately, cuadriceps, femur and tibiae from each animal were dissected and weighed, and histomorphometric and mechanical studies were performed. Serum a-CTX, osteocalcin, intact PTH, calcium and phosphorous were determined. Body protein (% prot) was measured in all groups. Food restriction induced detrimental effects on body and femoral growth, load-bearing capacity (Wf), % prot and cuadriceps weight in NGR us. C (p < 0.01). beta-blocker did not modify anthropometric and bone morphometric parameters in NGRP and CP us. NGR and C, respectively (p > 0.05). However, Wf NGRP vs. NGR was significantly higher (p < 0.01). alpha-CTX was significantly higher in NGR vs. C (p < 0.01). No significant differences were observed in alpha-CTX levels between CP, NGRP and C (p > 0.05). Serum osteocalcin, intact PTH, calcium and phospho- rous showed no significant difference between groups (p > 0.05). These results suggest that modeling increase in bone mass and strength in NGRP rats could be due to an anticatabolic interaction of the beta-blocker propranolol on operational mechanism of bone mechanostat in an animal model of nutritional stress.

The effect of hyperglycaemia on osseointegration: a review of animal models of diabetes mellitus and titanium implant placement.

PubMed

King, Shalinie; Klineberg, Iven; Levinger, Itamar; Brennan-Speranza, Tara C

2016-12-01

Patients with type 2 diabetes mellitus have a higher risk of dental and/or orthopaedic implant failure. However, the mechanism behind this phenomenon is unclear, and animal studies may prove useful in shedding light on the processes involved. This review considers the available literature on rat models of diabetes and titanium implantation. The process of osseointegration whereby direct contact is achieved between bone and an implant surface depends on healthy bone metabolism. Collective evidence suggests that hyperglycaemia adversely affects bone turnover and the quality of the organic matrix resulting in an overall deterioration in the quality, resilience and structure of the bone tissue. This in turn results in compromised osseointegration in patients receiving dental and orthopaedic implants. The incidence of diabetes mellitus (DM), which is a chronic metabolic disorder resulting in hyperglycaemia, is rising. Of particular significance is the rising incidence of adult onset type 2 diabetes mellitus (T2DM) in an ageing population. Understanding the effects of hyperglycaemia on osseointegration will enable clinicians to manage health outcomes for patients receiving implants. Much of our understanding of how hyperglycaemia affects osseointegration comes from animal studies. In this review, we critically analyse the current animal studies. Our review has found that most studies used a type 1 diabetes mellitus (T1DM) rodent model and looked at a young male population of rodents. The pathophysiology of T1DM is however very different to that of T2DM and is not representative of T2DM, the incidence of which is rising in the ageing adult population. Genetically modified rats have been used to model T2DM, but none of these studies have included female rats and the metabolic changes in bone for some of these models used are not adequately characterized. Therefore, the review suggests that the study population needs to be broadened to include both T1DM and T2DM models, older rats as well as young rats, and importantly animals from both sexes to reflect more accurately clinical practice.

Thrombospondin-1 modified bone marrow mesenchymal stem cells (BMSCs) promote neurite outgrowth and functional recovery in rats with spinal cord injury

PubMed Central

Pu, Yujie; Meng, Ke; Gu, Chuanlong; Wang, Linlin; Zhang, Xiaoming

2017-01-01

Stem cell therapies are currently gaining momentum in the treatment of spinal cord injury (SCI). However, unsatisfied intrinsic neurite growth capacity constitutes significant obstacles for injured spinal cord repair and ultimately results in neurological dysfunction. The present study assessed the efficacy of thrombospondin-1 (TSP-1), a neurite outgrowth-promoting molecule, modified bone marrow mesenchymal stem cells (BMSCs) on promoting neurite outgrowth in vitro and in vivo of Oxygen–Glucose Deprivation (OGD) treated motor neurons and SCI rat models. The present results demonstrated that the treatment of BMSCs+TSP-1 could promote the neurite length, neuronal survival, and functional recovery after SCI. Additionally, TSP-1 could activate transforming growth factor-β1 (TGF-β1) then induced the smad2 phosphorylation, and expedited the expression of GAP-43 to promote neurite outgrowth. The present study for the first time demonstrated that BMSCs+TSP-1 could promote neurite outgrowth and functional recovery after SCI partly through the TGF-β1/p-Samd2 pathway. The study provided a novel encouraging evidence for the potential treatment of BMSCs modification with TSP-1 in patients with SCI. PMID:29221205

[Effect of a modified low protein and low fat diet on histologic changes and metabolism in kidneys in an experimental model of polycystic kidney disease].

PubMed

Banković-Calić, Neda; Ogbori, Malkom R; Nicman, Evin

2002-01-01

Dietary protein restriction slows progression in numerous animal models of renal diseases. Flax seed has also demonstrated useful anti-inflammatory properties in a number of animal models and human diseases. We undertook several studies to determine if feeding with low protein casein, soy diet and flax seed diet would ameliorate renal injury in Han:SPRD-cy rat model of polycystic kidney disease. Male offspring of Han:SPRD-cy heterozygotes received protein modified diet: ad libidum LP 8% casein in test or 20% casein in control group for 8 weeks; 20% heat treated soy protein or 20% casein in control group two separate studies for 8 weeks ad libidum and pair feeding in 6 weeks; and 10% flax seed diet or control rat chow for 8 weeks from weaning. Tissue was harvested for histological assessment and metabolic changes in lipids, citric acid metabolites and osmolytes. Morphometrically after histochemical and immunohistochemical staining cystic changes, renal tubular proliferation and apoptosis, number of interstitial cells/macrophages infiltration and interstitial fibrosis were measured. Gas chromatography was used for lipid analysis in renal and liver tissue. 1-HNMR spectroscopy was used for urine and tissue organic anion and osmolytes content analysis. RESULTS IN PROTEIN MODIFIED DIET: Casein low protein as well as soy protein fed animals demonstrated reduced PKD pathology: significant reduction in cystic changes, interstitial inflammation and fibrosis and also reduction in tubular cells proliferation and apoptosis. Pair feeding protocol in second soy diet study confirmed that significant effect on renal histology was not because of protein deprivation and growth retardation. 1-H NMR spectroscopy revealed that progression of chronic renal failure in Han:SPRD-cy rat PKD is associated with renal depletion of citric acid cycle metabolite and betaine. Amelioration of PKD by soy protein diet is associated with renal retention of citric acid cycle anions, despite increased excretion and preservation of betaine in renal tissue. Soy feeding increased both hepatic and renal content of linoleic acid and increased renal alpha linolenic acid content, while decreased arachidonic hepatic content. RESULTS IN FLAX SEED SUPPLEMENTATION IN DIET: Flax seed fed animals had moderate decrease in cystic size and less interstitial inflammation and fibrosis while there were no differences in epithelial cell apoptosis and proliferation. Lipid analysis revealed significant renal enrichment of 18 and 20 carbon omega 3 polyunsaturated fatty acids. In flax fed animals there was an increased urinary citrate excretion without significant changes in urinary ammonia excretion, so increased citrate excretion was not due to alkaline effect of the diet. Kidney tissue 1H NMR spectroscopy revealed that disease amelioration was associated with tissue retention of succinate and betaine. Effect on histology: Low casein and soy feeding ameliorates Han: SPRD-cy rat polycystic kidney disease reducing both tubular remodeling and interstitial inflammation and fibrosis, while flax seed diet effect appears to be through moderation of associated interstitial nephritis. Metabolic effect: Soy diet alters the renal content of polyunsaturated fatty acids and enriched renal betaine content with retention of citric acid cycle metabolites despite increased excretion. Flax seed diet alters renal content of polyunsaturated fatty acids and promotes the formation of less inflammatory classes of renal prostanoides. Flax seed diet also enriched renal content of betaine and succinate. Amelioration of Hans:SPRD-cy rat polycystic kidney disease by diet is associated with alteration in the handling of citric acid cycle metabolites and betaine, and also in content of polyunsaturated fatty acids in kidneys and liver. Metabolic pathways in dietary modified renal pathology have to be established.

COMBINATION DOSE OF TWO PHTHALATES ADDITIVELY DEPRESSES TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RAT FETUSES

EPA Science Inventory

Diethylhexyl phthalate (DEHP) and di(n-butyl) phthalate (DBP) are phthalate esters used to modify plastic and polymer textures. Individually,DEHP and DBP reduce testosterone production, inhibit reproductive tract development, andinduce reproductive organ malformationsin male rats...

Clofibrate prevents and reverses the hemodynamic manifestations of hyperthyroidism in rats.

PubMed

Rodríguez-Gómez, Isabel; Cruz, Antonio; Moreno, Juan Manuel; Soler, Agatángelo; Osuna, Antonio; Vargas, Félix

2008-03-01

This study analyzed the effects of the chronic administration of clofibrate, a peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, on the development and established hemodynamic, morphologic, metabolic, and renal manifestations of hyperthyroidism in rats. The prevention study used four groups of male Wistar rats: control, clofibrate (240 mg/kg/day by gavage), T(4)(75 microg thyroxine/rat/day s.c.), and T(4)+clofibrate. All treatments were maintained for 3 weeks. Body weight (BW), tail systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, temperature, SBP, pulse pressure (PP) and HR were recorded in conscious rats, and morphologic, metabolic, plasma, and renal variables were measured. The reversion study used two groups of rats, T(4)(treated for 6 weeks) and T(4)+clofibrate, measuring their hemodynamic variables and temperature for 3 weeks. T(4) increased BP, HR, PP, and temperature when compared with control rats. Clofibrate prevented and reversed the increase in SBP, HR, PP, and temperature produced by T(4) administration, reduced plasma thyroid hormone levels, and increased plasma thyroid-stimulating hormone values and phenol-uridine diphosphate-glucuronosyl-transferase (UGT) activity. However, clofibrate did not modify the cardiac or renal hypertrophy, polyphagia, polydipsia, or proteinuria of hyperthyroid rats. In normal rats, clofibrate treatment did not significantly change thyroid hormone levels, phenol-UGT activity, or any hemodynamic, morphologic, or renal variables. Chronic clofibrate treatment suppressed the hemodynamic manifestations and increased temperature of hyperthyroidism, an effect that can be produced by direct antithyroid effects. However, clofibrate administration did not modify the morphologic, metabolic, or renal alterations of hyperthyroid rats, indicating specificity in the antithyroid actions of clofibrate.

Pumpkin polysaccharide modifies the gut microbiota during alleviation of type 2 diabetes in rats.

PubMed

Liu, Guimei; Liang, Li; Yu, Guoyong; Li, Quanhong

2018-04-24

Pumpkin polysaccharide is able to alleviate diabetes, but understanding of the underlining mechanism is still limited. In this study, we hypothesized that the alleviating effects of pumpkin polysaccharide is modulated via changes in the gut microbiota and short-chain fatty acid (SCFA) production in type 2 diabetic rats. After the type 2 diabetic model successfully was established, three groups of high-fat diet induced diabetic rats were intragastrically administered pumpkin polysaccharide, metformin, or saline solution respectively. We utilized 16S rRNA gene sequencing and multivariate statistics to analyze the structural and key species of gut microbiota in the type 2 diabetic rats. The results revealed that pumpkin polysaccharide alleviated the type 2 diabetes by improving the insulin tolerance and decreasing the levels of serum glucose (GLU), total cholesterol (TC), and low-density lipoprotein (LDL-C), while increasing the levels of high-density lipoprotein (HDL-C). Simultaneously, pumpkin polysaccharide changed the structure of gut microbiota and had selective enrichment in key species of Bacteroidetes, Prevotella, Deltaproteobacteria, Oscillospira, Veillonellaceae, Phascolarctobacterium, Sutterella, and Bilophila. The correlations between the key species and SCFA production indicated the underlining mechanisms of pumpkin polysaccharide on type 2 diabetes. Copyright © 2018. Published by Elsevier B.V.

Tetrapentylammonium block of chloramine-T and veratridine modified rat brain type IIA sodium channels

PubMed Central

Ghatpande, A S; Rao, S; Sikdar, S K

2001-01-01

Tetrapentylammonium (TPeA) block of rat brain type IIA sodium channel α subunit was studied using whole cell patch clamp. Results indicate that TPeA blocks the inactivating brain sodium channel in a potential and use-dependent manner similar to that of the cardiac sodium channel. Removal of inactivation using chloramine-T (CT) unmasks a time-dependent block by TPeA consistent with slow blocking kinetics. On the other hand, no time dependence is observed when inactivation is abolished by modification with veratridine. TPeA does not bind in a potential-dependent fashion to veratridine-modified channels and does not significantly affect gating of veratridine-modified channels suggesting that high affinity binding of TPeA to the brain sodium channel is lost after veratridine modification. PMID:11309247

Electroacupuncture improves neurobehavioral function and brain injury in rat model of intracerebral hemorrhage.

PubMed

Zhu, Yan; Deng, Li; Tang, Huajun; Gao, Xiaoqing; Wang, Youhua; Guo, Kan; Kong, Jiming; Yang, Chaoxian

2017-05-01

Acupuncture has been widely used as a treatment for stroke in China for a long time. Recently, studies have demonstrated that electroacupuncture (EA) can accelerate intracerebral hemorrhage (ICH)-induced angiogenesis in rats. In the present study, we investigated the effect of EA on neurobehavioral function and brain injury in ICH rats. ICH was induced by stereotactic injection of collagenase type I and heparin into the right caudate putamen. Adult ICH rats were randomly divided into the following three groups: model control group (MC), EA at non-acupoint points group (non-acupoint EA) and EA at Baihui and Dazhui acupoints group (EA). The neurobehavioral deficits of ICH rats were assessed by modified neurological severity score (mNSS) and gait analysis. The hemorrhage volume and glucose metabolism of hemorrhagic foci were detected by PET/CT. The expression levels of MBP, NSE and S100-B proteins in serum were tested by ELISA. The histopathological features were examined by haematoxylin-eosin (H&E) staining. Apoptosis-associated proteins in the perihematomal region were observed by immunohistochemistry. EA treatment significantly promoted the recovery of neurobehavioral function in ICH rats. Hemorrhage volume reduced in EA group at day 14 when compared with MC and non-acupoint EA groups. ELISA showed that the levels of MBP, NSE and S100-B in serum were all down-regulated by EA treatment. The brain tissue of ICH rat in the EA group was more intact and compact than that in the MC and non-acupoint groups. In the perihematomal regions, the expression of Bcl-2 protein increased and expressions of Caspase-3 and Bax proteins decreased in the EA group vs MC and non-acupoint EA groups. Our data suggest that EA treatment can improve neurobehavioral function and brain injury, which were likely connected with the absorption of hematoma and regulation of apoptosis-related proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

Influence of He-Ne laser radiation on biogenic amines content and cytochemical parameters of polymorphonuclear leukocytes in short-term stress

NASA Astrophysics Data System (ADS)

Brill, Gregory E.; Dobrovolsky, Gennady A.; Romanova, Tatyana P.; Porozova, Svetlana G.; Brill, Alexander G.

1997-06-01

In experiments on white male rats short-term immobilization- sound stress was modelled. Decrease of glycogen content and myeloperoxidase activity, increase of lysosomal cationic proteins level and NBT-test parameters as well as fall of adrenaline, dopamine and 5-hydroxytryptamine amount in polymorphonuclear leukocytes were observed. Preliminary transcutaneous He-Ne laser irradiation modified metabolic reaction of leukocytes to stress and prevented stress- induced decrease of biogenic amines content in cells.

Prediction of specific damage or infarction from the measurement of tissue impedance following repetitive brain ischaemia in the rat.

PubMed

Klein, H C; Krop-Van Gastel, W; Go, K G; Korf, J

1993-02-01

The development of irreversible brain damage during repetitive periods of hypoxia and normoxia was studied in anaesthetized rats with unilateral occlusion of the carotid artery (modified Levine model). Rats were exposed to 10 min hypoxia and normoxia until severe damage developed. As indices of damage, whole striatal tissue impedance (reflecting cellular water uptake), sodium/potassium contents (due to exchange with blood). Evans Blue staining (blood-brain barrier [BBB] integrity) and silver staining (increased in irreversibly damaged neurons) were used. A substantial decrease in blood pressure was observed during the hypoxic periods possibly producing severe ischaemia. Irreversibly increased impedance, massive changes in silver staining, accumulation of whole tissue Na and loss of K occurred only after a minimum of two periods of hypoxia, but there was no disruption of the BBB. Microscopic examination of tissue sections revealed that cell death was selective with reversible impedance changes, but became massive and non-specific after irreversible increase of the impedance. The development of brain infarcts could, however, not be predicted from measurements of physiological parameters in the blood. We suggest that the development of cerebral infarction during repetitive periods of hypoxia may serve as a model for the development of brain damage in a variety of clinical conditions. Furthermore, the present model allows the screening of potential therapeutic measuring of the prevention and treatment of both infarction and selective cell death.

Adipose-derived stem cells and BMP-2 delivery in chitosan-based 3D constructs to enhance bone regeneration in a rat mandibular defect model.

PubMed

Fan, Jiabing; Park, Hyejin; Lee, Matthew K; Bezouglaia, Olga; Fartash, Armita; Kim, Jinku; Aghaloo, Tara; Lee, Min

2014-08-01

Reconstructing segmental mandiblular defects remains a challenge in the clinic. Tissue engineering strategies provide an alternative option to resolve this problem. The objective of the present study was to determine the effects of adipose-derived stem cells (ASCs) and bone morphogenetic proteins-2 (BMP-2) in three-dimensional (3D) scaffolds on mandibular repair in a small animal model. Noggin expression levels in ASCs were downregulated by a lentiviral short hairpin RNA strategy to enhance ASC osteogenesis (ASCs(Nog-)). Chitosan (CH) and chondroitin sulfate (CS), natural polysaccharides, were fabricated into 3D porous scaffolds, which were further modified with apatite coatings for enhanced cellular responses and efficient delivery of BMP-2. The efficacy of 3D apatite-coated CH/CS scaffolds supplemented with ASCs(Nog-) and BMP-2 were evaluated in a rat critical-sized mandibular defect model. After 8 weeks postimplantation, the scaffolds treated with ASCs(Nog-) and BMP-2 significantly promoted rat mandibular regeneration as demonstrated by micro-computerized tomography, histology, and immunohistochemistry, compared with the groups treated with ASCs(Nog-) or BMP-2 alone. These results suggest that our combinatorial strategy of ASCs(Nog-)+BMP-2 in 3D apatite microenvironments can significantly promote mandibular regeneration, and these may provide a potential tissue engineering approach to repair large bony defects.

Safety evaluation of genetically modified DAS-40278-9 maize in a subchronic rodent feeding study.

PubMed

Zou, Shiying; Lang, Tianqi; Liu, Xu; Huang, Kunlun; He, Xiaoyun

2018-07-01

Genetically modified (GM) maize, DAS-40278-9, expresses the aryloxyalkanoate dioxygenase-1 (AAD-1) protein, which confers tolerance to 2,4-dichlorophenoxyacetic acid (2,4-D) and aryloxyphenoxypropionate (AOPP) herbicides. The aad-1 gene, which expresses the AAD-1 protein, was derived from Gram-negative soil bacterium, Sphingobium herbicidovorans. A 90-day sub-chronic toxicity study was conducted on rats as a component of the safety evaluation of DAS-40278-9 maize. Rats were given formulated diets containing maize grain from DAS-40278-9 or a non-GM near isogenic control comparator at an incorporation rate of 12.5%, 25%, or 50% (w/w), respectively for 90 days. In addition, another group of rats was fed a basic rodent diet. Animals were evaluated by cage-side and hand-held detailed clinical observations, ophthalmic examinations, body weights/body weight gains, feed consumption, hematology, serum chemistry, selected organ weights, and gross and histopathological examinations. Under the condition of this study, DAS-40278-9 maize did not cause any treatment-related effects in rats compared with rats fed diets containing non-GM maize. Copyright © 2018 Elsevier Inc. All rights reserved.

Acupuncture does not ameliorate metabolic disturbances in the P450 aromatase inhibitor-induced rat model of polycystic ovary syndrome.

PubMed

Maliqueo, Manuel; Benrick, Anna; Marcondes, Rodrigo Rodrigues; Johansson, Julia; Sun, Miao; Stener-Victorin, Elisabet

2017-01-01

What is the central question of this study? The effectiveness of low-frequency electroacupuncture in the treatment of metabolic disorders associated with polycystic ovary syndrome (PCOS), an endocrine-metabolic disorder characterized by an imbalance in sex steroid production, is controversial. What is the main finding and its importance? In a rat model of PCOS induced by the inhibition of P450 aromatase, low-frequency electroacupuncture increased low-density lipoprotein-cholesterol but did not improve the insulin resistance or the adipose tissue dysfunction, suggesting that a balance of sex steroids is needed to restore the metabolic function in this rat model of PCOS. Low-frequency electroacupuncture restores sex steroid synthesis and sympathetic activity in women with polycystic ovary syndrome, which may ameliorate its metabolic disturbances, probably by modulating sympathetic nerve activity or sex steroid synthesis. We investigated whether low-frequency electroacupuncture regulates the metabolic function to the same extent as treatment with estradiol or β-adrenergic blocking in a rat model of polycystic ovary syndrome induced by a P450 aromatase inhibitor (letrozole). Letrozole (200 μg day -1 ) or placebo pellets were implanted in prepubertal Wistar rats. Six weeks thereafter, rats were treated for 5-6 weeks with the following: low-frequency electroacupuncture (5 days per week); a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg kg -1 , 5 days per week); or 17β-estradiol (2.0 μg) every fourth day. Body weight development, body composition, locomotor activity, insulin sensitivity, tissue-specific glucose uptake, lipid profile, adipocyte size, serum concentrations of adiponectin and insulin, and gene expression in inguinal fat were measured. All treatments increased circulating levels of low-density lipoprotein-cholesterol. Estradiol treatment restored locomotor activity and increased insulin sensitivity but did not modify the glucose uptake in muscle and fat. An upregulation of genes related to insulin sensitivity and downregulation of genes related to adipogenesis were observed in subcutaneous adipose tissue from rats exposed to letrozole. Only estradiol treatment normalized the expression of these genes. In conclusion, low-frequency electroacupuncture increased low-density lipoprotein-cholesterol without affecting insulin sensitivity or adipose tissue function, which could suggest effects on hepatic lipid regulation, probably mediated by the action of estradiol or the β-adrenergic pathway. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Lupinus albus Conglutin Gamma Modifies the Gene Expressions of Enzymes Involved in Glucose Hepatic Production In Vivo.

PubMed

González-Santiago, Ana E; Vargas-Guerrero, Belinda; García-López, Pedro M; Martínez-Ayala, Alma L; Domínguez-Rosales, José A; Gurrola-Díaz, Carmen M

2017-06-01

Lupinus albus seeds contain conglutin gamma (Cγ) protein, which exerts a hypoglycemic effect and positively modifies proteins involved in glucose homeostasis. Cγ could potentially be used to manage patients with impaired glucose metabolism, but there remains a need to evaluate its effects on hepatic glucose production. The present study aimed to analyze G6pc, Fbp1, and Pck1 gene expressions in two experimental animal models of impaired glucose metabolism. We also evaluated hepatic and renal tissue integrity following Cγ treatment. To generate an insulin resistance model, male Wistar rats were provided 30% sucrose solution ad libitum for 20 weeks. To generate a type 2 diabetes model (STZ), five-day-old rats were intraperitoneally injected with streptozotocin (150 mg/kg). Each animal model was randomized into three subgroups that received the following oral treatments daily for one week: 0.9% w/v NaCl (vehicle; IR-Ctrl and STZ-Ctrl); metformin 300 mg/kg (IR-Met and STZ-Met); and Cγ 150 mg/kg (IR-Cγ and STZ-Cγ). Biochemical parameters were assessed pre- and post-treatment using colorimetric or enzymatic methods. We also performed histological analysis of hepatic and renal tissue. G6pc, Fbp1, and Pck1 gene expressions were quantified using real-time PCR. No histological changes were observed in any group. Post-treatment G6pc gene expression was decreased in the IR-Cγ and STZ-Cγ groups. Post-treatment Fbp1 and Pck1 gene expressions were reduced in the IR-Cγ group but increased in STZ-Cγ animals. Overall, these findings suggest that Cγ is involved in reducing hepatic glucose production, mainly through G6pc inhibition in impaired glucose metabolism disorders.

Effects of a hybrid micro/nanorod topography-modified titanium implant on adhesion and osteogenic differentiation in rat bone marrow mesenchymal stem cells.

PubMed

Zhang, Wenjie; Li, Zihui; Huang, Qingfeng; Xu, Ling; Li, Jinhua; Jin, Yuqin; Wang, Guifang; Liu, Xuanyong; Jiang, Xinquan

2013-01-01

Various methods have been used to modify titanium implant surfaces with the aim of achieving better osseointegration. In this study, we fabricated a clustered nanorod structure on an acid-etched, microstructured titanium plate surface using hydrogen peroxide. We also evaluated biofunctionalization of the hybrid micro/nanorod topography on rat bone marrow mesenchymal stem cells. Scanning electron microscopy and x-ray diffraction were used to investigate the surface topography and phase composition of the modified titanium plate. Rat bone marrow mesenchymal stem cells were cultured and seeded on the plate. The adhesion ability of the cells was then assayed by cell counting at one, 4, and 24 hours after cell seeding, and expression of adhesion-related protein integrin β1 was detected by immunofluorescence. In addition, a polymerase chain reaction assay, alkaline phosphatase and Alizarin Red S staining assays, and osteopontin and osteocalcin immunofluorescence analyses were used to evaluate the osteogenic differentiation behavior of the cells. The hybrid micro/nanoscale texture formed on the titanium surface enhanced the initial adhesion activity of the rat bone marrow mesenchymal stem cells. Importantly, the hierarchical structure promoted osteogenic differentiation of these cells. This study suggests that a hybrid micro/nanorod topography on a titanium surface fabricated by treatment with hydrogen peroxide followed by acid etching might facilitate osseointegration of a titanium implant in vivo.

Serosurvey of Leptospira spp. and Toxoplasma gondii in rats captured from two zoos in Southern Brazil.

PubMed

Pellizzaro, Maysa; Conrado, Francisco de Oliveira; Martins, Camila Marinelli; Joaquim, Sâmea Fernandes; Ferreira, Fernando; Langoni, Helio; Biondo, Alexander Welker

2017-01-01

Norway rats (Rattus norvegicus) are zoonotic reservoirs for Leptospira spp. and Toxoplasma gondii, and influence diseases in urban areas. Free-ranging and laboratory-raised rats from two zoos in southern Brazil were tested for Leptospira spp. and T. gondii using microscopic agglutination and modified agglutination tests, respectively. Overall, 25.6% and 4.6% free-ranging rats tested positive for Leptospira spp. and T. gondii, respectively, with co-seropositivity occurring in two animals. For laboratory-raised rats, 20% tested positive for Leptospira spp. Also, Leptospira biflexa serovar Patoc and Leptospira noguchii serovar Panama were found. Serosurveys can show the environmental prevalence of zoonotic pathogens.

Brain Localization and Neurotoxicity Evaluation of Polysorbate 80-Modified Chitosan Nanoparticles in Rats

PubMed Central

Yuan, Zhong-Yue; Hu, Yu-Lan; Gao, Jian-Qing

2015-01-01

The toxicity evaluation of inorganic nanoparticles has been reported by an increasing number of studies, but toxicity studies concerned with biodegradable nanoparticles, especially the neurotoxicity evaluation, are still limited. For example, the potential neurotoxicity of Polysorbate 80-modified chitosan nanoparticles (Tween 80-modified chitosan nanoparticles, TmCS-NPs), one of the most widely used brain targeting vehicles, remains unknown. In the present study, TmCS-NPs with a particle size of 240 nm were firstly prepared by ionic cross-linking of chitosan with tripolyphosphate. Then, these TmCS-NPs were demonstrated to be entered into the brain and specially deposited in the frontal cortex and cerebellum after systemic injection. Moreover, the concentration of TmCS-NPs in these two regions was found to decrease over time. Although no obvious changes were observed for oxidative stress in the in vivo rat model, the body weight was found to remarkably decreased in a dose-dependent manner after exposure to TmCS-NPs for seven days. Besides, apoptosis and necrosis of neurons, slight inflammatory response in the frontal cortex, and decrease of GFAP expression in the cerebellum were also detected in mouse injected with TmCS-NPs. This study is the first report on the sub-brain biodistribution and neurotoxicity studies of TmCS-NPs. Our results provide new insights into the toxicity evaluation of nanoparticles and our findings would help contribute to a better understanding of the neurotoxicity of biodegradable nanomaterials used in pharmaceutics. PMID:26248340

Brain Localization and Neurotoxicity Evaluation of Polysorbate 80-Modified Chitosan Nanoparticles in Rats.

PubMed

Yuan, Zhong-Yue; Hu, Yu-Lan; Gao, Jian-Qing

2015-01-01

The toxicity evaluation of inorganic nanoparticles has been reported by an increasing number of studies, but toxicity studies concerned with biodegradable nanoparticles, especially the neurotoxicity evaluation, are still limited. For example, the potential neurotoxicity of Polysorbate 80-modified chitosan nanoparticles (Tween 80-modified chitosan nanoparticles, TmCS-NPs), one of the most widely used brain targeting vehicles, remains unknown. In the present study, TmCS-NPs with a particle size of 240 nm were firstly prepared by ionic cross-linking of chitosan with tripolyphosphate. Then, these TmCS-NPs were demonstrated to be entered into the brain and specially deposited in the frontal cortex and cerebellum after systemic injection. Moreover, the concentration of TmCS-NPs in these two regions was found to decrease over time. Although no obvious changes were observed for oxidative stress in the in vivo rat model, the body weight was found to remarkably decreased in a dose-dependent manner after exposure to TmCS-NPs for seven days. Besides, apoptosis and necrosis of neurons, slight inflammatory response in the frontal cortex, and decrease of GFAP expression in the cerebellum were also detected in mouse injected with TmCS-NPs. This study is the first report on the sub-brain biodistribution and neurotoxicity studies of TmCS-NPs. Our results provide new insights into the toxicity evaluation of nanoparticles and our findings would help contribute to a better understanding of the neurotoxicity of biodegradable nanomaterials used in pharmaceutics.

Long-term treatment with green tea polyphenols modifies the gut microbiome of female sprague-dawley rats.

PubMed

Wang, Jincheng; Tang, Lili; Zhou, Hongyuan; Zhou, Jun; Glenn, Travis C; Shen, Chwan-Li; Wang, Jia-Sheng

2018-06-01

Green tea polyphenols (GTP) have been shown to exert a spectrum of health benefits to animals and humans. It is plausible that the beneficial effects of GTP are a result of its interaction with the gut microbiota. This study evaluated the effect of long-term treatment with GTP on the gut microbiota of experimental rats and the potential linkage between changes of the gut microbiota with the beneficial effects of GTP. Six-month-old Sprague-Dawley rats were randomly allocated into three dosing regimens (0, 0.5%, and 1.5% of GTP) and followed for 6 months. At the end of month 3 or month 6, half of the animals from each group were sacrificed and their colon contents were collected for microbiome analysis using 16S ribosomal RNA and shotgun metagenomic community sequencing. GTP treatment significantly decreased the biodiversity and modified the microbial community in a dose-dependent manner; similar patterns were observed at both sampling times. Multiple operational taxonomic units and phylotypes were modified: the phylotypes Bacteroidetes and Oscillospira, previously linked to the lean phenotype in human and animal studies, were enriched; and Peptostreptococcaceae previously linked to colorectal cancer phenotype was depleted in GTP treated groups in a dose-dependent manner. Several microbial gene orthologs were modified, among which genes related to energy production and conversion were consistently enriched in samples from month 6 in a dose-dependent manner. This study showed that long-term treatment with GTP induced a dose-dependent modification of the gut microbiome in experimental rats, which might be linked to beneficial effects of GTP. Copyright © 2018 Elsevier Inc. All rights reserved.

Acute Noxious Stimulation Modifies Morphine Effect in Serotonergic but not Dopaminergic Midbrain Areas

PubMed Central

Bajic, Dusica; Commons, Kathryn G.

2010-01-01

It is poorly understood if and how pain may modify the effect of opioids on neural systems that contribute to reward and addictive behavior. We hypothesized that the activation of ascending dopaminergic and serotonergic nuclei by morphine is modified by the presence of noxious stimulation. Immunohistochemical double-labeling technique with Fos was used to examine if an intraplantar formalin injection, an acute noxious input, changed the effect of morphine on dopaminergic neurons of the ventral tegmental area (VTA), and serotonergic neurons of the dorsal raphe nucleus (DR). Four groups of rats were analyzed: (1) CONTROL injected with normal saline subcutaneously, (2) rats treated with FORMALIN into the hind paw 30 minutes after normal saline injection, (3) rats injected with MORPHINE sulfate subcutaneously, and (4) rats treated with formalin into the hind paw 30 minutes after morphine injection (MORPHINE/FORMALIN). Following morphine injection, there was an increase in the number of dopaminergic neurons in the VTA with Fos immunolabeling. However, noxious stimulation did not detectably change morphine's effect on Fos expression in VTA dopamine neurons. In contrast, the number of serotonergic neurons containing Fos was increased in the morphine/formalin group compared to all other groups and this effect was topographically selective for the dorsal area of the DR at mid rostro-caudal levels. Therefore, morphine's activation of the VTA, which is associated with motivated behavior and reward seeking, appears similar in the context of pain. However, activation of the ascending serotonin system, which influences mood and has the capacity to modify reward pathways, appears different. In addition, these findings reveal interactions between nociceptive signaling and opioids that contrasts with the notion that opioids simply block access of nociceptive signaling to supraspinal structures. PMID:20026253

Parecoxib Increases Blood Pressure Through Inhibition of Cyclooxygenase-2 Messenger RNA in an Experimental Model.

PubMed

Vértiz-Hernández, Ángel Antonio; Martínez-Morales, Flavio; Valle-Aguilera, Roberto; López-Sánchez, Pedro; Villalobos-Molina, Rafael; Pérez-Urizar, José

2015-01-01

Cyclooxygenase-2 selective inhibitors have been developed to alleviate pain and inflammation; however, the use of a selective cyclooxygenase-2 inhibitor is associated with mild edema, hypertension, and cardiovascular risk. To evaluate, in an experimental model in normotensive rats, the effect of treatment with parecoxib in comparison with diclofenac and aspirin and L-NAME, a non-selective nitric oxide synthetase, on mean arterial blood pressure, and cyclooxygenase-1 and -2 messenger RNA and protein expression in aortic tissue. Rats were treated for seven days with parecoxib (10 mg/kg/day), diclofenac (3.2 mg/kg/day), aspirin (10 mg/kg/day), or L-NAME (10 mg/kg/day). Mean arterial blood pressure was evaluated in rat tail; cyclooxygenase-1 and -2 were evaluated by reverse transcription-polymerase chain reaction and Western blot analysis in aortic tissue. Parecoxib and L-NAME, but not aspirin and diclofenac, increased mean arterial blood pressure by about 50% (p < 0.05) without changes in cardiac frequency. Messenger RNA cyclooxygenase-1 expression in aortic tissue was not modified with any drug (p < 0.05). L-NAME and parecoxib treatment decreased messenger RNA cyclooxygenase-2 and cyclooxygenase-2 (p < 0.05). While cyclooxygenase-1 protein decreased with the three drugs tested but not with L-NAME (p < 0.05), the cyclooxygenase-2 protein decreased only with aspirin and parecoxib (p < 0.05). Parecoxib increases the blood pressure of normotensive rats by the suppression of COX-2 gene expression, which apparently induced cardiovascular control.

Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle.

PubMed

Liu, F; Ferreira, E; Porter, R M; Glatt, V; Schinhan, M; Shen, Z; Randolph, M A; Kirker-Head, C A; Wehling, C; Vrahas, M S; Evans, C H; Wells, J W

2015-09-21

Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials.

Vaginal hemodynamic changes during sexual arousal in a rat model by diffuse optical spectroscopy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Jeong, Hyeryun; Seong, Myeongsu; Lee, Hyun-Suk; Park, Kwangsung; Kim, Jae Gwan

2017-02-01

Not only men suffer from sexual dysfunction, but the number of women who have sexual dysfunction rises. Therefore, it is necessary to develop an objective diagnostic technique to examine the sexual dysfunction of female patients, who are afflicted with the disorders. For this purpose, we developed a diffuse optical spectroscopy (DOS) probe to measure the change of oxy-, deoxy-, and total hemoglobin concentration along with blood flow from vaginal wall of female rats. A cylindrical stainless steel DOS probe with a diameter of 3 mm was designed for the vaginal wall of rats which consisted of two lasers (785 and 850nm) and two spectrometers with a separation of 2 mm. A thermistor was placed on the top of the probe to measure the temperature change from vaginal wall during experiments. A modified Beer-Lambert's law is utilized to acquire the changes of oxy-, deoxy-, and total hemoglobin, and blood flow information is obtained by diffuse speckle contrast analysis technique. For the experiments, Sprague Dawley ( 400 g) female rats were divided into two groups (control and vaginal dryness model). Vaginal oxygenation, blood flow and temperature were continuously monitored before and after sexual around induced by apomorphine. After the measurement, histologic examination was performed to support the results from DOS probe in the vaginal wall. The hemodynamic information acquired by the DOS probe can be utilized to establish an objective and accurate standard of the female sexual disorders.

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – neurokinin-1 antagonist peptidomimetics

PubMed Central

Guillemyn, Karel; Kleczkowska, Patrycia; Lesniak, Anna; Dyniewicz, Jolanta; Van der Poorten, Olivier; Van den Eynde, Isabelle; Keresztes, Attila; Varga, Eva; Lai, Josephine; Porreca, Frank; Chung, Nga N.; Lemieux, Carole; Mika, Joanna; Rojewska, Ewelina; Makuch, Wioletta; Van Duppen, Joost; Przewlocka, Barbara; Broeck, Jozef Vanden; Lipkowski, Andrzej W.; Schiller, Peter W.; Tourwé, Dirk; Ballet, Steven

2014-01-01

A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3’,5’-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioral assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat. PMID:25544687

Prior parity positively regulates learning and memory in young and middle-aged rats.

PubMed

Zimberknopf, Erica; Xavier, Gilberto F; Kinsley, Craig H; Felicio, Luciano F

2011-08-01

Reproductive experience in female rats modifies acquired behaviors, induces long-lasting functional neuroadaptations and can also modify spatial learning and memory. The present study supports and expands this knowledge base by employing the Morris water maze, which measures spatial memory. Age-matched young adult (YNG) nulliparous (NULL; nonmated) and primiparous (PRIM; one pregnancy and lactation) female rats were tested 15 d after the litter's weaning. In addition, corresponding middle-aged (AGD) PRIM (mated in young adulthood so that pregnancy, parturition, and lactation occurred at the same age as in YNG PRIM) and NULL female rats were tested at 18 mo of age. Behavioral evaluation included: 1) acquisition of reference memory (platform location was fixed for 14 to 19 d of testing); 2) retrieval of this information associated with extinction of the acquired response (probe test involving removal of the platform 24 h after the last training session); and 3) performance in a working memory version of the task (platform presented in a novel location every day for 13 d, and maintained in a fixed location within each day). YNG PRIM outperformed NULL rats and showed different behavioral strategies. These results may be related to changes in locomotor, mnemonic, and cognitive processes. In addition, YNG PRIM exhibited less anxiety-like behavior. Compared with YNG rats, AGD rats showed less behavioral flexibility but stronger memory consolidation. These data, which were obtained by using a well-documented spatial task, demonstrate long lasting modifications of behavioral strategies in both YNG and AGD rats associated with a single reproductive experience.

The influence of social environment in early life on the behavior, stress response, and reproductive system of adult male Norway rats selected for different attitudes to humans.

PubMed

Gulevich, R G; Shikhevich, S G; Konoshenko, M Yu; Kozhemyakina, R V; Herbeck, Yu E; Prasolova, L A; Oskina, I N; Plyusnina, I Z

2015-05-15

The influence of social disturbance in early life on behavior, response of blood corticosterone level to restraint stress, and endocrine and morphometric indices of the testes was studied in 2-month Norway rat males from three populations: not selected for behavior (unselected), selected for against aggression to humans (tame), and selected for increased aggression to humans (aggressive). The experimental social disturbance included early weaning, daily replacement of cagemates from days 19 to 25, and subsequent housing in twos till the age of 2months. The social disturbance increased the latent period of aggressive behavior in the social interaction test in unselected males and reduced relative testis weights in comparison to the corresponding control groups. In addition, experimental unselected rats had smaller diameters of seminiferous tubules and lower blood testosterone levels. In the experimental group, tame rats had lower basal corticosterone levels, and aggressive animals had lower hormone levels after restraint stress in comparison to the control. The results suggest that the selection in two directions for attitude to humans modifies the response of male rats to social disturbance in early life. In this regard, the selected rat populations may be viewed as a model for investigation of (1) neuroendocrinal mechanisms responsible for the manifestation of aggression and (2) interaction of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems in stress. Copyright © 2015 Elsevier Inc. All rights reserved.

Brain maps 4.0-Structure of the rat brain: An open access atlas with global nervous system nomenclature ontology and flatmaps.

PubMed

Swanson, Larry W

2018-04-15

The fourth edition (following editions in 1992, 1998, 2004) of Brain maps: structure of the rat brain is presented here as an open access internet resource for the neuroscience community. One new feature is a set of 10 hierarchical nomenclature tables that define and describe all parts of the rat nervous system within the framework of a strictly topographic system devised previously for the human nervous system. These tables constitute a global ontology for knowledge management systems dealing with neural circuitry. A second new feature is an aligned atlas of bilateral flatmaps illustrating rat nervous system development from the neural plate stage to the adult stage, where most gray matter regions, white matter tracts, ganglia, and nerves listed in the nomenclature tables are illustrated schematically. These flatmaps are convenient for future development of online applications analogous to "Google Maps" for systems neuroscience. The third new feature is a completely revised Atlas of the rat brain in spatially aligned transverse sections that can serve as a framework for 3-D modeling. Atlas parcellation is little changed from the preceding edition, but the nomenclature for rat is now aligned with an emerging panmammalian neuroanatomical nomenclature. All figures are presented in Adobe Illustrator vector graphics format that can be manipulated, modified, and resized as desired, and freely used with a Creative Commons license. © 2018 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Skin derived precursor Schwann cell-generated acellular matrix modified chitosan/silk scaffolds for bridging rat sciatic nerve gap.

PubMed

Zhu, Changlai; Huang, Jing; Xue, Chengbin; Wang, Yaxian; Wang, Shengran; Bao, Shuangxi; Chen, Ruyue; Li, Yuan; Gu, Yun

2017-12-27

Extracellular/acellular matrix has been attracted much research interests for its unique biological characteristics, and ACM modified neural scaffolds shows the remarkable role of promoting peripheral nerve regeneration. In this study, skin-derived precursors pre-differentiated into Schwann cells (SKP-SCs) were used as parent cells to generate acellular(ACM) for constructing a ACM-modified neural scaffold. SKP-SCs were co-cultured with chitosan nerve guidance conduits (NGC) and silk fibroin filamentous fillers, followed by decellularization to stimulate ACM deposition. This NGC-based, SKP-SC-derived ACM-modified neural scaffold was used for bridging a 10 mm long rat sciatic nerve gap. Histological and functional evaluation after grafting demonstrated that regenerative outcomes achieved by this engineered neural scaffold were better than those achieved by a plain chitosan-silk fibroin scaffold, and suggested the benefits of SKP-SC-derived ACM for peripheral nerve repair. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

The cardiovascular and endocrine responses to voluntary and forced diving in trained and untrained rats

PubMed Central

DiNovo, Karyn. M.; Connolly, Tiffanny M.

2010-01-01

The mammalian diving response, consisting of apnea, bradycardia, and increased total peripheral resistance, can be modified by conscious awareness, fear, and anticipation. We wondered whether swim and dive training in rats would 1) affect the magnitude of the cardiovascular responses during voluntary and forced diving, and 2) whether this training would reduce or eliminate any stress due to diving. Results indicate Sprague-Dawley rats have a substantial diving response. Immediately upon submersion, heart rate (HR) decreased by 78%, from 453 ± 12 to 101 ± 8 beats per minute (bpm), and mean arterial pressure (MAP) decreased 25%, from 143 ± 1 to 107 ± 5 mmHg. Approximately 4.5 s after submergence, MAP had increased to a maximum 174 ± 3 mmHg. Blood corticosterone levels indicate trained rats find diving no more stressful than being held by a human, while untrained rats find swimming and diving very stressful. Forced diving is stressful to both trained and untrained rats. The magnitude of bradycardia was similar during both voluntary and forced diving, while the increase in MAP was greater during forced diving. The diving response of laboratory rats, therefore, appears to be dissimilar from that of other animals, as most birds and mammals show intensification of diving bradycardia during forced diving compared with voluntary diving. Rats may exhibit an accentuated antagonism between the parasympathetic and sympathetic branches of the autonomic nervous system, such that in the autonomic control of HR, parasympathetic activity overpowers sympathetic activity. Additionally, laboratory rats may lack the ability to modify the degree of parasympathetic outflow to the heart during an intense cardiorespiratory response (i.e., the diving response). PMID:19923359

Hydration status affects urea transport across rat urothelia.

PubMed

Spector, David A; Deng, Jie; Stewart, Kerry J

2011-12-01

Although mammalian urinary tract epithelium (urothelium) is generally considered impermeable to water and solutes, recent data suggest that urine constituents may be reabsorbed during urinary tract transit and storage. To study water and solute transport across the urothelium in an in vivo rat model, we instilled urine (obtained during various rat hydration conditions) into isolated in situ rat bladders and, after a 1-h dwell, retrieved the urine and measured the differences in urine volume and concentration and total quantity of urine urea nitrogen and creatinine between instilled and retrieved urine in rat groups differing by hydration status. Although urine volume did not change >1.9% in any group, concentration (and quantity) of urine urea nitrogen in retrieved urine fell significantly (indicating reabsorption of urea across bladder urothelia), by a mean of 18% (489 mg/dl, from an instilled 2,658 mg/dl) in rats receiving ad libitum water and by a mean of 39% (2,544 mg/dl, from an instilled 6,204 mg/dl) in water-deprived rats, but did not change (an increase of 15 mg/dl, P = not significant, from an instilled 300 mg/dl) in a water-loaded rat group. Two separate factors affected urea nitrogen reabsorption rates, a urinary factor related to hydration status, likely the concentration of urea nitrogen in the instilled urine, and a bladder factor(s), also dependent on the animal's state of hydration. Urine creatinine was also absorbed during the bladder dwell, and hydration group effects on the concentration and quantity of creatinine reabsorbed were qualitatively similar to the hydration group effect on urea transport. These findings support the notion(s) that urinary constituents may undergo transport across urinary tract epithelia, that such transport may be physiologically regulated, and that urine is modified during transit and storage through the urinary tract.

Inhibitory effects of alprazolam on the development of acute experimental autoimmune encephalomyelitis in stressed rats.

PubMed

Núñez-Iglesias, María J; Novío, Silvia; Almeida-Dias, Antonio; Freire-Garabal, Manuel

2010-12-01

The progression and development of multiple sclerosis (MS) has long been hypothesized to be associated with stress. Benzodiazepines have been observed to reduce negative consequences of stress on the immune system in experimental and clinical models, but there are no data on their effects on MS, or experimental autoimmune encephalomyelitis (EAE), a model for human MS. We designed experiments conducted to ascertain whether alprazolam could modify the clinical, histological and neuroendocrine manifestations of acute EAE in Lewis rats exposed to a chronic auditory stressor. EAE was induced by injection of an emulsion of MBP and complete Freund's adjuvant containing Mycobacterium tuberculosis H37Ra. Stress application and treatment with drugs (placebo or alprazolam) were initiated 5days before inoculation and continued daily for the duration of the experiment (days 14 or 34 postinoculation).Our results show significant increases in the severity of neurological signs, the histological lesions of the spinal cord (inflammation), and the corticosterone plasmatic levels in stressed rats compared to those non-stressed ones. Treatment with alprazolam reversed the adverse effects of stress. These findings could have clinical implications in patients suffering from MS treated with benzodiazepines, so besides the psychopharmacological properties of alprazolam against stress, it has beneficial consequences on EAE. Copyright © 2010 Elsevier Inc. All rights reserved.

4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid attenuates spontaneous recurrent seizures and vasogenic edema following lithium-pilocarpine induced status epilepticus.

PubMed

Yang, Tingting; Lin, Zhenzhou; Xie, Ling; Wang, Yao; Pan, Suyue

2017-07-13

Vasogenic edema induced by blood brain barrier disruption and neuronal loss play an important role in the epileptogenic process. 4,4'- diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) is a commonly used anion channel inhibitor that has been reported to exert an anticonvulsant effect in rat hippocampus in vitro. The present study aimed to investigate whether DIDS could prevent epileptogenic process in rat lithium-pilocarpine model of temporal lobe epilepsy. The tight junction proteins and serum extravasation were examined in the piriform cortex 3days after status epilepticus. The findings showed that status epilepticus induced vasogenic edema. Based on these findings, rats were intracerebroventricularly infused with saline and DIDS 1 week after surgery, DIDS reduced vasogenic edema and prevented neuronal loss following status epilepticus in the piriform cortex. Moreover, spontaneous recurrent seizures were recorded by continuous video monitoring. DIDS significantly reduced the frequency and duration of spontaneous recurrent seizures from day 28 to day 42 post status epilepticus. These findings demonstrated that DIDS attenuated vasogenic edema and neuronal apoptosis and might exert disease-modifying effect in animal model of temporal lobe epilepsy. These results explored a novel therapeutic strategy for treatment of epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

Gram-negative shock in rats depends on the presence of capsulated bacteria and is modified by laparotomy.

PubMed

Heemskerk, A E; Huisman, E; van Lambalgen, A A; Appelmelk, B J; van den Bos, G C; Thijs, L G; Tangelder, G J

1996-12-01

To develop a hyperdynamic sepsis model in rats, four Escherichia coli strains were used, which differed in the presence or absence of a capsule or K antigen (K1 and K-, respectively) and/or in O serogroup (O9 and O18). Of the two clinical isolates, O9K- did not survive in rat serum, whereas O18K1 and two isogenic laboratory strains (O18K1 and O18K-) were able to resist serum bacteriolysis. Pentobarbital-anesthetized rats (n = 21) received an intravenous bolus of 10(9) bacteria. In contrast to the two noncapsulated strains, both capsulated strains induced hyperdynamic shock; arterial lactate rose from a mean value of .91 to 3.09 mmol.L-1, systemic vascular resistance dropped from 1.15 to .78 mmHg.min.mL-1, and cardiac output transiently increased from 98 to 115 mL.min-1; renal plasma flow remained at 3-4 mL.min-1, whereas glomerular filtration rate decreased from 1.3 to .7 mL.min-1. Laparotomy, which is often performed to study kidney function, completely abolished the hyperdynamic condition, while glomerular filtration rate was still decreased. We conclude that in rats, in contrast to humans, capsulated bacteria are required to induce a hyperdynamic septic shock; the hyperdynamic characteristics of the shock do not occur in animals subjected to a laparotomy.

Influence of Prostanoids in the Diuretic and Natriuretic Effects of Extracts and Kaempferitrin from Bauhinia forficata Link Leaves in Rats.

PubMed

de Souza, Priscila; da Silva, Luisa Mota; Boeing, Thaise; Somensi, Lincon Bordignon; Cechinel-Zanchett, Camile Cecconi; Campos, Adriana; Krueger, Clarissa de Medeiros Amorim; Bastos, Jairo Kenupp; Cechinel-Filho, Valdir; Andrade, Sérgio Faloni de

2017-10-01

Although Bauhinia forficata Link is popularly used in Brazil to induce diuresis, no scientific investigation has focused on demonstrating its efficacy in preclinical trials. For that, normotensive male Wistar and spontaneously hypertensive rats were used to test the effect of extracts and kaempferitrin obtained from Bauhinia forficata leaves in the experimental model of diuresis. Cumulative urine volume, Na + and K + excretion, calcium, creatinine, prostaglandin E 2 , pH, density, and conductivity were measured at the end of the experiment (after 8 or 24 h). The treatment with aqueous infusion, methanolic extract, trichloromethane, or ethyl acetate-butanolic fractions significantly increase urinary volume and electrolytes levels when orally given to rats, without altering the pH or density parameters. Kaempferitrin induced diuretic, natriuretic, but not kaliuretic effects in both normotensive and hypertensive rats. In addition, kaempferitrin enhanced urinary creatinine and prostaglandin E 2 excretion, without modifying calcium levels. Kaempferitrin-induced diuresis was unaffected by previous treatment with a nonselective inhibitor of nitric oxide synthase and neither with a nonselective muscarinic receptor antagonist. On the other hand, a cyclooxygenase inhibitor was able to decrease its effect when compared with vehicle-treated rats, suggesting that the diuretic and natriuretic properties from kaempferitrin are associated with endogenous prostanoids generation. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development

PubMed Central

2014-01-01

Introduction Micronized dehydrated human amnion/chorion membrane (μ-dHACM) is derived from donated human placentae and has anti-inflammatory, low immunogenic and anti-fibrotic properties. The objective of this study was to quantitatively assess the efficacy of μ-dHACM as a disease modifying intervention in a rat model of osteoarthritis (OA). It was hypothesized that intra-articular injection of μ-dHACM would attenuate OA progression. Methods Lewis rats underwent medial meniscal transection (MMT) surgery to induce OA. Twenty four hours post-surgery, μ-dHACM or saline was injected intra-articularly into the rat joint. Naïve rats also received μ-dHACM injections. Microstructural changes in the tibial articular cartilage were assessed using equilibrium partitioning of an ionic contrast agent (EPIC-μCT) at 21 days post-surgery. The joint was also evaluated histologically and synovial fluid was analyzed for inflammatory markers at 3 and 21 days post-surgery. Results There was no measured baseline effect of μ-dHACM on cartilage in naïve animals. Histological staining of treated joints showed presence of μ-dHACM in the synovium along with local hypercellularity at 3 and 21 days post-surgery. In MMT animals, development of cartilage lesions at 21 days was prevented and number of partial erosions was significantly reduced by treatment with μ-dHACM. EPIC-μCT analysis quantitatively showed that μ-dHACM reduced proteoglycan loss in MMT animals. Conclusions μ-dHACM is rapidly sequestered in the synovial membrane following intra-articular injection and attenuates cartilage degradation in a rat OA model. These data suggest that intra-articular delivery of μ-dHACM may have a therapeutic effect on OA development. PMID:24499554

S-Ketamine Rapidly Reverses Synaptic and Vascular Deficits of Hippocampus in Genetic Animal Model of Depression.

PubMed

Ardalan, Maryam; Wegener, Gregers; Rafati, Ali H; Nyengaard, Jens R

2017-03-01

The neurovascular plasticity of hippocampus is an important theory underlying major depression. Ketamine as a novel glutamatergic antidepressant drug can induce a rapid antidepressant effect within hours. In a mechanistic proof of this concept, we examined whether ketamine leads to an increase in synaptogenesis and vascularization within 24 hours after a single injection in a genetic rat model of depression. Flinders Sensitive Line and Flinders Resistant Line rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline. One day later, their behavior was evaluated by a modified forced swim test. Microvessel length was evaluated with global spatial sampling and optical microscopy, whereas the number of asymmetric synapses was quantified through serial section electron microscopy by using physical disector method in the CA1.stratum radiatum area of hippocampus. The immobility time in the forced swim test among Flinders Sensitive Line rats with ketamine treatment was significantly lower compared with Flinders Sensitive Line rats without treatment. The number of nonperforated and perforated synapses was significantly higher in the Flinders Sensitive Line-ketamine vs the Flinders Sensitive Line-vehicle group; however, ketamine did not induce a significant increase in the number of shaft synapses. Additionally, total length of microvessels was significantly increased 1 day after ketamine treatment in Flinders Sensitive Line rats in the hippocampal subregions, including the CA1.stratum radiatum. Our findings indicate that hippocampal vascularization and synaptogenesis is co-regulated rapidly after ketamine, and microvascular elongation may be a supportive factor for synaptic plasticity and neuronal activity. These findings go hand-in-hand with the behavioral observations, where ketamine acts as a potent antidepressant. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Prophylactic treatment with levetiracetam after status epilepticus: lack of effect on epileptogenesis, neuronal damage, and behavioral alterations in rats.

PubMed

Brandt, Claudia; Glien, Maike; Gastens, Alexandra M; Fedrowitz, Maren; Bethmann, Kerstin; Volk, Holger A; Potschka, Heidrun; Löscher, Wolfgang

2007-08-01

Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.

Effect of a cocoa-enriched diet on immune response and anaphylaxis in a food allergy model in Brown Norway rats.

PubMed

Abril-Gil, Mar; Pérez-Cano, Francisco J; Franch, Àngels; Castell, Margarida

2016-01-01

Previous studies have demonstrated that cocoa intake decreased Th2 immune-related antibodies in rats. In consequence, we aimed to study in depth this cocoa action, particularly assessing its effect on a rat model of food allergy (FA) and also on an anaphylactic response. The involvement of the intestinal immune system was analyzed to allow the action mechanisms to be investigated. The role of cocoa flavonoids in the antiallergic properties of cocoa was also established. Brown Norway rats were fed either a reference diet or diets containing conventional cocoa (CC) or nonfermented cocoa (NFC). FA to ovalbumin (OVA) was induced and, later, an anaphylactic response was provoked. As expected, the synthesis of anti-OVA IgE and other Th2-related antibodies was inhibited by CC diet. In addition, the release of mast cell protease II after anaphylaxis was partially prevented by CC, although other variables were not modified. The CC diet also attenuated the increase of some Th2-related cytokines released from mesenteric lymph node and spleen cells, and modulated the intestinal gene expression of molecules involved in allergic response. These results demonstrated the local and systemic influence of CC diet. The effects of the NFC diet were weaker than those of CC, suggesting that cocoa components other than flavonoids play a role in cocoa's action. In conclusion, by acting on intestinal and systemic immune functions, a cocoa-enriched diet in rats exhibited a protective effect against FA and partially against anaphylaxis, making this a food of high interest to the fields of health and immunonutrition. Copyright © 2015 Elsevier Inc. All rights reserved.

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

PubMed Central

Sagar, Devi Rani; Ashraf, Sadaf; Xu, Luting; Burston, James J; Menhinick, Matthew R; Poulter, Caroline L; Bennett, Andrew J; Walsh, David A; Chapman, Victoria

2014-01-01

Background Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). Objectives To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Methods Male Sprague Dawley rats (140–260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1–15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Results Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Conclusions Our data suggest that early targeting of osteoclasts may reduce pain associated with OA. PMID:23723320

Comparative effects of sodium channel blockers in short term rat whole embryo culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nilsson, Mats F, E-mail: Mats.Nilsson@farmbio.uu.se; Sköld, Anna-Carin; Ericson, Ann-Christin

2013-10-15

This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effectmore » on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.« less

Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs.

PubMed

Lipska, Barbara K; Lerman, Daniel N; Khaing, Zin Z; Weickert, Cynthia Shannon; Weinberger, Daniel R

2003-07-01

We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase-67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment-naïve sham and neonatally VH-lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down-regulated in the striatum, GAD67 mRNA was down-regulated in the prefrontal cortex and prodynorphin mRNA was up-regulated in the striatum of the VH-lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up-regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug-induced expression of any genes examined in this study.

Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure.

PubMed

Rouas, Caroline; Souidi, Maâmar; Grandcolas, Line; Grison, Stephane; Baudelin, Cedric; Gourmelon, Patrick; Pallardy, Marc; Gueguen, Yann

2009-11-01

The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. Copyright © 2009 Elsevier B.V. All rights reserved.

Tempol effect on epithelial-mesenchymal transition induced by hyperglycemia

PubMed Central

Jafari, Mohammad; Dadras, Farahnaz; Ghadimipour, Hamid Reza; Seif Rabiei, Mohamad Ali; Khoshjou, Farhad

2017-01-01

Background One of common mechanisms in pathophysiology of chronic kidney diseases is epithelial-mesenchymal transition (EMT). On the other hand oxidative stress has been known to participate in kidney damage of diabetic nephropathy (DN). Objectives We studied if tempol, a well-known antioxidant agent, can ameliorate EMT in DN induced in male rats. Materials and Methods Twenty-seven male rats were equally divided in to 4 groups. Group I (control or C), group II (diabetic or D), group III (T) rats which was given tempol (100 mg/kg/day) by gavages for 28 days and group IV (D&T) was diabetic rats that also received same dose of tempol. After treatment, their kidneys were studied by immunohistochemicalstaining. Results Pathological changes in the kidney were detected concurrently with increasing kidney weight and urinary albumin excretion. In addition, EMT indices, i.e. decline of E-cadherin and increase of α SMA staining were significantly emerged in the renal tubular cells of diabetic group and were partially modified in diabetic group which were simultaneously treated by tempol. Conclusions Tempol can modify, but not significantly, EMT induced by DN. PMID:28042546

Effects of Trichostatin A on drug uptake transporters in primary rat hepatocyte cultures

PubMed Central

Ramboer, Eva; Rogiers, Vera; Vanhaecke, Tamara; Vinken, Mathieu

2015-01-01

The present study was set up to investigate the effects of Trichostatin A (TSA), a prototypical epigenetic modifier, on the expression and activity of hepatic drug uptake transporters in primary cultured rat hepatocytes. To this end, the expression of the sinusoidal transporters sodium-dependent taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 4 (Oatp4) was monitored by real-time quantitative reverse transcriptase polymerase chain reaction analysis and immunoblotting. The activity of the uptake transporters was analyzed using radiolabeled substrates and chemical inhibitors. Downregulation of the expression and activity of Oatp4 and Ntcp was observed as a function of the cultivation time and could not be counteracted by TSA. In conclusion, the epigenetic modifier TSA does not seem to exert a positive effect on the expression and activity of the investigated uptake transporters in primary rat hepatocyte cultures. PMID:26648816

Lactobacillus johnsonii N6.2 Mitigates the Development of Type 1 Diabetes in BB-DP Rats

PubMed Central

Li, Nan; Williams, Emily; Lai, Kin-Kwan; Abdelgeliel, Asmaa Sayed; Gonzalez, Claudio F.; Wasserfall, Clive H.; Larkin, Joseph; Schatz, Desmond; Atkinson, Mark A.; Triplett, Eric W.; Neu, Josef; Lorca, Graciela L.

2010-01-01

Background The intestinal epithelium is a barrier that composes one of the most immunologically active surfaces of the body due to constant exposure to microorganisms as well as an infinite diversity of food antigens. Disruption of intestinal barrier function and aberrant mucosal immune activation have been implicated in a variety of diseases within and outside of the gastrointestinal tract. With this model in mind, recent studies have shown a link between diet, composition of intestinal microbiota, and type 1 diabetes pathogenesis. In the BioBreeding rat model of type 1 diabetes, comparison of the intestinal microbial composition of diabetes prone and diabetes resistant animals found Lactobacillus species were negatively correlated with type 1 diabetes development. Two species, Lactobacillus johnsonii and L. reuteri, were isolated from diabetes resistant rats. In this study diabetes prone rats were administered pure cultures of L. johnsonii or L. reuteri isolated from diabetes resistant rats to determine the effect on type 1 diabetes development. Methodology/Principal Findings Results Rats administered L. johnsonii, but not L. reuteri, post-weaning developed type 1 diabetes at a protracted rate. Analysis of the intestinal ileum showed administration of L. johnsonii induced changes in the native microbiota, host mucosal proteins, and host oxidative stress response. A decreased oxidative intestinal environment was evidenced by decreased expression of several oxidative response proteins in the intestinal mucosa (Gpx1, GR, Cat). In L. johnsonii fed animals low levels of the pro-inflammatory cytokine IFNγ were correlated with low levels of iNOS and high levels of Cox2. The administration of L. johnsonii also resulted in higher levels of the tight junction protein claudin. Conclusions It was determined that the administration of L. johnsonii isolated from BioBreeding diabetes resistant rats delays or inhibits the onset of type 1 diabetes in BioBreeding diabetes prone rats. Taken collectively, these data suggest that the gut and the gut microbiota are potential agents of influence in type 1 diabetes development. These data also support therapeutic efforts that seek to modify gut microbiota as a means to modulate development of this disorder. PMID:20463897

Lactobacillus johnsonii N6.2 mitigates the development of type 1 diabetes in BB-DP rats.

PubMed

Valladares, Ricardo; Sankar, Dhyana; Li, Nan; Williams, Emily; Lai, Kin-Kwan; Abdelgeliel, Asmaa Sayed; Gonzalez, Claudio F; Wasserfall, Clive H; Larkin, Joseph; Schatz, Desmond; Atkinson, Mark A; Triplett, Eric W; Neu, Josef; Lorca, Graciela L

2010-05-06

The intestinal epithelium is a barrier that composes one of the most immunologically active surfaces of the body due to constant exposure to microorganisms as well as an infinite diversity of food antigens. Disruption of intestinal barrier function and aberrant mucosal immune activation have been implicated in a variety of diseases within and outside of the gastrointestinal tract. With this model in mind, recent studies have shown a link between diet, composition of intestinal microbiota, and type 1 diabetes pathogenesis. In the BioBreeding rat model of type 1 diabetes, comparison of the intestinal microbial composition of diabetes prone and diabetes resistant animals found Lactobacillus species were negatively correlated with type 1 diabetes development. Two species, Lactobacillus johnsonii and L. reuteri, were isolated from diabetes resistant rats. In this study diabetes prone rats were administered pure cultures of L. johnsonii or L. reuteri isolated from diabetes resistant rats to determine the effect on type 1 diabetes development. Findings Results Rats administered L. johnsonii, but not L. reuteri, post-weaning developed type 1 diabetes at a protracted rate. Analysis of the intestinal ileum showed administration of L. johnsonii induced changes in the native microbiota, host mucosal proteins, and host oxidative stress response. A decreased oxidative intestinal environment was evidenced by decreased expression of several oxidative response proteins in the intestinal mucosa (Gpx1, GR, Cat). In L. johnsonii fed animals low levels of the pro-inflammatory cytokine IFNgamma were correlated with low levels of iNOS and high levels of Cox2. The administration of L. johnsonii also resulted in higher levels of the tight junction protein claudin. It was determined that the administration of L. johnsonii isolated from BioBreeding diabetes resistant rats delays or inhibits the onset of type 1 diabetes in BioBreeding diabetes prone rats. Taken collectively, these data suggest that the gut and the gut microbiota are potential agents of influence in type 1 diabetes development. These data also support therapeutic efforts that seek to modify gut microbiota as a means to modulate development of this disorder.

Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive-like behaviour in the WAG/Rij rat model of absence epilepsy

PubMed Central

Citraro, Rita; Leo, Antonio; De Fazio, Pasquale; De Sarro, Giovambattista; Russo, Emilio

2015-01-01

Background and Purpose Two of the most relevant unmet needs in epilepsy are represented by the development of disease-modifying drugs able to affect epileptogenesis and/or the study of related neuropsychiatric comorbidities. No systematic study has investigated the effects of chronic treatment with antipsychotics or antidepressants on epileptogenesis. However, such drugs are known to influence seizure threshold. Experimental Approach We evaluated the effects of an early long-term treatment (ELTT; 17 weeks), started before seizure onset (P45), with fluoxetine (selective 5-HT-reuptake inhibitor), duloxetine (dual-acting 5-HT-noradrenaline reuptake inhibitor), haloperidol (typical antipsychotic drug), risperidone and quetiapine (atypical antipsychotic drugs) on the development of absence seizures and comorbid depressive-like behaviour in the WAG/Rij rat model. Furthermore, we studied the effects of these drugs on established absence seizures in adult (6-month-old) rats after a chronic 7 weeks treatment. Key Results ELTT with all antipsychotics did not affect the development of seizures, whereas, both ELTT haloperidol (1 mg·kg−1 day−1) and risperidone (0.5 mg·kg−1 day−1) increased immobility time in the forced swimming test and increased absence seizures only in adult rats (7 weeks treatment). In contrast, both fluoxetine (30 mg·kg−1 day−1) and duloxetine (10–30 mg·kg−1 day−1) exhibited clear antiepileptogenic effects. Duloxetine decreased and fluoxetine increased absence seizures in adult rats. Duloxetine did not affect immobility time; fluoxetine 30 mg·kg−1 day−1 reduced immobility time while at 10 mg·kg−1 day−1 an increase was observed. Conclusions and Implications In this animal model, antipsychotics had no antiepileptogenic effects and might worsen depressive-like comorbidity, while antidepressants have potential antiepileptogenic effects even though they have limited effects on comorbid depressive-like behaviour. PMID:25754610

Central and peripheral anti-hyperalgesic effects of diosmin in a neuropathic pain model in rats.

PubMed

Carballo-Villalobos, Azucena Ibeth; González-Trujano, María Eva; Pellicer, Francisco; Alvarado-Vásquez, Noé; López-Muñoz, Francisco Javier

2018-01-01

Flavonoids are natural compounds showing anti-hyperalgesic activity in models of pain. Diosmin is a compound poorly studied in the treatment of neuropathic pain. This study evaluates the anti-hyperalgesic actions of diosmin and possible mechanisms of action involved by using a neuropathic pain model in rats. Experimental neuropathic pain was induced by chronic constriction injury (CCI) in male Wistar rats, then aesthesiometric index and plantar tests were assessed to evaluate mechanical and thermal hyperalgesia, respectively, in order to explore the analgesic effects of acute and sub-chronic treatment with diosmin. The GABA A , 5-HT 1A , D 2 -like and opioid receptors participation, as well as levels of TNF-α, IL-1β and IL-6, were evaluated in the spinal cord and sciatic nerve tissues after acute and subchronic diosmin administration. In addition, the presence of diosmin on cerebral samples was determined by UHPLC-MS analysis. Acute and sub-chronic treatment with diosmin significantly diminished the mechanical and thermal hyperalgesia induced by CCI in rats. This anti-hyperalgesic effects of diosmin were modified in the presence of naloxone (1mg/kg, i.p.) and haloperidol (0.1mg/kg, i.p.), but not by GABA A and 5-HT 1A receptor antagonists. The anti-hyperalgesic effects of diosmin were also linked with reduced levels of TNF-α, IL-1β and IL-6. The presence of diosmin in the cerebral samples was confirmed by chromatographic analysis. In conclusion, our results provide evidence that diosmin produces significant anti-hyperalgesic effects acting at central level by an opioid and D 2 dopaminergic receptors participation, and at peripheral level by reducing proinflammatory cytokines. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor.

PubMed

Armour, S L; Foord, S; Kenakin, T; Chen, W J

1999-12-01

Receptor-activity-modifying proteins (RAMPs) are a family of single transmembrane domain proteins shown to be important for the transport and ligand specificity of the calcitonin gene-related peptide (CGRP) receptor. In this report, we describe the analysis of pharmacological properties of the human calcitonin receptor (hCTR) coexpressed with different RAMPs with the use of the Xenopus laevis melanophore expression system. We show that coexpression of RAMP3 with human calcitonin receptor changed the relative potency of hCTR to human calcitonin (hCAL) and rat amylin. RAMP1 and RAMP2, in contrast, had little effect on the change of hCTR potency to hCAL or rat amylin. When coexpressed with RAMP3, hCTR reversed the relative potency by a 3.5-fold loss in sensitivity to hCAL and a 19-fold increase in sensitivity to rat amylin. AC66, an inverse agonist, produced apparent simple competitive antagonism of hCAL and rat amylin, as indicated by linear Schild regressions. The potency of AC66 was changed in the blockade of rat amylin but not hCAL responses with RAMP3 coexpression. The mean pK(B) for AC66 to hCAL was 9.4 +/- 0.3 without RAMP3 and 9.45 +/- 0.07 with RAMP3. For the antagonism of AC66 to rat amylin, the pK(B) was 9.25 +/- 0.15 without RAMP3 and 8.2 +/- 0.35 with RAMP3. The finding suggests that RAMP3 might modify the active states of calcitonin receptor in such a way as to create a new receptor phenotype that is "amylin-like." Irrespective of the physiological association of the new receptor species, the finding that a coexpressed membrane protein can completely change agonist and antagonist affinities for a receptor raises implications for screening in recombinant receptor systems.

Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically

PubMed Central

Oliva, Joan; Dedes, Jennifer; Li, Jun; French, Samuel W; Bardag-Gorce, Fawzia

2009-01-01

AIM: To examine the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms. METHODS: Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341 (Bortezomib, Velcade™) by intraperitoneal injection. Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei. RESULTS: Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus, which led to changes in the turnover of transcriptional factors, histone-modifying enzymes, and, therefore, affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation, and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes, and, therefore, regulated the chromatin structure, allowing easy access to chromatin by RNA polymerase, and, thus, proper gene expression. Proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition, proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine, and, in particular, a significant decrease in the betaine-homocysteine methyltransferase enzyme. This suggested that hypomethylation was associated with proteasome inhibition, as indicated by the decrease in histone methylation. CONCLUSION: The role of proteasome inhibition in regulating epigenetic mechanisms, and its link to liver injury in alcoholic liver disease, is thus a promising approach to study liver injury due to chronic ethanol consumption. PMID:19222094

Neuroprotective effects of ebselen in traumatic brain injury model: involvement of nitric oxide and p38 mitogen-activated protein kinase signalling pathway.

PubMed

Wei, Liang; Zhang, Yanfei; Yang, Cheng; Wang, Qi; Zhuang, Zhongwei; Sun, Zhiyang

2014-02-01

Previous investigations have found that ebselen is able to treat neurodegenerative diseases caused by radical and acute total cerebral ischaemia. The aim of the present study was to investigate the neuroprotective effects of ebselen in a traumatic brain injury (TBI) model. Ninety Sprague-Dawley rats were randomly divided into five groups (n = 18 in each): (i) sham operation; (ii) an injury model group; (iii) low-dose (3 mg/kg) ebselen-treated group; (iv) a moderate-dose (10 mg/kg) ebselen-treated group; and (v) a high-dose (30 mg/kg) ebselen-treated group. The TBI model was created according using a modified weight-drop model. Neurological severity score (NSS), brain water content and histopathological deficits were assessed as parameters of injury severity. Expression of nitric oxide (NO), inducible NO synthase (iNOS) mRNA, Toll-like receptor (TLR) and phosphorylated (p-) p38 mitogen-activated protein kinase (MAPK) were examined by chemical colorimetry, quantitative polymerase chain reaction and western blotting 24 h after intragastric ebselen administration. Rats in the TBI model group exhibited markedly more severe neurological injury (higher NSS, more brain water content and more histopathological deficits) than those in the sham-operated group. Ebselen treatment significantly ameliorated the neurological injury of TBI rats in a dose-dependent manner. Moreover, ebselen significantly reduced the NO and iNOS mRNA levels and inhibited TLR4 and p-p38 MAPK expression, indicating the involvement of NO and p38 MAPK signalling pathways in the neuroprotection afforded by ebselen. In conclusion, ebselen ameliorated neurological injury, possibly by reducing NO levels and modulating the TLR4-mediated p38 MAPK signalling pathway. Therefore, ebselen may have potential to treat secondary injuries of TBI. © 2013 Wiley Publishing Asia Pty Ltd.

Role of mitochondrial dysfunction in renal fibrosis promoted by hypochlorite-modified albumin in a remnant kidney model and protective effects of antioxidant peptide SS-31.

PubMed

Zhao, Hao; Liu, Yan-Jun; Liu, Zong-Rui; Tang, Dong-Dong; Chen, Xiao-Wen; Chen, Yi-Hua; Zhou, Ru-Ning; Chen, Si-Qi; Niu, Hong-Xin

2017-06-05

Oxidative stress aggravates renal fibrosis, a pathway involved in almost all forms of chronic kidney disease (CKD). However, the underlying mechanism involved in the pathogenesis of renal oxidative stress has not been completely elucidated. In this study, we explored the role and mechanism of hypochlorite-modified albumin (HOCl-alb) in mediating oxidative stress and fibrotic response in a remnant-kidney rat model. Five-sixths nephrectomy (5/6 NX) was performed on the rats and then the animals were randomly assigned to intravenous treatment with either vehicle alone, or HOCl-rat serum albumin (RSA) in the presence or absence of SS-31 (administered intraperitoneally). A sham-operation control group was set up concurrently. Compared with the control group, 5/6 NX animals displayed marked mitochondrial (mt) dysfunction, as evidenced by decrease of mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and manganese superoxide dismutase (MnSOD) activity, release of cytochrome C (Cyto C) from mitochondria to the cytoplasm, and increase of mitochondrial reactive oxygen species in renal tissues. They also displayed increased levels of HOCl-alb in both plasma and renal tissues. These changes were accompanied by accumulation of extracellular matrix, worsened proteinuria, deteriorated renal function, and a marked increase of macrophage infiltration along with up-regulation of monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-β1 expression. HOCl-alb challenge further exacerbated the above biological effects in 5/6 NX animals, but these adverse effects were prevented by administration of SS-31, a mitochondrial targeted antioxidant peptide. These data suggest that accumulation of HOCl-alb may promote renal inflammation and fibrosis, probably related to mitochondrial oxidative stress and dysfunction and that the mitochondrial targeted peptide SS-31 might be a novel therapy for renal fibrosis and chronic renal failure (CRF). Copyright © 2017 Elsevier B.V. All rights reserved.

LTP Induction Modifies Functional Relationship among Hippocampal Neurons

ERIC Educational Resources Information Center

Yun, Sung H.; Lee, Deok S.; Lee, Hyunjung; Baeg, Eun H.; Kim, Yun B.; Jung, Min W.

2007-01-01

To obtain evidence linking long-term potentiation (LTP) and memory, we examined whether LTP induction modifies functional relationship among neurons in the rat hippocampus. In contrast to neurons in low-frequency stimulated or AP5-treated slices, LTP induction altered "functional connectivity," as defined by the degree of synchronous firing, among…

Longitudinal studies of time-dependent changes in both bladder and erectile function after streptozotocin-induced diabetes in Fischer 344 male rats.

PubMed

Melman, Arnold; Zotova, Elena; Kim, Mimi; Arezzo, Joseph; Davies, Kelvin; DiSanto, Michael; Tar, Moses

2009-11-01

To provide sensitive physiological endpoints for the onset and long-term progression of deficits induced by diabetes mellitus (DM) in bladder and erectile function in male rats, and to evaluate parallel changes in urogenital and nerve function induced by hyperglycaemia over a protracted period as a model for chronic deficits in patients with diabetes. The study comprised in 877 male, 3-month-old, Fischer 344 rats; 666 were injected intraperitoneally with 35 mg/kg streptozotocin (STZ) and divided into insulin-treated and untreated diabetic groups. The rats were studied over 8 months and measurements made of both erectile and bladder function, as well as nerve conduction studies over the duration of the study. There was an early (first month) abnormality of both erectile and bladder function that persisted through the 8 months of the study. The erectile dysfunction was manifest as reduced intracavernous pressure/blood pressure ratio, and the bladder dysfunction as a persistent increase in detrusor overactivity with no detrusor decompensation. Insulin treatment prevented or modified the abnormality in each organ. Hyperglycaemia caused a progressive decrease in caudal nerve conduction velocity. The mean digital sensory and tibial motor nerve conduction velocity did not deteriorate over time. Correlation measurements of nerve and organ function were not consistent. The results of this extensive long-term study show early and profound effects of hyperglycaemia on the smooth muscle of the penis and bladder, that were persistent and stable in surviving rats over the 8 months. The physiological changes did not correlate well with neurological measurements of those organs. Significantly, diverse smooth-muscle cellular and subcellular events antedated the measured neurological manifestations of the hyperglycaemia by several months. Although autonomic diabetic neuropathy is a primary life-threatening complication of long-term diabetes in humans, this rat model of STZ-induced diabetes showed that the rapid onset of physiological manifestations was based on many molecular changes in the smooth muscle cells in this model of type 1 DM.

Impact of exercise on fecal and cecal metabolome over aging: a longitudinal study in rats.

PubMed

Deda, Olga; Gika, Helen; Panagoulis, Theodoros; Taitzoglou, Ioannis; Raikos, Nikolaos; Theodoridis, Georgios

2017-01-01

Physical exercise can reduce adverse conditions during aging, while both exercise and aging act as metabolism modifiers. The present study investigates rat fecal and cecal metabolome alterations derived from exercise during rats' lifespan. Groups of rats trained life-long or for a specific period of time were under study. The training protocol consisted of swimming, 15-18 min per day, 3-5 days per week, with load of 4-0% of rat's weight. Fecal samples and cecal extracts were analyzed by targeted and untargeted metabolic profiling methods (GC-MS and LC-MS/MS). Effects of exercise and aging on the rats' fecal and cecal metabolome were observed. Fecal and cecal metabolomics are a promising field to investigate exercise biochemistry and age-related alterations.

Polysaccharide peptide from Coriolus versicolor induces interleukin 6-related extension of endotoxin fever in rats.

PubMed

Jedrzejewski, Tomasz; Piotrowski, Jakub; Kowalczewska, Malgorzata; Wrotek, Sylwia; Kozak, Wieslaw

2015-01-01

Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. In a previous study we showed that PSP induced a tumour necrosis factor-α (TNF-α)-dependent anapyrexia-like response in rats. Thus, PSP appears to be a factor which modifies a number of pathophysiological responses. Because of this, PSP is suggested as a potential adjuvant for cancer therapy during which cancer patients frequently contract microbial infections accompanied by fever. The aim of the present study was to investigate whether or not PSP can modulate the course of the fever in response to an antigen such as lipopolysaccharide (LPS). Body temperature (Tb) of male Wistar rats was measured by biotelemetry. PSP was injected intraperitoneally (i.p.) at a dose of 100 mg kg(-1), 2 h before LPS administration (50 µg kg(-1), i.p.). The levels of interleukin (IL)-6 and TNF-α in the plasma of rats were estimated 3 h and 14 h post-injection of PSP using a standard sandwich ELISA kit. We report that i.p. pre-injection of PSP 2 h before LPS administration expanded the duration of endotoxin fever in rats. This phenomenon was accompanied by a significant elevation of the blood IL-6 level of rats both 3 h and 14 h post-injection of PSP. Pre-treatment i.p. of the rats with anti-IL-6 antibody (30 µg/rat) prevented the PSP-induced prolongation of endotoxin fever. Based on these data, we conclude that PSP modifies the LPS-induced fever in IL-6-related fashion.

Restoration of CpG Methylation in The Egf Promoter Region during Rat Liver Regeneration.

PubMed

Deming, Li; Ziwei, Li; Xueqiang, Guo; Cunshuan, Xu

2015-01-01

Epidermal growth factor (EGF) is an important factor for healing after tissue damage in diverse experimental models. It plays an important role in liver regeneration (LR). The objective of this experiment is to investigate the methylation variation of 10 CpG sites in the Egf promoter region and their relevance to Egf expression during rat liver regenera- tion. As a follow up of our previous study, rat liver tissue was collected after rat 2/3 partial hepatectomy (PH) during the re-organization phase (from days 14 to days 28). Liver DNA was extracted and modified by sodium bisulfate. The methylation status of 10 CpG sites in Egf promoter region was determined using bisulfite sequencing polymerase chain reaction (PCR), as BSP method. The results showed that 3 (sites 3, 4 and 9) out of 10 CpG sites have strikingly methylation changes during the re-organization phase compared to the regeneration phase (from 2 hours to 168 hours, P=0.002, 0.048 and 0.018, respectively). Our results showed that methylation modification of CpGs in the Egf promoter region could be restored to the status before PH operation and changes of methylation didn't affect Egf mRNA expression during the re-organization phase.

Effects of insulin, dexamethasone and cytokines on {alpha}{sub 1}-acid glycoprotein gene expression in primary cultures of normal rat hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barraud, B.; Balavoine, S.; Feldmann, G.

1996-04-01

While the effects of insulin, dexamethasone and cytokines on {alpha}{sub 1}-acid glycoprotein gene expression have been investigated in various hepatoma cell lines, the individual and combined effects of these components on the expression of this gene have been rarely studied in cultured normal rat hepatocytes. In this cell model, we have shown that mRNA levels of {alpha}{sub 1}-acid glycoprotein were not decreased at least during the first 24 h of culture under basal conditions. During these short-term cultures, the expression of {alpha}{sub 1}-acid glycoprotein in normal hepatocytes showed a high degree of responsiveness to dexamethasone alone (20-fold increase) and tomore » dexamethasone associated with various cytokines (interleukin-1{beta}, interleukin-6 and tumor necrosis factor {alpha}) with a 40 to 100-fold increase depending on the cytokine. Insulin alone did not modify {alpha}{sub 1}-acid glycoprotein mRNA; however, this hormone exerted a positive effect (about 50% increase) in the presence of dexamethasone or dexamethasone with cytokines. These results indicate that the regulation of {alpha}{sub 1}-acid glycoprotein in cultured normal rat hepatocytes presents major differences when compared to reported observations in rat hepatoma cell lines. 49 refs., 2 figs., 2 tabs.« less

Aspartame Administration and Insulin Treatment Altered Brain Levels of CYP2E1 and CYP3A2 in Streptozotocin-Induced Diabetic Rats.

PubMed

Nosti-Palacios, Rosario; Gómez-Garduño, Josefina; Molina-Ortiz, Dora; Calzada-León, Raúl; Dorado-González, Víctor Manuel; Vences-Mejía, Araceli

2014-07-01

This study demonstrates that aspartame consumption and insulin treatment in a juvenile diabetic rat model leads to increase in cytochrome P450 (CYP) 2E1 and CYP3A2 isozymes in brain. Diabetes mellitus was induced in postweaned 21-day-old Wistar male rat by streptozotocin. Animals were randomly assigned to one of the following groups: untreated control, diabetic (D), D-insulin, D-aspartame, or the D-insulin + aspartame-treated group. Brain and liver tissue samples were used to analyze the activity of CYP2E1 and CYP3A2 and protein levels. Our results indicate that combined treatment with insulin and aspartame in juvenile diabetic rats significantly induced CYP2E1 in the cerebrum and cerebellum without modifying it in the liver, while CYP3A2 protein activity increased both in the brain and in the liver. The induction of CYP2E1 in the brain could have important in situ toxicological effects, given that this CYP isoform is capable of bioactivating various toxic substances. Additionally, CYP3A2 induction in the liver and brain could be considered a decisive factor in the variation of drug response and toxicity. © The Author(s) 2014.

Norfloxacin is more effective than Rifaximin in avoiding bacterial translocation in an animal model of cirrhosis.

PubMed

Gómez-Hurtado, Isabel; Gimenez, Paula; García, Irma; Zapater, Pedro; Francés, Rubén; González-Navajas, José M; Manichanh, Chaysavanh; Ramos, José M; Bellot, Pablo; Guarner, Francisco; Such, José

2018-02-01

Norfloxacin administration is useful in preventing bacterial infections in cirrhosis but associated to the generation of resistant species. Rifaximin is known to reach high concentrations in the intestinal lumen without generating relevant resistance in the intestinal flora. Our aim was to compare the effect of Norfloxacin and Rifaximin on intestinal flora composition, bacterial translocation and survival in cirrhotic rats. Cirrhosis was induced in rats by oral administration of CCl 4 . Animals were divided into three groups: only CCl 4 (group I, n = 10); CCl 4 + Norfloxacin (group II, n = 17) and CCl 4 + Rifaximin (group III, n = 14). Gut bacterial composition, bacterial translocation and cytokine levels were measured. Forty-one rats were finally included. The incidence of viable and non-viable bacterial translocation was significantly reduced in animals receiving Norfloxacin; Rifaximin also decreased the incidence of viable and non-viable bacterial translocation, but did not reach statistical significance. Serum TNF-α levels were significantly lower in antibiotic groups. Norfloxacin modified intestinal microbiota, depleting significantly more pathobionts than Rifaximin. Norfloxacin is more effective than Rifaximin in preventing bacterial translocation in rats with cirrhosis probably because of its capacity to reduce pathobionts from intestinal microbiota. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bioavailability of zinc, copper, and manganese from infant diets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bell, J.G.

1987-01-01

A series of trace element absorption experiments were performed using the Sprague-Dawley suckling rat put and infant rhesis monkey (Macaca mulatta) with extrinsic radiolabeling to assess the bioavailability of Zn, Cu, and Mn from infant diets and to examine specific factors that affect absorption of these essential nutrients. Bioavailability of Cu as assessed by 6 h liver uptake (% of /sup 64/Cu dose) was highest from human milk and cow milk based formula and significantly lower from cow milk and soy based formula. Copper bioavailability from infant cereal products as assessed by whole body uptake (% of /sup 64/Cu dose)more » in d 20 rats, 9 h postintubation, was low compared to the bioavailability from cow milk or human milk alone. /sup 65/Zn uptake in d 20 rats, 9 h postintubation, was significantly lower from cereals fed alone or in combination with cow or human milk as compared to the uptake from the milks fed alone. Zn bioavailability varied among cereal diets, (lowest from cereals containing phytate and highest from cereal/fruit products). Mn bioavailability from infant diets was assessed using a modified suckling rat pup model. Bioavailability (24 h whole body retention of /sup 54/Mn) was high from all milks and commercial formulas tested.« less

Restoration of CpG Methylation in The Egf Promoter Region during Rat Liver Regeneration

PubMed Central

Deming, Li; Ziwei, Li; Xueqiang, Guo; Cunshuan, Xu

2015-01-01

Epidermal growth factor (EGF) is an important factor for healing after tissue damage in diverse experimental models. It plays an important role in liver regeneration (LR). The objective of this experiment is to investigate the methylation variation of 10 CpG sites in the Egf promoter region and their relevance to Egf expression during rat liver regenera- tion. As a follow up of our previous study, rat liver tissue was collected after rat 2/3 partial hepatectomy (PH) during the re-organization phase (from days 14 to days 28). Liver DNA was extracted and modified by sodium bisulfate. The methylation status of 10 CpG sites in Egf promoter region was determined using bisulfite sequencing polymerase chain reaction (PCR), as BSP method. The results showed that 3 (sites 3, 4 and 9) out of 10 CpG sites have strikingly methylation changes during the re-organization phase compared to the regeneration phase (from 2 hours to 168 hours, P=0.002, 0.048 and 0.018, respectively). Our results showed that methylation modification of CpGs in the Egf promoter region could be restored to the status before PH operation and changes of methylation didn’t affect Egf mRNA expression during the re-organization phase. PMID:26464832

Modified citrus pectin stops progression of liver fibrosis by inhibiting galectin-3 and inducing apoptosis of stellate cells.

PubMed

Abu-Elsaad, Nashwa M; Elkashef, Wagdi Fawzi

2016-05-01

Modified citrus pectin (MCP) is a pH modified form of the dietary soluble citrus peel fiber known as pectin. The current study aims at testing its effect on liver fibrosis progression. Rats were injected with CCl4 (1 mL/kg, 40% v/v, i.p., twice a week for 8 weeks). Concurrently, MCP (400 or 1200 mg/kg) was administered daily in drinking water from the first week in groups I and II (prophylactic model) and in the beginning of week 5 in groups III and IV (therapeutic model). Liver function biomarkers (ATL, AST, and ALP), fibrosis markers (laminin and hyaluronic acid), and antioxidant biomarkers (reduced glutathione (GSH) and superoxide dismutase (SOD)) were measured. Stained liver sections were scored for fibrosis and necroinflammation. Additionally, expression of galectin-3 (Gal-3), α-smooth muscle actin (SMA), tissue inhibitor metalloproteinase (TIMP)-1, collagen (Col)1A1, caspase (Cas)-3, and apoptosis related factor (FAS) were assigned. Modified pectin late administration significantly (p < 0.05) decreased malondialdehyde (MDA), TIMP-1, Col1A1, α-SMA, and Gal-3 levels and increased levels of FAS, Cas-3, GSH, and SOD. It also decreased percentage of fibrosis and necroinflammation significantly (p < 0.05). It can be concluded that MCP can attenuate liver fibrosis through an antioxidant effect, inhibition of Gal-3 mediated hepatic stellate cells activation, and induction of apoptosis.

[Comparison of anti-inflammatory activity between crude Atractylodes lancea and their processed products by stir-baking with bran in rat models of gastric ulcer].

PubMed

Yu, Yan; Jia, Tian-Zhu; Cai, Qian

2016-02-01

To compare the anti-inflammatory activity of the crude Atractylodes lancea (AL) and AL processed products by stir-baking with bran in rat models of gastric ulcer, and preliminarily explore the anti-ulcer mechanisms of AL, the model of gastric ulcer was imitated by local acetic acid injection into gastric mucosa in rats by surgery according to the modified Okabe method. All rats were randomly divided into the following 10 groups： sham-operation group, model group, omeprazole group, Sanjiu Weitai granule group, crude AL low dose group, crude AL middle dose group, crude AL high dose group, processed AL low dose group, processed AL middle dose group, and processed AL high dose group. Rats were administered via intragastric (ig) two times each day, for 10 consecutive days. Blood was collected from the abdominal aorta, serum was separated, and the ulcer tissues were taken. The levels of inflammatory factors interleukin 6, 8 (IL-6, 8), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) in serum and gastric tissues were determined by enzyme-linked immunosorbent assay (ELISA), and the mRNA expressions of TNF-α and IL-8 in gastric tissues were detected by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). The protein expressions of TNF-α and IL-8 in gastric tissues were detected by immunohistochemistry. Compared with sham-operation group, the levels of TNF-α, IL-8, IL-6, PGE2 as well as the mRNA expressions and protein expressions of TNF-α, IL-8 in gastric tissues were significantly higher in model group. The above levels were reduced in different degrees in all treatment groups. Compared with the crude AL, same dose of processed AL was more effective in decreasing the levels of TNF-α, IL-8, IL-6, PGE2 in serum and gastric tissues and down-regulating the mRNA expressions of TNF-α and IL-8 in gastric tissues, with significant difference in middle dose groups and high dose groups. The results showed that AL had potent anti-inflammatory effects in rat models of gastric ulcer induced by acetic acid, and the processed AL had more obvious effect. The anti-ulcer action of AL could be attributed partly to down-regulating the levels of TNF-α, IL-8, IL-6 and PGE2. Copyright© by the Chinese Pharmaceutical Association.

Acute biotoxic effect of styrene on rat liver. Correlation with enzyme-mediated mutagenicity of benzpyrene and acrylonitrile.

PubMed

Roberfroid, M; Poncelet, F; Lambotte-Vandepaer, M; Duverger-Van Bogaert, M; de Meester, C; Mercier, M

1978-01-01

Styrene is commonly used in western Europe for the manufacture of plastics suitable for packaging foodstuffs. This report demonstrates that, injected intraperitoneally at a dose as low as 10 mg/kg, styrene modifies the catalytic properties of aryl hydrocarbon hydroxylase by reducing its KM value. A similar effect is reported for two potent chemical carcinogens, 3-methylcholanthrene and benzo(a)pyrene. Ethylbenzene and benzo(e)pyrene and phenobarbital do not produce the same effect. Pretreatments of the rats with chemicals which modify aryl hydrocarbon hydroxylase also increase the capacity of the liver enzymes to activate benzopyrene to a mutagenic intermediate in vitro, as measured by the Ames test for mutagenicity. Exposure to both styrene and the other modifiers of the xenobiotic-metabolizing enzymes could thus influence the carcinogenic and toxic effects of chemicals which are activated by these enzymes. This hypothesis needs further investigation.

Effects of hydrocortisone and insulin on oxidative phosphorylation in liver and spleen mitochondria of rats exposed to fast neutrons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sutkovoi, D.A.; Alferov, A.N.; Letov, V.N.

The radioprotective effects of hydrocortisone and insulin on postradiation disturbances of energy metabolism in rats was investigated. The effects of neutron radiation on oxidative phosphorylation in mitochondria of the liver and spleen as well as the response modifying effects of hydrocortisone and insulin were discussed.

A 90-Day Toxicology Study of Meat from Genetically Modified Sheep Overexpressing TLR4 in Sprague-Dawley Rats

PubMed Central

Hu, Rui; Kan, Tongtong; Li, Yan; Zhang, Xiaosheng; Zhang, Jinlong; Lian, Ling; Han, Hongbing; Lian, Zhengxing

2015-01-01

Genetic modification offers alternative strategies to traditional animal breeding. However, the food safety of genetically modified (GM) animals has attracted increasing levels of concern. In this study, we produced GM sheep overexpressing TLR4, and the transgene-positive offsprings (F1) were confirmed using the polymerase chain reaction (PCR) and Southern blot. The expression of TLR4 was 2.5-fold compared with that of the wild-type (WT) sheep samples. During the 90-day safety study, Sprague-Dawley rats were fed with three different dietary concentrations (3.75%, 7.5%, and 15% wt/wt) of GM sheep meat, WT sheep meat or a commercial diet (CD). Blood samples from the rats were collected and analyzed for hematological and biochemical parameters, and then compared with hematological and biochemical reference ranges. Despite a few significant differences among the three groups in some parameters, all other values remained within the normal reference intervals and thus were not considered to be affected by the treatment. No adverse diet-related differences in body weights or relative organ weights were observed. Furthermore, no differences were observed in the gross necropsy findings or microscopic pathology of the rats whose diets contained the GM sheep meat compared with rats whose diets contained the WT sheep meat. Therefore, the present 90-day rat feeding study suggested that the meat of GM sheep overexpressing TLR4 had no adverse effect on Sprague-Dawley rats in comparison with WT sheep meat. These results provide valuable information regarding the safety assessment of meat derived from GM animals. PMID:25874566

Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs.

PubMed

Forner, Kristin; Roos, Carl; Dahlgren, David; Kesisoglou, Filippos; Konerding, Moritz A; Mazur, Johanna; Lennernäs, Hans; Langguth, Peter

2017-02-01

Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIF mod ) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. Fa/FeSSIF mod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. The compatibility of Fa/FeSSIF mod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. The optimized setup uses FaSSIF mod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

In situ monitoring of myenteric neuron activity using acetylcholinesterase-modified AlGaN/GaN solution-gate field-effect transistors.

PubMed

Müntze, Gesche Mareike; Pouokam, Ervice; Steidle, Julia; Schäfer, Wladimir; Sasse, Alexander; Röth, Kai; Diener, Martin; Eickhoff, Martin

2016-03-15

The response characteristics of acetylcholinesterase-modified AlGaN/GaN solution-gate field-effect transistors (AcFETs) are quantitatively analyzed by means of a kinetic model. The characterization shows that the covalent enzyme immobilization process yields reproducible AcFET characteristics with a Michaelis constant KM of (122 ± 4) μM for the immobilized enzyme layer. The increase of KM by a factor of 2.4 during the first four measurement cycles is attributed to partial denaturation of the enzyme. The AcFETs were used to record the release of acetylcholine (ACh) by neuronal tissue cultivated on the gate area upon stimulation by rising the extracellular K(+) concentration. The neuronal tissue constituted of isolated myenteric neurons from four to 12 days old Wistar rats, or sections from the muscularis propria containing the myenteric plexus from adult rats. For both cases the AcFET response was demonstrated to be related to the activity of the immobilized acetylcholinesterase using the reversible acetylcholinesterase blocker donepezil. A concentration response curve of this blocking agent revealed a half maximal inhibitory concentration of 40 nM which is comparable to values measured by complementary in vitro methods. Copyright © 2015 Elsevier B.V. All rights reserved.

Modifying influence of swine-serum-induced liver fibrosis on development of preneoplastic lesions in rat liver.

PubMed

Wada, S; Kato, T; Mutai, M; Ozaki, K; Yamaguchi, S; Kim, D J; Baba-Toriyama, H; Asamoto, M; Ito, N; Tsuda, H

1996-03-01

Modifying effects of fibrosis or a cirrhotic state, caused by treatment with swine serum (SS), on the induction of preneoplastic focal lesions were assessed in a rat medium-term liver bioassay model for the detection of environmental carcinogens, in which the test compound is administered during the promotion phase after initiation with diethylnitrosamine. In experiment I, repeated intraperitoneal administration of SS concomitantly with the hepatopromoting agent deoxycholic acid (DCA) or phenobarbital (PB) resulted in a cirrhotic state and a significant increase in the number or size of preneoplastic glutathione S-transferase placental form (GST-P)-positive liver cell foci as compared to the corresponding DCA or PB alone groups. In experiment II, SS was given prior to commencement of the same medium-term bioassay system, in which a known hepatopromoting agent, DCA, 17-alpha-ethynylestradiol, or 2-acetylaminofluorene, was applied. In this case, the liver did not show obvious cirrhotic change and, rather than any enhancement, slight inhibition of promotion occurred. The results indicate that a coexisting, but not a pre-existing, cirrhotic condition acts to increase growth pressure on GST-P+ preneoplastic foci, and suggest that concomitant administration of SS with the promoting agent could be applied to improve the sensitivity of the assay protocol.

Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats.

PubMed

Medina-López, Raúl; Vara-Gama, Nancy; Soria-Arteche, Olivia; Moreno-Rocha, Luis A; López-Muñoz, Francisco J

2018-01-26

The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of ( S )-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of ( S )-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in C max , AUC 0-24 , and AUC 0-∞ values were observed with caffeine administration ( p < 0.05). Also, significant differences in E max , T max , and AUC 0-4 values were determined when comparing the treatments with and without caffeine ( p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal E max model, a satisfactory correlation was found (R² > 0.99) as well as significant differences in E max and EC 50 values ( p < 0.05). With caffeine, E max and EC 50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action.

Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats

PubMed Central

Vara-Gama, Nancy; Soria-Arteche, Olivia; Moreno-Rocha, Luis A.; López-Muñoz, Francisco J.

2018-01-01

The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in Cmax, AUC0-24, and AUC0-∞ values were observed with caffeine administration (p < 0.05). Also, significant differences in Emax, Tmax, and AUC0-4 values were determined when comparing the treatments with and without caffeine (p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal Emax model, a satisfactory correlation was found (R2 > 0.99) as well as significant differences in Emax and EC50 values (p < 0.05). With caffeine, Emax and EC50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action. PMID:29373537

Progressive brain damage, synaptic reorganization and NMDA activation in a model of epileptogenic cortical dysplasia.

PubMed

Colciaghi, Francesca; Finardi, Adele; Nobili, Paola; Locatelli, Denise; Spigolon, Giada; Battaglia, Giorgio Stefano

2014-01-01

Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE) and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i) is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii) changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii) induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv) activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.

Oral administration of metal chelator ameliorates motor dysfunction after a small hemorrhage near the internal capsule in rat.

PubMed

Masuda, Tadashi; Hida, Hideki; Kanda, Yoshie; Aihara, Noritaka; Ohta, Kengo; Yamada, Kazuo; Nishino, Hitoo

2007-01-01

Cerebral hemorrhage leads to local production of free iron, radicals, cytokines, etc. To investigate whether a decrease of iron-mediated radical production influences functional recovery after intracerebral hemorrhage (ICH), a modified ICH rat model with a small hemorrhage near the internal capsule (IC) accompanied with relatively severe motor dysfunction was first developed. Then clioquinol (CQ), an iron chelator that reduces hydroxyl radical production, was orally administrated. Injection of different doses of Type IV collagenase (1.4 mul 1-200 U/ml) into the left striatum near the IC in Wistar rats showed that injection of 7.5 U/ml collagenase resulted in a small hemorrhoidal lesion near the IC with relatively severe motor dysfunction (IC model). Retrograde labeling of neurons in the sensory-motor cortex and axons in the corticospinal tract using Fluoro-gold (FG) injection into the spinal cord (C3-C4) showed that few labeled neurons in the sensory-motor cortex were detected in the IC model, FG-labeled axons disappeared, and FG-including ED-1-positive cells appeared within 24 hr in the IC. Assessments of behavior and histologic analysis after oral administration of CQ in the IC model indicated that oral administration of CQ prevented a decrease of FG-labeled neurons, and resulted in better motor-function recovery. CQ inhibited hydrogen peroxide-induced cell toxicity in oligodendrocytes in vitro, but not in neurons. Our data suggests that CQ ameliorated motor dysfunction after a small hemorrhage near the IC by a mechanism that is related to reduction of chain-reactive hydroxyl radical production in oligodendrocytes.

DEET potentiates the development and persistence of anticholinesterase dependent chronic pain signs in a rat model of Gulf War Illness pain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flunker, L.K., E-mail: lflunker@dental.ufl.edu

Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400 mg/kg; 50% topical) to an exposure protocol of permethrin (2.6 mg/kg; topical), chlorpyrifos (CP; 120 mg/kg), and pyridostigmine bromide (PB;13 mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (). Rats underwent behavioral testing before, during and after a 4 week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration. Additional studies were conducted tomore » assess the influence of acute DEET (10–100 μM) on muscle and vascular nociceptor K{sub v}7, K{sub DR}, Na{sub v}1.8 and Na{sub v}1.9. We report that a 50% concentration of DEET enhanced the development and persistence of pain-signs. Rats exposed to all 4 compounds exhibited ambulation deficits that appeared 5–12 weeks post-exposure and persisted through weeks 21–24. Rats exposed to only three agents (CP or PB excluded), did not fully develop ambulation deficits. When PB was excluded, rats also developed rest duration pain signs, in addition to ambulation deficits. There was no evidence that physiological doses of DEET acutely modified nociceptor K{sub v}7, K{sub DR}, Na{sub v}1.8 or Na{sub v}1.9 activities. Nevertheless, DEET augmented protocols decreased the conductance of K{sub v}7 expressed in vascular nociceptors harvested from chronically exposed rats. We concluded that DEET enhanced the development and persistence of pain behaviors, but the anticholinesterases CP and PB played a determinant role. - Highlights: • DEET accelerated and prolonged pain-like behaviors in a rat model of Gulf War Illness. • The development of pain behaviors were dependent upon chlorpyrifos and pyridostigmine. • Conductance of vascular nociceptor Kv7 was diminished 12 weeks following exposures. • DEET did not have any acute influence on nociceptor Kv7, Nav1.8, Nav1.9 or KDR.« less

Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase.

PubMed

Julienne, Cloé Mimsy; Tardieu, Marine; Chevalier, Stéphan; Pinault, Michelle; Bougnoux, Philippe; Labarthe, François; Couet, Charles; Servais, Stéphane; Dumas, Jean-François

2014-05-01

Cancer-induced cachexia describes the progressive skeletal muscle wasting associated with many cancers leading to shortened survival time in cancer patients. We previously reported that cardiolipin content and energy-wasting processes were both increased in liver mitochondria in a rat model of peritoneal carcinosis (PC)-induced cachexia. To increase the understanding of the cellular biology of cancer cachexia, we investigated the involvement of adenine nucleotide translocator (ANT) in mitochondrial energy-wasting processes in liver mitochondria of PC and pair-fed control rats and its interactions with cardiolipin in isolated liver mitochondria from healthy rats exposed to cardiolipin-enriched liposomes. We showed in this study that functional ANT content was decreased in liver mitochondria from PC rats but without any effects on the efficiency of ATP synthesis. Moreover, non-phosphorylating energy wasting was not affected by saturating concentrations of carboxyatractylate (CAT), a potent inhibitor of ANT, in liver mitochondria from PC rats. Decreased efficiency of ATP synthesis was found in normal liver mitochondria exposed to cardiolipin-enriched liposomes, with increased non-phosphorylating energy wasting, thus mimicking mitochondria from PC rats. However, the functional ANT content in these cardiolipin-enriched mitochondria was unchanged, although non-phosphorylating energy wasting was reduced by CAT-induced inhibition of ANT. Finally, non-phosphorylating energy wasting was increased in cardiolipin-enriched mitochondria with substrates for complexes 1 and 2, but not for complex 4. In conclusion, increased energy wasting measured in liver mitochondria from rats with cancer cachexia is dependent on cardiolipin but independent of ANT. Interactions between ANT and cardiolipin are modified when cancer cachexia occurs. Copyright © 2014 Elsevier B.V. All rights reserved.

Mct8 and trh co-expression throughout the hypothalamic paraventricular nucleus is modified by dehydration-induced anorexia in rats.

PubMed

Alvarez-Salas, Elena; Mengod, Guadalupe; García-Luna, Cinthia; Soberanes-Chávez, Paulina; Matamoros-Trejo, Gilberto; de Gortari, Patricia

2016-04-01

Thyrotropin-releasing hormone (TRH) is a neuropeptide with endocrine and neuromodulatory effects. TRH from the paraventricular hypothalamic nucleus (PVN) participates in the control of energy homeostasis; as a neuromodulator TRH has anorexigenic effects. Negative energy balance decreases PVN TRH expression and TSH concentration; in contrast, a particular model of anorexia (dehydration) induces in rats a paradoxical increase in TRH expression in hypophysiotropic cells from caudal PVN and high TSH serum levels, despite their apparent hypothalamic hyperthyroidism and low body weight. We compared here the mRNA co-expression pattern of one of the brain thyroid hormones' transporters, the monocarboxylate transporter-8 (MCT8) with that of TRH in PVN subdivisions of dehydration-induced anorexic (DIA) and control rats. Our aim was to identify whether a low MCT8 expression in anorexic rats could contribute to their high TRH mRNA content.We registered daily food intake and body weight of 7-day DIA and control rats and analyzed TRH and MCT8 mRNA co-expression throughout the PVN by double in situ hybridization assays. We found that DIA rats showed increased number of TRHergic cells in caudal PVN, as well as a decreased percentage of TRH-expressing neurons that co-expressed MCT8 mRNA signal. Results suggest that the reduced proportion of double TRH/MCT8 expressing cells may be limiting the entry of hypothalamic triiodothyronine to the greater number of TRH-expressing neurons from caudal PVN and be in part responsible for the high TRH expression in anorexia rats and for the lack of adaptation of their hypothalamic-pituitary-thyroid axis to their low food intake.

Protective Effect of Ad-VEGF-Bone Mesenchymal Stem Cells on Cerebral Infarction.

PubMed

Chen, Bo; Zhang, Feng; Li, Qiao-Yu; Gong, Aihua; Lan, Qing

2016-01-01

To understand the mechanism of intracerebroventricular transplantation of vascular endothelial growth factor (VEGF) genemodified bone mesenchymal stem cells (BMSCs) in rats after cerebral infarction. The middle cerebral artery occlusion ischemia/reperfusion (MCAO I/R) model was established in rats using the Zea-Longa suture method. A recombinant adenovirus (Ad-VEGF) was engineered to express VEGF. The rats were divided into 3 groups. Control BMSC infected with control adenovirus (BMSC-Ad), BMSC infected by Ad-VEGF (BMSC-Ad-VEGF), and phosphate buffered saline (PBS) suspension were injected into the intracerebroventricular system of the rats in groups 1, 2 and 3 respectively, 24 hours after middle cerebral artery occlusion (MCAO). The neurological function of rats was evaluated with the modified Neurological Severity Scores (mNSS). The infarct volume of brain in rats was determined using 2,3,5-triphenyltetrazolium chloride (TTC) stain at 14 days. GFAP and pGSK3β expression of ischemic penumbra was determined using immunohistochemical method. GFAP, pAKT, AKT, and pGSK3β expressions were determined with Western blot. Functional improvement was accelerated in animals receiving BMSC-Ad, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with BMSC-Ad-VEGF than for other treated animals. The number of GFAP-labeled cells was prevented by post-ischemic BMSC-Ad-VEGF treatment; pMCAO activate the PI3K/AKT/GSK3β pathway to reduce reactive gliosis. Our findings demonstrate that PI3K/AKT/GSK3β pathway could reduce reactive gliosis, ameliorate neurological deficit, diminish the percentage of cerebral infarction volume in rats, and facilitate angiogenesis.

Multigeneration reproductive and developmental toxicity study of bar gene inserted into genetically modified potato on rats.

PubMed

Rhee, Gyu Seek; Cho, Dae Hyun; Won, Yong Hyuck; Seok, Ji Hyun; Kim, Soon Sun; Kwack, Seung Jun; Lee, Rhee Da; Chae, Soo Yeong; Kim, Jae Woo; Lee, Byung Mu; Park, Kui Lea; Choi, Kwang Sik

2005-12-10

Each specific protein has an individual gene encoding it, and a foreign gene introduced to a plant can be used to synthesize a new protein. The identification of potential reproductive and developmental toxicity from novel proteins produced by genetically modified (GM) crops is a difficult task. A science-based risk assessment is needed in order to use GM crops as a conventional foodstuff. In this study, the specific characteristics of GM food and low-level chronic exposure were examined using a five-generation animal study. In each generation, rats were fed a solid pellet containing 5% GM potato and non-GM potato for 10 wk prior to mating in order to assess the potential reproductive and developmental toxic effects. In the multigeneration animal study, there were no GM potato-related changes in body weight, food consumption, reproductive performance, and organ weight. Polymerase chain reaction (PCR) was carried out using extracted genomic DNA to examine the possibility of gene persistence in the organ tissues after a long-term exposure to low levels of GM feed. In each generation, the gene responsible for bar was not found in any of the reproductive organs of the GM potato-treated male and female rats, and the litter-related indexes did not show any genetically modified organism (GMO)-related changes. The results suggest that genetically modified crops have no adverse effects on the multigeneration reproductive-developmental ability.

Growth on poly(L-lactic acid) porous scaffold preserves CD73 and CD90 immunophenotype markers of rat bone marrow mesenchymal stromal cells.

PubMed

Zamparelli, Alessandra; Zini, Nicoletta; Cattini, Luca; Spaletta, Giulia; Dallatana, Davide; Bassi, Elena; Barbaro, Fulvio; Iafisco, Michele; Mosca, Salvatore; Parrilli, Annapaola; Fini, Milena; Giardino, Roberto; Sandri, Monica; Sprio, Simone; Tampieri, Anna; Maraldi, Nadir M; Toni, Roberto

2014-10-01

Few data are available on the effect of biomaterials on surface antigens of mammalian bone marrow-derived, adult mesenchymal stromal cells (MSCs). Since poly(L-lactic acid) or PLLA is largely used in tissue engineering of human bones, and we are developing a reverse engineering program to prototype with biomaterials the vascular architecture of bones for their bioartificial reconstruction, both in humans and animal models, we have studied the effect of porous, flat and smooth PLLA scaffolds on the immunophenotype of in vitro grown, rat MSCs in the absence of any coating, co-polymeric enrichment, and differentiation stimuli. Similar to controls on plastic, we show that our PLLA scaffold does not modify the distribution of some surface markers in rat MSCs. In particular, the maintained expression of CD73 and CD90 on two different subpopulations (small and large cells) is consistent with their adhesion to the PLLA scaffold through specialized appendages, and to their prominent content in actin. In addition, our PLLA scaffold favours retention of the intermediate filament desmin, believed a putative marker of undifferentiated state. Finally, it preserves all rat MSCs morphotypes, and allows for their survival, adhesion to the substrate, and replication. Remarkably, a subpopulation of rat MSCs grown on our PLLA scaffold exhibited formation of membrane protrusions of uncertain significance, although in a size range and morphology compatible with either motility blebs or shedding vesicles. In summary, our PLLA scaffold has no detrimental effect on a number of features of rat MSCs, primarily the expression of CD73 and CD90.

Memantine reduces alcohol drinking but not relapse in alcohol-dependent rats.

PubMed

Alaux-Cantin, Stéphanie; Buttolo, Romain; Houchi, Hakim; Jeanblanc, Jérôme; Naassila, Mickaël

2015-09-01

Alcoholism is a chronic relapsing disorder with consequences on health and that requires more effective treatments. Among alternative therapies, the therapeutic potential of the non-competitive N-methyl-D-aspartate receptor antagonist memantine has been suggested. Despite promising results, its efficiency in the treatment of alcoholism remains controversial. Currently, there is no pre-clinical data regarding its effects on the motivation for ethanol in post-dependent (PD) animals exposed to intermittent ethanol vapor, a validated model of alcoholism. Thus, the objectives of this study were to evaluate the effects of acute injections of memantine (0, 12.5, 25 and 50 mg/kg) on operant ethanol self-administration in non-dependent (ND) and PD rats tested either during acute withdrawal or relapse after protracted abstinence. Our results showed that memantine (25 mg/kg) abolished ethanol self-administration in ND rats and reduced by half the one of PD rats during acute withdrawal. While this effect was observed only 6 hours after treatment in ND rats, it was long lasting in PD rats (at least 30 hours after injection). Furthermore, our results indicated that memantine did not modify the breaking point for ethanol. This suggests that memantine probably act by potentiating the pharmacological effect of ethanol but not by reducing motivation for ethanol. Finally, memantine was also ineffective in reducing relapse after protracted abstinence. Altogether, our pre-clinical results highlighted a potential therapeutic use of memantine that may be used as a replacement therapy drug but not as relapse-preventing drug. © 2014 Society for the Study of Addiction.

Effects of fictive reward on rat's choice behavior

PubMed Central

Kim, Ko-Un; Huh, Namjung; Jang, Yunsil; Lee, Daeyeol; Jung, Min Whan

2015-01-01

Choices of humans and non-human primates are influenced by both actually experienced and fictive outcomes. To test whether this is also the case in rodents, we examined rat's choice behavior in a binary choice task in which variable magnitudes of actual and fictive rewards were delivered. We found that the animal's choice was significantly influenced by the magnitudes of both actual and fictive rewards in the previous trial. A model-based analysis revealed, however, that the effect of fictive reward was more transient and influenced mostly the choice in the next trial, whereas the effect of actual reward was more sustained, consistent with incremental learning of action values. Our results suggest that the capacity to modify future choices based on fictive outcomes might be shared by many different animal species, but fictive outcomes are less effective than actual outcomes in the incremental value learning system. PMID:25623929

Characterization of modified allergen extracts by in vitro beta-hexosaminidase release from rat basophils.

PubMed

Gehlhar, Kirsten; Peters, Marcus; Brockmann, Kirsten; van Schijndel, Hans; Bufe, Albrecht

2005-04-01

To date, there is no well-established test available that can be used to measure functional properties of modified allergens (allergoids). Due to the cross-linking process, the IgE-binding capacity of the allergens, normally necessary for their characterization, is lost. The aim of this study was to test whether the rat basophilic leukaemia (RBL) cell assay (beta-hexosaminidase release by rat basophils upon allergen stimulation) can be adopted to characterize allergoids and to evaluate the assay for testing allergoids and native allergens as well. Mice were immunized with native and modified Phleumpratense extracts in the presence of alum. Their sera were used to sensitize RBL-2H3 cells and measure basophil stimulation induced by different allergen extracts in the presence or absence of various additives. Sera containing specific IgE against both extract formulations were obtained. Native as well as modified extracts induced dose-dependent beta-hexosaminidase release from RBL cells. Both extracts were used to evaluate the characteristics of the assay, which showed high precision. Storage conditions were chosen to enhance extract degradation, which could be read directly from the altered stimulatory capacity of the extracts. Additives turned out to have diverse effects on the assay, whereas phenol had no measurable effect, alum had an inhibitory effect and glycerol elevated basophil activation. For the first time, a reliable, precise in vitro assay is available that is able to directly measure the properties of modified allergen extracts after their production process. The test is well evaluated and its advantages and limitations are discussed in this report. Copyright (c) 2005 S. Karger AG, Basel

A 90-day subchronic feeding study of genetically modified rice expressing Cry1Ab protein in Sprague-Dawley rats.

PubMed

Song, Huan; He, Xiaoyun; Zou, Shiying; Zhang, Teng; Luo, Yunbo; Huang, Kunlun; Zhu, Zhen; Xu, Wentao

2015-04-01

Bacillus thuringiensis (Bt) transgenic rice line (mfb-MH86) expressing a synthetic cry1Ab gene can be protected against feeding damage from Lepidopteran insects, including Sesamia inferens, Chilo suppressalis, Tryporyza incertulas and Cnaphalocrocis medinalis. Rice flour from mfb-MH86 and its near-isogenic control MH86 was separately formulated into rodent diets at concentrations of 17.5, 35 and 70 % (w/w) for a 90-day feeding test with rats, and all of the diets were nutritionally balanced. In this study, the responses of rats fed diets containing mfb-MH86 were compared to those of rats fed flour from MH86. Overall health, body weight and food consumption were comparable between groups fed diets containing mfb-MH86 and MH86. Blood samples were collected prior to sacrifice and a few significant differences (p < 0.05) were observed in haematological and biochemical parameters between rats fed genetically modified (GM) and non-GM diets. However, the values of these parameters were within the normal ranges of values for rats of this age and sex, thus not considered treatment related. In addition, upon sacrifice a large number of organs were weighed, macroscopic and histopathological examinations were performed with only minor changes to report. In conclusion, these results demonstrated that no toxic effect was observed in the conditions of the experiment, based on the different parameters assessed. GM rice mfb-MH86 is as safe and nutritious as non-GM rice.

Effects of Manufacturing Methods on Dissolution and Absorption of Ketoconazole in the Presence of Organic Acid as a pH Modifier.

PubMed

Adachi, Masashi; Hinatsu, Yuta; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Nakatani, Manabu; Wada, Koichi; Yamamoto, Akira

2017-05-01

Poorly water-soluble compounds have a potential risk of low and variable bioavailability caused by incomplete dissolution. Incorporation of organic acids as pH modifiers is effective method for solubility enhancement of basic compounds and requires no special technique and equipment. The purpose of this study was to evaluate the effect of manufacturing method on the extent of drug solubility enhancement. We successfully prepared the granules and tablets containing ketoconazole (KZ), which is weakly basic, as a model compound and citric acid as a pH modifier using conventional wet and dry granulations. KZ solubility under non-sink condition was enhanced with supersaturation using both wet and dry granulations. High-shear granulation was the most effective method in terms of KZ dissolution enhancement, because both an intimate contact and strong bonding between KZ and incorporated acid were achieved. KZ dissolved amount from the granules prepared by high-shear granulation was about eight times higher than that from the granules without the acid. The granulation involved to suppress a diffusion of acid dissolved, leading to the effectively maintained supersaturation state. The bioavailability of KZ after oral administration to rats was improved by applying high-shear granulation with citric acid independent of gastrointestinal pH. The granules prepared by high-shear granulation showed the bioavailability about 1.7-fold higher than that of the physical mixture in rats with and without neutralization of stomach. As a result, both the dissolution and absorption rates of KZ after oral administration were enhanced using conventional manufacturing technology.

Characterization, efficacy, pharmacokinetics, and biodistribution of 5kDa mPEG modified tetrameric canine uricase variant.

PubMed

Zhang, Chun; Fan, Kai; Luo, Hua; Ma, Xuefeng; Liu, Riyong; Yang, Li; Hu, Chunlan; Chen, Zhenmin; Min, Zhiqiang; Wei, Dongzhi

2012-07-01

PEGylated uricase is a promising anti-gout drug, but the only commercially marketed 10kDa mPEG modified porcine-like uricase (Pegloticase) can only be used for intravenous infusion. In this study, tetrameric canine uricase variant was modified by covalent conjugation of all accessible ɛ amino sites of lysine residues with a smaller 5kDa mPEG (mPEG-UHC). The average modification degree and PEGylation homogeneity were evaluated. Approximately 9.4 5 kDa mPEG chains were coupled to each monomeric uricase and the main conjugates contained 7-11 mPEG chains per subunit. mPEG-UHC showed significantly therapeutic or preventive effect on uric acid nephropathy and acute urate arthritis based on three different animal models. The clearance rate from an intravenous injection of mPEG-UHC varied significantly between species, at 2.61 mL/h/kg for rats and 0.21 mL/h/kg for monkeys. The long elimination half-life of mPEG-UHC in non-human primate (191.48 h, intravenous injection) indicated the long-term effects in humans. Moreover, the acceptable bioavailability of mPEG-UHC after subcutaneous administration in monkeys (94.21%) suggested that subcutaneous injection may be regarded as a candidate administration route in clinical trails. Non-specific tissue distribution was observed after administration of (125)I-labeled mPEG-UHC in rats, and elimination by the kidneys into the urine is the primary excretion route. Copyright © 2012 Elsevier B.V. All rights reserved.

Molecular, cellular, and tissue impact of depleted uranium on xenobiotic-metabolizing enzymes.

PubMed

Gueguen, Yann; Rouas, Caroline; Monin, Audrey; Manens, Line; Stefani, Johanna; Delissen, Olivia; Grison, Stéphane; Dublineau, Isabelle

2014-02-01

Enzymes that metabolize xenobiotics (XME) are well recognized in experimental models as representative indicators of organ detoxification functions and of exposure to toxicants. As several in vivo studies have shown, uranium can alter XME in the rat liver or kidneys after either acute or chronic exposure. To determine how length or level of exposure affects these changes in XME, we continued our investigation of chronic rat exposure to depleted uranium (DU, uranyl nitrate). The first study examined the effect of duration (1-18 months) of chronic exposure to DU, the second evaluated dose dependence, from a level close to that found in the environment near mining sites (0.2 mg/L) to a supra-environmental dose (120 mg/L, 10 times the highest level naturally found in the environment), and the third was an in vitro assessment of whether DU exposure directly affects XME and, in particular, CYP3A. The experimental in vivo models used here demonstrated that CYP3A is the enzyme modified to the greatest extent: high gene expression changed after 6 and 9 months. The most substantial effects were observed in the liver of rats after 9 months of exposure to 120 mg/L of DU: CYP3A gene and protein expression and enzyme activity all decreased by more than 40 %. Nonetheless, no direct effect of DU by itself was observed after in vitro exposure of rat microsomal preparations, HepG2 cells, or human primary hepatocytes. Overall, these results probably indicate the occurrence of regulatory or adaptive mechanisms that could explain the indirect effect observed in vivo after chronic exposure.

Xylopia aethiopica (Annonaceae) fruit extract suppresses Freund's adjuvant-induced arthritis in Sprague-Dawley rats.

PubMed

Obiri, David D; Osafo, Newman; Ayande, Patrick G; Antwi, Aaron O

2014-03-28

Xylopia aethiopica is used in a decoction of the dried fruit to treat bronchitis, asthma, arthritis, rheumatism, headache, neuralgia and colic pain. The aim of the study is to evaluate the anti-arthritic effects of a 70% aqueous ethanol extract of the fruit of Xylopia aethiopica in a chronic inflammatory model. Adjuvant arthritis was induced in Sprague-Dawley rats by intraplantar injection of Complete Freund's adjuvant into the right hind paw. Foot volume was measured by water displacement plethysmometry. The oedema component of inflammation was evaluated as the percentage change in paw swelling and the total oedema induced calculated as area under the time course curves. In addition to X-ray radiography, histopathology of ankle joints supported by haematological analysis was used to assess the anti-arthritic action of the extract of Xylopia aethiopica (XAE). Xylopia aethiopica extract (100, 300 and 600 mg kg(-1)) modified the time course curve significantly reducing hind paw oedema in the ipsilateral paw at all dose levels when administered both prophylactically and therapeutically. In addition XAE significantly suppressed the systemic spread of the arthritis from the ipsilateral to the contralateral limbs. The radiological pictures of the joints particularly metatarsal, phalanges and the ankle joint space of rats in the XAE-treated group showed protective effect against adjuvant-induced arthritis while histopathology revealed significant reduction in mononuclear infiltration, pannus formation and bone erosion. The haematological analysis in the test animals revealed significant improvement relative to the CFA model group. Xylopia aethiopica XAE suppresses joint inflammation and destruction in arthritic rats. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Restraint hypothermia in cold-exposed rats at 3 G and 1 G

NASA Technical Reports Server (NTRS)

Monson, C. B.; Horowitz, J. M.; Horwitz, B. A.

1982-01-01

The relationship between heat loss, heat production, and hypothermia was investigated in experiments with rats which determined if hypergravity affects heat production by altering oxygen consumption and if restraint modifies the ability of the rats to activate thermogenic mechanisms after cold exposure in a hypergravic field. Restrained and unrestrained rats were exposed for 1 hr periods to 1 G and 3 G at ambient temperatures of 24 C or 10 C, and the rate of oxygen consumption, the core temperatures, and the tail temperatures were measured. Results show that thermoregulatory mechanisms are impaired when rats are exposed to 3 G fields, and at 24 C as well as at 10 C this impairment leads to an inappropriate increase in heat loss.

Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.

PubMed

Hadar, R; Bikovski, L; Soto-Montenegro, M L; Schimke, J; Maier, P; Ewing, S; Voget, M; Wieske, F; Götz, T; Desco, M; Hamani, C; Pascau, J; Weiner, I; Winter, C

2018-04-01

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

Imaging prostate cancer (PCa) with [99m Tc(CO)3 ]finasteride dithiocarbamate.

PubMed

Shah, Syed Qaiser; Gul-E-Raana; Uddin, Ghias

2018-06-15

This investigation aimed to modify finasteride (1) to finasteride dithiocarbamate (2) for subsequent synthesis of the rhenium analogue (3) and [ 99m Tc]tricarbonyl complexes (4), to assess its prostate cancer (PCa) targeting potential in a rat model. To validate the identity of (4), reference (3) has been synthesized by using fac-[Net 4 ] 2 [ReBr 3 (CO) 3 ] precursor and characterized by 1 H-NMR, 13 C-NMR, ESI-MS, and elemental analysis. The analogue (4) was synthesized by using fac-[ 99m Tc(H 2 O) 3 (CO) 3 ] + precursor, and its structure was confirmed by comparative HPLC by using (3) as a reference. Further, the suitability of (4) as a PCa imaging agent was investigated in vitro and in vivo. At room temperature, (4) had ≥99% radiochemical purity and remained ≥84% stable in serum. In preclinical studies, biodistribution of (4) in histopathologically established rat model showed adequately high in vivo uptake in the prostate attracting the possibility of using it for noninvasive imaging of PCa. Copyright © 2018 John Wiley & Sons, Ltd.

Effects of the methylene chloride fraction from modified Boyang-Hwan-o-Tang, a polyherbal medicine on transient middle cerebral artery occlusion-induced ischemia in rats.

PubMed

Oh, Tae Woo; Jung, Hyo Won; Shin, Gil Jo; Park, Yong-Ki

2014-01-28

To study the neuroprotective effect of the methylene chloride fraction from modified Boyang-Hwan-o-Tang (mBHT-MC), especially against neuronal apoptosis. mBHT-MC (10, 25 or 50 mg/kg) was orally administered once per day for 7 days in transient middle cerebral artery occlusion (MCAO)-induced ischemic rats. Infarction volumes was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining, neurological deficit score and the expression of apoptotic proteins such as Bcl-2, Bax and caspase-3 by Western blot in MCAO-induced ischemic brain. Neuronal apoptosis in ischemic phenumbra was also investigated by staining with hematoxylin and eosin, Nissl and Hoechst 33342. mBHT-MC administration in MCAO rats significantly decreased infarction volume and neurological deficit scores. mBHT-MC significantly enhanced Bcl-2 expression, and inhibited Bax and caspase-3 expression in ischemic brain. In addition, mBHT-MC significantly decreased the number of apoptotic neuronal cells in ischemic brains. mBHT-MC administration inhibits neuronal death induced by cerebral ischemia in rats, suggesting that mBHT-MC has a neuroprotective property in brain ischemia.

Evaluation of basal DNA damage and oxidative stress in Wistar rat leukocytes after exposure to microwave radiation.

PubMed

Garaj-Vrhovac, Vera; Gajski, Goran; Trosić, Ivancica; Pavicić, Ivan

2009-05-17

The aim of this study was to assess whether microwave-induced DNA damage is basal or it is also generated through reactive oxygen species (ROS) formation. After having irradiated Wistar rats with 915MHz microwave radiation, we assessed different DNA alterations in peripheral leukocytes using standard and formamidopyrimidine DNA-glycosylase (Fpg)-modified comet assay. The first is a sensitive tool for detecting primary DNA damage, and the second is much more specific for detecting oxidative damage. The animals were irradiated for 1h a day for 2 weeks at a field power density of 2.4W/m(2), and the whole-body average specific absorption rate (SAR) of 0.6W/kg. Both the standard and the Fpg-modified comet assay detected increased DNA damage in blood leukocytes of the exposed rats. The significant increase in Fpg-detected DNA damage in the exposed rats suggests that oxidative stress is likely to be responsible. DNA damage detected by the standard comet assay indicates that some other mechanisms may also be involved. In addition, both methods served proved sensitive enough to measure basal and oxidative DNA damage after long-term exposure to 915MHz microwave radiation in vivo.

Functionally Convergent B Cell Receptor Sequences in Transgenic Rats Expressing a Human B Cell Repertoire in Response to Tetanus Toxoid and Measles Antigens.

PubMed

Bürckert, Jean-Philippe; Dubois, Axel R S X; Faison, William J; Farinelle, Sophie; Charpentier, Emilie; Sinner, Regina; Wienecke-Baldacchino, Anke; Muller, Claude P

2017-01-01

The identification and tracking of antigen-specific immunoglobulin (Ig) sequences within total Ig repertoires is central to high-throughput sequencing (HTS) studies of infections or vaccinations. In this context, public Ig sequences shared by different individuals exposed to the same antigen could be valuable markers for tracing back infections, measuring vaccine immunogenicity, and perhaps ultimately allow the reconstruction of the immunological history of an individual. Here, we immunized groups of transgenic rats expressing human Ig against tetanus toxoid (TT), Modified Vaccinia virus Ankara (MVA), measles virus hemagglutinin and fusion proteins expressed on MVA, and the environmental carcinogen benzo[a]pyrene, coupled to TT. We showed that these antigens impose a selective pressure causing the Ig heavy chain (IgH) repertoires of the rats to converge toward the expression of antibodies with highly similar IgH CDR3 amino acid sequences. We present a computational approach, similar to differential gene expression analysis, that selects for clusters of CDR3s with 80% similarity, significantly overrepresented within the different groups of immunized rats. These IgH clusters represent antigen-induced IgH signatures exhibiting stereotypic amino acid patterns including previously described TT- and measles-specific IgH sequences. Our data suggest that with the presented methodology, transgenic Ig rats can be utilized as a model to identify antigen-induced, human IgH signatures to a variety of different antigens.

Neuroanatomic and behavioral correlates of urinary dysfunction induced by vaginal distension in rats.

PubMed

Palacios, J L; Juárez, M; Morán, C; Xelhuantzi, N; Damaser, M S; Cruz, Y

2016-05-01

The aim of the present study was to use a model of simulated human childbirth in rats to determine the damage to genitourinary structures and behavioral signs of urinary dysfunction induced by vaginal distension (VD) in female rats. In experiment 1, the length of the genitourinary tract and the nerves associated with it were measured immediately after simulated human delivery induced by VD or sham (SH) procedures. Electroneurograms of the dorsal nerve of the clitoris (DNC) were also recorded. In experiment 2, histological characteristics of the bladder and major pelvic ganglion of VD and SH rats were evaluated. In experiment 3, urinary parameters were determined in conscious animals during 6 h of dark and 6 h of light before and 3 days after VD or SH procedures. VD significantly increased distal vagina width (P < 0.001) and the length of the motor branch of the sacral plexus (P < 0.05), DNC (P < 0.05), and vesical nerves (P < 0.01) and decreased DNC frequency and amplitude of firing. VD occluded the pelvic urethra, inducing urinary retention, hematomas in the bladder, and thinness of the epithelial (P < 0.05) and detrusor (P < 0.01) layers of the bladder. Major pelvic ganglion parameters were not modified after VD. Rats dripped urine in unusual places to void, without the stereotyped behavior of micturition after VD. The neuroanatomic injuries after VD occur alongside behavioral signs of urinary incontinence as determined by a new behavioral tool for assessing micturition in conscious animals.

Morphological and cytohistochemical evaluation of renal effects of cadmium-doped silica nanoparticles given intratracheally to rat

NASA Astrophysics Data System (ADS)

Coccini, T.; Roda, E.; Barni, S.; Manzo, L.

2013-04-01

Renal morphological parameters were determined in rats intratracheally instilled with model cadmium-containing silica nanoparticles (Cd-SiNPs, 1mg/rat), also exploring whether their potential modifications would be associated with toxicogenomic changes. Cd-SiNP effects, evaluated 7 and 30 days post-exposure, were assessed by (i) histopathology (Haematoxylin/Eosin Staining), (ii) characterization of apoptotic features by TUNEL staining. Data were compared with those obtained by CdCl2 (400μg/rat), SiNPs (600μg/rat), 0.1 ml saline. Area-specific cell apoptosis was observed in all treatment groups: cortex and inner medulla were the most affected regions. Apoptotic changes were apparent at 7 days post-exposure in both areas, and were still observable in inner medulla 30 days after treatment. Increase in apoptotic frequency was more pronounced in Cd-SiNP-treated animals compared to either CdCl2 or SiNPs. Histological findings showed comparable alterations in the renal glomerular (cortex) architecture occurring in all treatment groups at both time-points considered. The glomeruli appeared often collapsed, showing condensed, packed mesangial and endothelial cells. Oedematous haemorrhagic glomeruli were also observed in Cd-SiNPs-treated animals. Bare SiNPs caused morphological and apoptotic changes without modifying the renal gene expression profile. These findings support the concept that multiple assays and an integrated testing strategy should be recommended to characterize toxicological responses to nanoparticles in mammalian systems.

Monobromobimane as an affinity label of the xenobiotic binding site of rat glutathione S-transferase 3-3.

PubMed

Hu, L; Colman, R F

1995-09-15

Monobromobimane (mBBr), besides being a substrate in the presence of glutathione, inactivates rat liver glutathione S-transferase 3-3 at pH 7.5 and 25 degrees C as assayed using 1-chloro-2,4-dinitrobenzene (CDNB). The rate of inactivation is enhanced about 5-fold by S-methylglutathione. Substrate analogs bromosulfophthalein and 2,4-dinitrophenol decrease the rate of inactivation at least 20-fold. Upon incubation for 60 min with 0.25 mM mBBr and S-methylglutathione, the enzyme loses 91% of its activity toward CDNB and incorporates 2.14 mol of reagent/mol of subunit, whereas incubation under the same conditions but with added protectant 2,4-dinitrophenol yields an enzyme that is catalytically active and contains only 0.89 mol of reagent/mol of subunit. mBBR-modified enzyme is fluorescent, and fluorescence energy transfer occurs between intrinsic tryptophan and covalently bound bimane in modified enzyme. Both Tyr115 and Cys114 are modified, but Tyr115 is the initial reaction target and its modification correlates with loss of activity toward CDNB. The fact that the activity toward mBBr is retained by the enzyme after modification suggests that rat isozyme 3-3 has two binding sites for mBBr.

Proliferation and osteogenic differentiation of rat BMSCs on a novel Ti/SiC metal matrix nanocomposite modified by friction stir processing

NASA Astrophysics Data System (ADS)

Zhu, Chenyuan; Lv, Yuting; Qian, Chao; Qian, Haixin; Jiao, Ting; Wang, Liqiang; Zhang, Fuqiang

2016-12-01

The aims of this study were to fabricate a novel titanium/silicon carbide (Ti/SiC) metal matrix nanocomposite (MMNC) by friction stir processing (FSP) and to investigate its microstructure and mechanical properties. In addition, the adhesion, proliferation and osteogenic differentiation of rat bone marrow stromal cells (BMSCs) on the nanocomposite surface were investigated. The MMNC microstructure was observed by both scanning and transmission electron microscopy. Mechanical properties were characterized by nanoindentation and Vickers hardness testing. Integrin β1 immunofluorescence, cell adhesion, and MTT assays were used to evaluate the effects of the nanocomposite on cell adhesion and proliferation. Osteogenic and angiogenic differentiation were evaluated by alkaline phosphatase (ALP) staining, ALP activity, PCR and osteocalcin immunofluorescence. The observed microstructures and mechanical properties clearly indicated that FSP is a very effective technique for modifying Ti/SiC MMNC to contain uniformly distributed nanoparticles. In the interiors of recrystallized grains, characteristics including twins, fine recrystallized grains, and dislocations formed concurrently. Adhesion, proliferation, and osteogenic and angiogenic differentiation of rat BMSCs were all enhanced on the novel Ti/SiC MMNC surface. In conclusion, nanocomposites modified using FSP technology not only have superior mechanical properties under stress-bearing conditions but also provide improved surface and physicochemical properties for cell attachment and osseointegration.

The Use of Trace Eyeblink Classical Conditioning to Assess Hippocampal Dysfunction in a Rat Model of Fetal Alcohol Spectrum Disorders

PubMed Central

Tran, Tuan D.; Amin, Aenia; Jones, Keith G.; Sheffer, Ellen M.; Ortega, Lidia; Dolman, Keith

2017-01-01

Neonatal rats were administered a relatively high concentration of ethyl alcohol (11.9% v/v) during postnatal days 4-9, a time when the fetal brain undergoes rapid organizational change and is similar to accelerated brain changes that occur during the third trimester in humans. This model of fetal alcohol spectrum disorders (FASDs) produces severe brain damage, mimicking the amount and pattern of binge-drinking that occurs in some pregnant alcoholic mothers. We describe the use of trace eyeblink classical conditioning (ECC), a higher-order variant of associative learning, to assess long-term hippocampal dysfunction that is typically seen in alcohol-exposed adult offspring. At 90 days of age, rodents were surgically prepared with recording and stimulating electrodes, which measured electromyographic (EMG) blink activity from the left eyelid muscle and delivered mild shock posterior to the left eye, respectively. After a 5 day recovery period, they underwent 6 sessions of trace ECC to determine associative learning differences between alcohol-exposed and control rats. Trace ECC is one of many possible ECC procedures that can be easily modified using the same equipment and software, so that different neural systems can be assessed. ECC procedures in general, can be used as diagnostic tools for detecting neural pathology in different brain systems and different conditions that insult the brain. PMID:28809846

Moderate red-wine consumption partially prevents body weight gain in rats fed a hyperlipidic diet.

PubMed

Vadillo, Montserrat; Bargalló, Montserrat Vadillo; Ardévol, Anna; Grau, Anna Ardévol; Fernández-Larrea, Juan; Fernández-Larrea, Juan de Dios; Pujadas, Gerard; Anguiano, Gerard Pujadas; Bladé, Cinta; Segarra, Maria Cinta Bladé; Salvadó, Maria Josepa; Rovira, Maria Josepa Salvadó; Arola, Lluís; Ferré, Lluia Arola; Blay, Mayte; Olivé, Mayte Blay

2006-02-01

Red wine is a beverage that can exert a broad spectrum of health-promoting actions both in humans and laboratory animal models if consumed moderately. However, information about its effect on body weight is scarce. We have evaluated the effect of moderate red wine consumption on body weight and energy intake in male Zucker lean rats fed a hypercaloric diet for 8 weeks. For this purpose, we used three 5-animal groups: a high-fat diet group (HFD), a high-fat-diet red-wine-drinking group (HFRWD), and a standard diet group (SD). After 8 weeks, the HFRWD group had a lower body weight gain (175.66 +/- 2.78% vs 188.22 +/- 4.83%; P<.05) and lower energy intake (269.45 +/- 4.02 KJ/animal.day vs day vs 300.81 +/- 4.52 KJ/animal.day; P<.05) and had less fat mass at epididymal location respect to the whole body weight (0.014 +/- 0.001 vs 0.017 +/- 0.001; P<.05) than the HFD group. However, the red wine didn't modified the fed efficiency 0.012 +/- 0.001 g/KJ for HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). These findings, though preliminary, show that moderate red wine intake can prevent the increase of body weight by modulating energy intake in a rat diet-induced model of obesity.

In vivo imaging of brain infarct with the novel fluorescent probe PSVue 794 in a rat middle cerebral artery occlusion-reperfusion model.

PubMed

Chu, Chun; Huang, Xiaofang; Chen, Chiung-Tong; Zhao, Yuanli; Luo, Jin J; Gray, Brian D; Pak, Koon Y; Dun, Nae J

2013-01-01

The utility of PSVue 794 (PS794), a near-infrared fluorescent dye conjugated to a bis[zinc (II)-dipicolylamine] (Zn-DPA) targeting moiety, in imaging brain infarct was assessed in a rat middle cerebral artery occlusion-reperfusion model. Following reperfusion, 1 mM PS794 solution was administered intravenously via a tail vein. Fluorescence images were captured between 6 to 72 hours postinjection using a LI-COR Biosciences Pearl Imaging System. Strong fluorescence signals, which may represent the infarct core, were detected in the right hemisphere, ipsilateral to the injured site, and weaker signals in areas surrounding the core. In ischemia-reperfusion rats injected with a control dye not linked to a targeting agent, fluorescence was distributed diffusely throughout the brain. To address the issue of whether Zn-DPA targets apoptotic/necrotic cells, HT22 mouse hippocampal neurons were cultured in either Dulbecco's Modified Eagle's Medium, serum-deprived medium, Hank's Balanced Salt Solution, or L-glutamate (10 mM)-containing medium for up to 33 hours. Cells were then double-labeled with PSVue 480 (Zn-DPA conjugated to fluorescein isothiocyanate) and propidium iodide, which labels necrotic cells. Microscopic examination revealed that PS480 targeted apoptotic and necrotic cells. The result indicates that PS794 is applicable to in vivo imaging of brain infarct and that Zn-DPA selectively targets apoptotic/necrotic cells.

High-Moisture Diet for Laboratory Rats: Complete Blood Counts, Serum Biochemical Values, and Intestinal Enzyme Activity

NASA Technical Reports Server (NTRS)

Battles, August H.; Knapka, Joseph T.; Stevens, Bruce R.; Lewis, Laura; Lang, Marie T.; Gruendel, Douglas J.

1991-01-01

Rats were fed an irradiated high-moisture diet (KSC-25) with or without access to a water bottle. Physiologic values were compared between these two groups and a group of rats fed a purified diet. Hematologic and serum biochemical values, urine specific gravity, and intestinal enzyme activities were determined from samples collected from the three groups of rats. Sprague Dawley rats (n=32) fed the irradiated high-moisture diet with or without a water bottle were the test animals. Rats (n=16) fed an irradiated purified diet and water provided via a water bottle were the control group. The purified diet formulation, modified AIN-76A, is a commonly used purified diet for laboratory rodents. All rats remained alert and healthy throughout the study. A comparison of the physiologic values of rats in this study with reported normal values indicated that all of the rats in the study were in good health. Significant differences (P less than 0.05) of the physiologic values from each rat group are reported.

Brain Targeting Delivery Facilitated by Ligand-Functionalized Layered Double Hydroxide Nanoparticles.

PubMed

Chen, Weiyu; Zuo, Huali; Zhang, Enqi; Li, Li; Henrich-Noack, Petra; Cooper, Helen; Qian, Yujin; Xu, Zhi Ping

2018-06-20

A delivery platform with highly selective permeability through the blood-brain barrier (BBB) is essential for brain disease treatment. In this research, we designed and prepared a novel target nanoplatform, that is, layered double hydroxide (LDH) nanoparticle conjugated with targeting peptide-ligand Angiopep-2 (Ang2) or rabies virus glycoprotein (RVG) via intermatrix bovine serum albumin for brain targeting. In vitro studies show that functionalization with the target ligand significantly increases the delivery efficiency of LDH nanoparticles to the brain endothelial (bEnd.3) cells and the transcytosis through the simulated BBB model, that is, bEnd.3 cell-constructed multilayer membrane. In vivo confocal neuroimaging of the rat's blood-retina area dynamically demonstrates that LDH nanoparticles modified with peptide ligands have shown a prolonged retention period within the retina vessel in comparison with the pristine LDH group. Moreover, Ang2-modified LDH nanoparticles are found to more specifically accumulate in the mouse brain than the control and RVG-modified LDH nanoparticles after 2 and 48 h intravenous injection. All these findings strongly suggest that Ang2-modified LDHs can serve as an effective targeting nanoplatform for brain disease treatment.

Effects of bitter melon (Momordica charantia L.) on the gut microbiota in high fat diet and low dose streptozocin-induced rats.

PubMed

Zhu, Ying; Bai, Juan; Zhang, Yi; Xiao, Xiang; Dong, Ying

2016-09-01

The effects on gut microbiota of type 2 diabetic rats fed a bitter melon formulation (BLSP, a lyophilized superfine powder) were investigated. BLSP treatment significantly reduced fasting blood glucose levels (p < 0.05) and serum insulin levels (p < 0.05) of the diabetic rats. The gut microbiota of treated and control rats were profiled by PCR amplification and pyrosequencing of 16S rRNA genes (V3-V9 region). BLSP significantly reduced the ratio of Firmicutes to Bacteroidetes in diabetic rats, while the relative abundances of Ruminococcaceae, Bacteroides and Ruminococcus were significantly lowered in BLSP-treated rats compared to diabetic rats. Additionally, BLSP significantly suppressed the activation of MAPK (JNK and p38). The results indicate that BLSP can significantly modify the proportions of particular gut microbiota in diabetic rats without disturbing the normal population diversity. By suppressing the activation of MAPK signaling pathway, a BLSP containing diet may ameliorate type 2 diabetes.

Dihydroquercetin Does Not Affect Age-Dependent Increase in Blood Pressure and Angiotensin-Converting Enzyme Activity in the Aorta of Hypertensive Rats.

PubMed

Slashcheva, G A; Rykov, V A; Lobanov, A V; Murashev, A N; Kim, Yu A; Arutyunyan, T V; Korystova, A F; Kublik, L N; Levitman, M Kh; Shaposhnikona, V V; Korystov, Yu N

2016-09-01

We analyzed changes in angiotensin-converting enzyme activity in the aorta of hypertensive SHR rats against the background of age-related BP increase (from week 7 to 14) and the effect of dihydroquercetin on BP rise and angiotensin-converting enzyme activity. Normotensive WKY rats of the same age were used as the control. BP and activity of angiotensin-converting enzyme in the aorta of SHR rats increased with age. Dihydroquercetin in doses of 100 and 300 μg/kg per day had no effect on the increase of these parameters; dihydroquercetin administered to 14-week-old WKY rats in a dose of 300 μg/kg reduced activity of the angiotensin-converting enzyme. Thus, the early (7-14 weeks) increase in BP and angiotensin-converting enzyme activity in the aorta of SHR rats was not modified by flavonoids (dihydroquercetin) in contrast to other rat strains and humans, which is indicative of specificity of hypertension mechanism in SHR rats.

Aqueous Humor Dynamics of the Brown-Norway Rat

PubMed Central

Ficarrotta, Kayla R.; Bello, Simon A.; Mohamed, Youssef H.; Passaglia, Christopher L.

2018-01-01

Purpose The study aimed to provide a quantitative description of aqueous humor dynamics in healthy rat eyes. Methods One eye of 26 anesthetized adult Brown-Norway rats was cannulated with a needle connected to a perfusion pump and pressure transducer. Pressure-flow data were measured in live and dead eyes by varying pump rate (constant-flow technique) or by modulating pump duty cycle to hold intraocular pressure (IOP) at set levels (modified constant-pressure technique). Data were fit by the Goldmann equation to estimate conventional outflow facility (\\begin{document}\

Radioprotective effects of honeybee venom (Apis mellifera) against 915-MHz microwave radiation-induced DNA damage in wistar rat lymphocytes: in vitro study.

PubMed

Gajski, Goran; Garaj-Vrhovac, Vera

2009-01-01

The aim of this study is to investigate the radioprotective effect of bee venom against DNA damage induced by 915-MHz microwave radiation (specific absorption rate of 0.6 W/kg) in Wistar rats. Whole blood lymphocytes of Wistar rats are treated with 1 microg/mL bee venom 4 hours prior to and immediately before irradiation. Standard and formamidopyrimidine-DNA glycosylase (Fpg)-modified comet assays are used to assess basal and oxidative DNA damage produced by reactive oxygen species. Bee venom shows a decrease in DNA damage compared with irradiated samples. Parameters of Fpg-modified comet assay are statistically different from controls, making this assay more sensitive and suggesting that oxidative stress is a possible mechanism of DNA damage induction. Bee venom is demonstrated to have a radioprotective effect against basal and oxidative DNA damage. Furthermore, bee venom is not genotoxic and does not produce oxidative damage in the low concentrations used in this study.

Effects of chronic dietary exposure to monosodium glutamate on feeding behavior, adiposity, gastrointestinal motility, and cardiovascular function in healthy adult rats.

PubMed

López-Miranda, V; Soto-Montenegro, M L; Uranga-Ocio, J A; Vera, G; Herradón, E; González, C; Blas, C; Martínez-Villaluenga, M; López-Pérez, A E; Desco, M; Abalo, R

2015-11-01

Monosodium glutamate (MSG) is a flavor-enhancer widely used as a food additive. However, its safe dietary concentration and its toxicity, including its possible implication in the recent metabolic syndrome pandemia, is still a controversial issue. Therefore, a deep knowledge of its effects upon regular dietary use is needed. Our aim was to evaluate the effects of chronic exposure to MSG on feeding behavior, abdominal fat, gastrointestinal motility, and cardiovascular function in rats. Two groups of adult male Wistar rats were used: control and treated with MSG (4 g/L in drinking water) for 6 weeks. Different functional parameters were determined and the histological structure was analyzed in tissues of interest. Compared to control animals, chronic MSG increased water intake but did not modify food ingestion or body weight gain. Neither the abdominal fat volume nor the fat fraction, measured by magnetic resonance imaging, was modified by MSG. Monosodium glutamate did not alter general gastrointestinal motility, but significantly increased the colonic response to mechanical stimulation. It slightly reduced endothelium-dependent relaxation in aorta, without significantly modifying any other cardiovascular parameters. No significant histological alterations were detected in salivary glands, intestinal wall, aorta, heart, and kidney. Chronic treatment with MSG in the adult rat increased water intake. This supports its potential to improve acceptance of low-fat regimens and to increase hydration in the elderly and sportspeople, often at risk of dehydration. Changes in colonic contractility and cardiovascular function could have some long-term repercussions warranting further research. © 2015 John Wiley & Sons Ltd.

Controlled release of modified insulin glargine from novel biodegradable injectable gels.

PubMed

Anand, Om; Almoazen, Hassan; Mehrotra, Nitin; Johnson, James; Shukla, Atul

2012-03-01

The objective of this study was to investigate the duration of biological effects of modified insulin glargine released from a novel biodegradable injectable gel in type II diabetic Zucker diabetic fatty (ZDF) rats. Modified insulin glargine was purified from the marketed formulation by process of dialysis followed by freeze-drying, and the purity was confirmed by the single peak, corresponding to insulin glargine in the HPLC chromatogram. To determine and to compare the biological activity of purified insulin glargine with marketed formulation, it was suspended in isotonic saline solutions and administered subcutaneously to ZDF rats at a dose of 10 IU/kg of insulin and the blood glucose levels were measured. The blood glucose levels of ZDF rats after a subcutaneous injection of a suspension of purified insulin glargine decreased below 200 mg/dL within 2 h and remained at this level up to 6 h, then steadily raised above 400 mg/dL in 12 h. Insulin glargine particles were loaded into a novel biodegradable injectable gel formulation prepared from a blend of polylactic-co-glycolic acid (PLGA) and biocompatible plasticizers. Approximately 0.1 mL of insulin glargine-loaded gel prepared with PLGA was administered subcutaneously to the ZDF rats, and blood glucose levels were measured. The PLGA gel formulations prepared with insulin glargine particles had duration of action of 10 days following a single subcutaneous injection. The addition of zinc sulfate to the formulations prepared with purified insulin glargine particles further slowed down the drop in blood glucose concentrations.

The beneficial effect of genetically engineered Schwann cells with enhanced motility in peripheral nerve regeneration: review.

PubMed

Gravvanis, A I; Lavdas, A A; Papalois, A; Tsoutsos, D A; Matsas, R

2007-01-01

The importance of Schwann cells in promoting nerve regeneration across a conduit has been extensively reported in the literature, and Schwann cell motility has been acknowledged as a prerequisite for myelination of the peripheral nervous system during regeneration after injury. Review of recent literature and retrospective analysis of our studies with genetically modified Schwann Cells with increased motility in order to identify the underlying mechanism of action and outline the future trends in peripheral nerve repair. Schwann cell transduction with the pREV-retrovirus, for expression of Sialyl-Transferase-X, resulting in conferring Polysialyl-residues (PSA) on NCAM, increases their motility in-vitro and ensures nerve regeneration through silicone tubes after end-to-side neurorraphy in the rat sciatic nerve model, thus significantly promoting fiber maturation and functional outcome. An artificial nerve graft consisting of a type I collagen tube lined with the genetically modified Schwann cells with increased motility, used to bridge a defect in end-to-end fashion in the rat sciatic nerve model, was shown to promote nerve regeneration to a level equal to that of a nerve autograft. The use of genetically engineered Schwann cells with enhanced motility for grafting endoneural tubes promotes axonal regeneration, by virtue of the interaction of the transplanted cells with regenerating axonal growth cones as well as via the recruitment of endogenous Schwann cells. It is envisaged that mixed populations of Schwann cells, expressing PSA and one or more trophic factors, might further enhance the regenerating and remyelinating potential of the lesioned nerves.

Superparamagnetic iron oxide nanoparticles modified with dimyristoylphosphatidylcholine and their distribution in the brain after injection in the rat substantia nigra.

PubMed

Su, Lichao; Zhang, Baolin; Huang, Yinping; Zhang, Hao; Xu, Qin; Tan, Jie

2017-12-01

The subcellular distributions of nanoparticles in the brain are important for their biological application. We synthesized and characterized the superparamagnetic iron oxide nanoparticles (SPIONs) modified with poly (ethylene glycol) (PEG) and polyethylenimine (PEI) (PEG/PEI-SPIONs), and with dimyristoylphosphatidylcholine (DMPC) (DMPC-SPIONs). The nanoparticles were unilaterally injected into the left substantia nigra of rat brains. The distributions of the nanoparticles in the left brains of the rats were examined by ICP-OES (inductively coupled plasma optical emission spectrometer) and TEM (transmission electron microscopy) at 24h after the injection. Iron was found in the olfactory bulb, temporal lobe, frontal cortex, thalamus and brain stem at 24h after the injection of DMPC-SPIONs and PEG/PEI-SPIONs. In the rat substantia nigra, most DMPC-SPIONs were distributed in and on the myelin sheath around axons or on cell membranes, some were in cells. As a comparison, less iron was found in the rat brains at 24h after the injection of PEG/PEI-SPIONs. Our experiments suggest DMPC modification on SPIONs be a safe and effective method for increasing SPIONs distribution on the cell membranes. This work is encouraging for further study on using DMPC-SPIONs for efficient drug delivery or for deep brain stimulation of neurons in a magnetic field. Copyright © 2017 Elsevier B.V. All rights reserved.

Stress exposure alters brain mRNA expression of the genes involved in insulin signalling, an effect modified by a high fat/high fructose diet and cinnamon supplement

PubMed Central

Qin, Bolin; Arvy, Nathalie; Poulet, Laurent; Batandier, Cécile; Roussel, Anne-Marie; Anderson, Richard A.

2018-01-01

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement. PMID:29813096

Stress exposure alters brain mRNA expression of the genes involved in insulin signalling, an effect modified by a high fat/high fructose diet and cinnamon supplement.

PubMed

Canini, Frédéric; Qin, Bolin; Arvy, Nathalie; Poulet, Laurent; Batandier, Cécile; Roussel, Anne-Marie; Anderson, Richard A

2018-01-01

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.

The Effect of Early Intervention and Rehabilitation in the Expression of Aquaporin-4; and Ultrastructure Changes on Rat's Offspring's Damaged Brain Caused by Intrauterine Infection

PubMed Central

Rajesh, Kumar; Xiangying, Kong

2015-01-01

Objective To study the effect of early intervention and rehabilitation in the expression of aquaporin-4 and ultrastructure changes on cerebral palsy pups model induced by intrauterine infection. Methods 20 pregnant Wistar rats were consecutively injected with lipopolysaccharide intraperitoneally. 60 Pups born from lipopolysaccharide group were randomly divided into intervention group (n=30) and non-intervention group (n=30); intervention group further divided into early intervention and rehabilitation group (n=10), acupuncture group (n=10) and consolidate group (n=10). Another 5 pregnant rats were injected with normal saline intraperitoneally; 30 pups born from the normal saline group were taken as control group. The intervention group received early intervention, rehabilitation and acupuncture treatment. The motor functions of all pups were assessed via suspension test and modified BBB locomotor score. Aquaporin-4 expression in brain tissue was studied through immunohistochemical and western-blot analysis. Ultrastructure changes in damaged brain and control group were studied electron-microscopically. Results The scores of suspension test and modified BBB locomotor test were significantly higher in the control group than the intervention and non intervention group (p<0.01); higher in the intervention group than the non-intervention group (p<0.01). The expression of Aquaporin-4 was lower in intervention and non intervention group than in the control group (p<0.01); also lower in non-intervention group than the intervention group (p<0.01). Marked changes were observed in ultrastructure of cortex and hippocampus CAI in brain damaged group. Conclusion Early intervention and rehabilitation training can improve the motor function in offspring with brain injury and reduce the expression of aquaporin-4 in damaged brain. PMID:26279808

Absolute quantitation of NAPQI-modified rat serum albumin by LC-MS/MS: monitoring acetaminophen covalent binding in vivo.

PubMed

LeBlanc, André; Shiao, Tze Chieh; Roy, René; Sleno, Lekha

2014-09-15

Acetaminophen is known to cause hepatoxicity via the formation of a reactive metabolite, N-acetyl p-benzoquinone imine (NAPQI), as a result of covalent binding to liver proteins. Serum albumin (SA) is known to be covalently modified by NAPQI and is present at high concentrations in the bloodstream and is therefore a potential biomarker to assess the levels of protein modification by NAPQI. A newly developed method for the absolute quantitation of serum albumin containing NAPQI covalently bound to its active site cysteine (Cys34) is described. This optimized assay represents the first absolute quantitation of a modified protein, with very low stoichiometric abundance, using a protein-level standard combined with isotope dilution. The LC-MS/MS assay is based on a protein standard modified with a custom-designed reagent, yielding a surrogate peptide (following digestion) that is a positional isomer to the target peptide modified by NAPQI. To illustrate the potential of this approach, the method was applied to quantify NAPQI-modified SA in plasma from rats dosed with acetaminophen. The resulting method is highly sensitive (capable of quantifying down to 0.0006% of total RSA in its NAPQI-modified form) and yields excellent precision and accuracy statistics. A time-course pharmacokinetic study was performed to test the usefulness of this method for following acetaminophen-induced covalent binding at four dosing levels (75-600 mg/kg IP), showing the viability of this approach to directly monitor in vivo samples. This approach can reliably quantify NAPQI-modified albumin, allowing direct monitoring of acetaminophen-related covalent binding.

Modification of Rat Lung Decellularization Protocol Based on Dynamic Conductometry of Working Solution.

PubMed

Kuevda, E V; Gubareva, E A; Gumenyuk, I S; Sotnichenko, A S; Gilevich, I V; Nakokhov, R Z; Rusinova, T V; Yudina, T G; Red'ko, A N; Alekseenko, S N

2017-03-01

We modified the protocol of obtaining of biological scaffolds of rat lungs based on dynamic recording of specific resistivity of working detergent solution (conductometry) during perfusion decellularization. Termination of sodium deoxycholate exposure after attaining ionic equilibrium plateau did not impair the quality of decellularization and preserved structural matrix components, which was confirmed by morphological analysis and quantitative assay of residual DNA.

Evaluation of a novel delayed-type hypersensitivity assay to Candida albicans in adult and neonatal rats.

PubMed

Thorn, Mitchell; Hudson, Adam W; Kreeger, John; Kawabe, Thomas T; Bowman, Christopher J; Collinge, Mark

2015-01-01

Delayed-type hypersensitivity (DTH) is a T-cell-mediated immune response that may be used for immunotoxicity testing in non-clinical species. However, in some cases DTH assays using T-dependent antigens may be confounded by the production of antibodies to the antigen. The authors have previously modified a DTH assay, initially validated in the mouse, for use in juvenile rats to assess the effect of immunosuppressive drugs on the developing rat immune system. The assay measures footpad swelling induced by subcutaneous footpad injection of Candida albicans (C. albicans) derived-chitosan in rats previously sensitized with C. albicans. Antibodies to chitosan are not produced in this model. However, considerable inter-animal variability inherent in the footpad swelling assay can make it difficult to precisely quantify the magnitude of the immune response and inhibition by immunosuppressants, particularly if complete suppression is not observed. This report describes the development of an ex vivo assay to assess DTH in rats using interferon (IFN)-γ production by splenocytes, obtained from rats sensitized with C. albicans, as the quantifiable measure of the DTH response. Adult and neonatal rats administered dexamethasone (DEX), a known immunosuppressant, exhibited immunosuppression as evidenced by a reduction in ex vivo IFNγ production from splenocytes challenged with C. albicans-derived chitosan. Current data indicate that the ex vivo based DTH assay is more sensitive than the conventional footpad swelling assay due to a lower background response and the ability to detect a response as early as post-natal day (PND) 12. The ex vivo based rat DTH assay offers a highly sensitive and quantitative alternative to the footpad swelling assay for the assessment of the immunotoxic potential of drugs. The increased sensitivity of the ex vivo DTH assay may be useful for identifying smaller changes in response to immunotoxic drugs, as well as detecting responses earlier in animal development.

Activation of Peripheral κ-Opioid Receptors Normalizes Caffeine Effects Modified in Nicotine-Dependent Rats during Nicotine Withdrawal.

PubMed

Sudakov, S K; Bogdanova, N G

2016-10-01

The study examined the effect of peripheral (intragastric) ICI-204,448, an agonist of gastric κ-opioid receptors, on the psychostimulating and anxiolytic effects of caffeine in nicotinedependent rats at the stage of nicotine withdrawal. In these rats, the effects of caffeine (10 mg/kg) were perverted. In nicotine-dependent rats, caffeine produced an anxiolytic effect accompanied by pronounced stimulation of motor activity, in contrast to anxiogenic effect induced by caffeine in intact rats without nicotine dependence. During nicotine withdrawal, nicotine-dependent rats demonstrated enhanced sensitivity to nicotine. Intragastric administration of κ-opioid receptor agonist ICI-204,448 normalized the effect of caffeine in nicotinedependent rats. We have previously demonstrated that activation of peripheral κ-opioid receptors inhibited central κ-opioid activity and eliminated manifestations of nicotine withdrawal syndrome in nicotine-dependent rats, e.g. metabolism activation, stimulation of motor activity, and enhancement of food consumption. In its turn, inhibition of central κ-opioid structures activates the brain adenosine system, which can attenuate the caffeine-induced effects in nicotine-dependent rats.

In vitro biocompatibility of the surface ion modified NiTi alloy

NASA Astrophysics Data System (ADS)

Gudimova, Ekaterina Yu.; Meisner, Ludmila L.; Lotkov, Aleksander I.; Matveeva, Vera A.; Meisner, Stanislav N.; Matveev, Andrey L.; Shabalina, Olga I.

2016-11-01

This paper presents the results of the chemical, topographic and structural properties of the NiTi alloy surface and their changes after surface treatments by ion implantation techniques with use of ions Ta+ and Si+. The influence of physicochemical properties of the surface ion modified NiTi alloy was studied on in vitro cultured mesenchymal stem cells of the rats' bone marrow. It is shown that the ion surface modification improves histocompatibility of the NiTi alloy and leads to increase of proliferative activity of mesenchymal stem cells on its surface. It was experimentally found that a major contribution to viability improvement mesenchymal stem cells of rat marrow has the chemical composition and the microstructure of the surface area.

Chronic food restriction and the circadian rhythms of pituitary-adrenal hormones, growth hormone and thyroid-stimulating hormone.

PubMed

Armario, A; Montero, J L; Jolin, T

1987-01-01

Adult male Sprague-Dawley rats were subjected to food restriction so that they ate 65% of food ingested by control rats. While control rats had free access to food over the 24-hour period, food-restricted rats were provided with food daily at 10 a.m. The experimental period lasted for 34 days. On day 35, rats from both experimental groups were killed at 08.00, 11.00, 14.00, 24.00 and 02.00 h. Food restriction modified the circadian rhythms of ACTH and corticosterone. In addition, total circulating corticosterone throughout the day was higher in food-restricted than in control rats. In contrast, food restriction resulted in depressed secretion of thyroid-stimulating hormone and growth hormone. The results indicate that time of food availability entrained circadian corticosterone rhythm but not thyroid-stimulating hormone and growth hormone rhythms.

Detection and molecular identification of Cryptosporidium species in laboratory rats (Rattus norvegicus) in Ibadan, Nigeria

PubMed

Ayinmode, Adekunle Bamidele; Ogbonna, Nkeiruka Fortunate; Widmer, Giovanni

To study the occurrence of Cryptosporidium infection in laboratory rats (Rattus norvegicus) raised for experimental usage, 134 faecal samples were obtained from two rearing houses in Ibadan and examined for the presence of Cryptosporidium oocyst using the modified acid fast staining technique. Cryptosporidium species in 2 samples positive for microscopy were further characterized by a nested polymerase chain reaction (PCR) amplifying the 18S rRNA gene. Two of 134 samples were positive for the Cryptosporidium oocysts. Sequencing of the small-subunit rRNA amplicons identified the species in the two PCR positive samples as Cryptosporidium andersoni and Cryptosporidium rat genotype. These findings showed that laboratory rat is a potential reservoir for diverse Cryptosporidium species and suggests that laboratory rats should be screened for Cryptosporidium infection prior to experiments, especially where pathogen free animals are not available. This the first report to identify Cryptosporidium species infecting laboratory rats in Nigeria.

Blockage of neonatal leptin signaling induces changes in the hypothalamus associated with delayed pubertal onset and modifications in neuropeptide expression during adulthood in male rats.

PubMed

Mela, Virginia; Jimenez, Sara; Freire-Regatillo, Alejandra; Barrios, Vicente; Marco, Eva-María; Lopez-Rodriguez, Ana-Belén; Argente, Jesús; Viveros, María-Paz; Chowen, Julie A

2016-12-01

The neonatal leptin surge, occurring from postnatal day (PND) 5 to 13 and peaking at PND9 in rodents, is important for the development of neuroendocrine circuits involved in metabolic control and reproductive function. We previously demonstrated that treatment with a leptin antagonist from PND 5 to 9, coincident with peak leptin levels in the neonatal surge, modified trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus of peri-pubertal rats. The kisspeptin system and metabolic neuropeptide and hormone levels were also modified. Here our aim was to investigate if the timing of pubertal onset is altered by neonatal leptin antagonism and if the previously observed peripubertal modifications in hormones and neuropeptides persist into adulthood and affect male sexual behavior. To this end, male Wistar rats were treated with a pegylated super leptin antagonist (5mg/kg, s.c.) from PND 5 to 9 and killed at PND102-103. The appearance of external signs of pubertal onset was delayed. Hypothalamic kiss1 mRNA levels were decreased in adult animals, but sexual behavior was not significantly modified. Although there was no effect on body weight or food intake, circulating leptin, insulin and triglyceride levels were increased, while hypothalamic leptin receptor, POMC and AgRP mRNA levels were decreased. In conclusion, alteration of the neonatal leptin surge can modify the timing of pubertal onset and have long-term effects on hypothalamic expression of reproductive and metabolic neuropeptides. Copyright © 2016 Elsevier Inc. All rights reserved.

Lumbar Facet Joint Compressive Injury Induces Lasting Changes in Local Structure, Nociceptive Scores, and Inflammatory Mediators in a Novel Rat Model

PubMed Central

Henry, James L.; Yashpal, Kiran; Vernon, Howard; Kim, Jaesung; Im, Hee-Jeong

2012-01-01

Objective. To develop a novel animal model of persisting lumbar facet joint pain. Methods. Sprague Dawley rats were anaesthetized and the right lumbar (L5/L6) facet joint was exposed and compressed to ~1 mm with modified clamps applied for three minutes; sham-operated and naïve animals were used as control groups. After five days, animals were tested for hind-paw sensitivity using von Frey filaments and axial deep tissue sensitivity by algometer on assigned days up to 28 days. Animals were sacrificed at selected times for histological and biochemical analysis. Results. Histological sections revealed site-specific loss of cartilage in model animals only. Tactile hypersensitivity was observed for the ipsi- and contralateral paws lasting 28 days. The threshold at which deep tissue pressure just elicited vocalization was obtained at three lumbar levels; sensitivity at L1 > L3/4 > L6. Biochemical analyses revealed increases in proinflammatory cytokines, especially TNF-α, IL-1α, and IL-1β. Conclusions. These data suggest that compression of a facet joint induces a novel model of local cartilage loss accompanied by increased sensitivity to mechanical stimuli and by increases in inflammatory mediators. This new model may be useful for studies on mechanisms and treatment of lumbar facet joint pain and osteoarthritis. PMID:22966427

Paclitaxel-loaded PLGA nanoparticles surface modified with transferrin and Pluronic((R))P85, an in vitro cell line and in vivo biodistribution studies on rat model.

PubMed

Shah, Neha; Chaudhari, Kiran; Dantuluri, Prudhviraju; Murthy, R S R; Das, Susobhan

2009-08-01

The development of multidrug resistance (due to drug efflux by P-glycoproteins) is a major drawback with the use of paclitaxel (PTX) in the treatment of cancer. The rationale behind this study is to prepare PTX nanoparticles (NPs) for the reversal of multidrug resistance based on the fact that PTX loaded into NPs is not recognized by P-glycoproteins and hence is not effluxed out of the cell. Also, the intracellular penetration of the NPs could be enhanced by anchoring transferrin (Tf) on the PTX-PLGA-NPs. PTX-loaded PLGA NPs (PTX-PLGA-NPs), Pluronic((R))P85-coated PLGA NPs (P85-PTX-PLGA-NPs), and Tf-anchored PLGA NPs (Tf-PTX-PLGA-NPs) were prepared and evaluted for cytotoxicity and intracellular uptake using C6 rat glioma cell line. A significant increase in cytotoxicity was observed in the order of Tf-PTX-PLGA-NPs > P85-PTX-PLGA-NPs > PTX-PLGA-NPs in comparison to drug solution. In vivo biodistribution on male Sprague-Dawley rats bearing C6 glioma (subcutaneous) showed higher tumor PTX concentrations in animals administered with PTX-NPs compared to drug solution.

Assessment of the Sensitizing Potential of Processed Peanut Proteins in Brown Norway Rats: Roasting Does Not Enhance Allergenicity

PubMed Central

Kroghsbo, Stine; Rigby, Neil M.; Johnson, Philip E.; Adel-Patient, Karine; Bøgh, Katrine L.; Salt, Louise J.; Mills, E. N. Clare; Madsen, Charlotte B.

2014-01-01

Background IgE-binding of process-modified foods or proteins is the most common method for examination of how food processing affects allergenicity of food allergens. How processing affects sensitization capacity is generally studied by administration of purified food proteins or food extracts and not allergens present in their natural food matrix. Objectives The aim was to investigate if thermal processing increases sensitization potential of whole peanuts via the oral route. In parallel, the effect of heating on sensitization potential of the major peanut allergen Ara h 1 was assessed via the intraperitoneal route. Methods Sensitization potential of processed peanut products and Ara h 1 was examined in Brown Norway (BN) rats by oral administration of blanched or oil-roasted peanuts or peanut butter or by intraperitoneal immunization of purified native (N-), heated (H-) or heat glycated (G-)Ara h 1. Levels of specific IgG and IgE were determined by ELISA and IgE functionality was examined by rat basophilic leukemia (RBL) cell assay. Results In rats dosed orally, roasted peanuts induced significant higher levels of specific IgE to NAra h 1 and 2 than blanched peanuts or peanut butter but with the lowest level of RBL degranulation. However, extract from roasted peanuts was found to be a superior elicitor of RBL degranulation. Process-modified Ara h 1 had similar sensitizing capacity as NAra h 1 but specific IgE reacted more readily with process-modified Ara h 1 than with native. Conclusions Peanut products induce functional specific IgE when dosed orally to BN rats. Roasted peanuts do not have a higher sensitizing capacity than blanched peanuts. In spite of this, extract from roasted peanuts is a superior elicitor of RBL cell degranulation irrespectively of the peanut product used for sensitization. The results also suggest that new epitopes are formed or disclosed by heating Ara h 1 without glucose. PMID:24805813

Cocktail of Superoxide Dismutase and Fasudil Encapsulated in Targeted Liposomes Slows PAH Progression at a Reduced Dosing Frequency.

PubMed

Gupta, Nilesh; Rashid, Jahidur; Nozik-Grayck, Eva; McMurtry, Ivan F; Stenmark, Kurt R; Ahsan, Fakhrul

2017-03-06

Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR. We evaluated the effect of the formulations on pulmonary hemodynamics in monocrotaline-induced PAH rats (MCT-induced PAH) and assessed the formulation's efficacy in slowing the disease progression in Sugen-5416/hypoxia-induced PAH rats (SU/hypoxia-induced PAH). For acute studies, we monitored both mean pulmonary and systemic arterial pressures (mPAP and mSAP) for 2 to 6 h after a single dose of the plain drugs or formulations. In chronic studies, PAH rats received plain drugs every 48 h and the formulations every 72 h for 21 days. In MCT-induced PAH rats, CAR-modified liposomes containing fasudil plus SOD elicited a more pronounced, prolonged, and selective reduction in mPAP than unmodified liposomes and plain drugs did. In SU/hypoxia-induced PAH rats, the formulation produced a >50% reduction in mPAP and slowed right ventricular hypertrophy. When compared with individual plain drugs or combination, CAR-modified-liposomes containing both drugs reduced the extent of collagen deposition, muscularization of arteries, increased SOD levels in the lungs, and decreased the expression of pSTAT-3 and p-MYPT1. Overall, CAR-modified-liposomes of SOD plus fasudil, given every 72 h, was as efficacious as plain drugs, given every 48 h, suggesting that the formulation can reduce the total drug intake, systemic exposures, and dosing frequency.

Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

PubMed

Panahifar, A; Jaremko, J L; Tessier, A G; Lambert, R G; Maksymowych, W P; Fallone, B G; Doschak, M R

2014-10-01

We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Efficacy, Pharmacokinetics, and Metabolism of Tetrahydroquinoline Inhibitors of Plasmodium falciparum Protein Farnesyltransferase▿ †

PubMed Central

Van Voorhis, Wesley C.; Rivas, Kasey L.; Bendale, Pravin; Nallan, Laxman; Hornéy, Carolyn; Barrett, Lynn K.; Bauer, Kevin D.; Smart, Brian P.; Ankala, Sudha; Hucke, Oliver; Verlinde, Christophe L. M. J.; Chakrabarti, Debopam; Strickland, Corey; Yokoyama, Kohei; Buckner, Frederick S.; Hamilton, Andrew D.; Williams, David K.; Lombardo, Louis J.; Floyd, David; Gelb, Michael H.

2007-01-01

New antimalarials are urgently needed. We have shown that tetrahydroquinoline (THQ) protein farnesyltransferase (PFT) inhibitors (PFTIs) are effective against the Plasmodium falciparum PFT and are effective at killing P. falciparum in vitro. Previously described THQ PFTIs had limitations of poor oral bioavailability and rapid clearance from the circulation of rodents. In this paper, we validate both the Caco-2 cell permeability model for predicting THQ intestinal absorption and the in vitro liver microsome model for predicting THQ clearance in vivo. Incremental improvements in efficacy, oral absorption, and clearance rate were monitored by in vitro tests; and these tests were followed up with in vivo absorption, distribution, metabolism, and excretion studies. One compound, PB-93, achieved cure when it was given orally to P. berghei-infected rats every 8 h for a total of 72 h. However, PB-93 was rapidly cleared, and dosing every 12 h failed to cure the rats. Thus, the in vivo results corroborate the in vitro pharmacodynamics and demonstrate that 72 h of continuous high-level exposure to PFTIs is necessary to kill plasmodia. The metabolism of PB-93 was demonstrated by a novel technique that relied on double labeling with a radiolabel and heavy isotopes combined with radiometric liquid chromatography and mass spectrometry. The major liver microsome metabolite of PB-93 has the PFT Zn-binding N-methyl-imidazole removed; this metabolite is inactive in blocking PFT function. By solving the X-ray crystal structure of PB-93 bound to rat PFT, a model of PB-93 bound to malarial PFT was constructed. This model suggests areas of the THQ PFTIs that can be modified to retain efficacy and protect the Zn-binding N-methyl-imidazole from dealkylation. PMID:17606674

Effects of chronic REM sleep restriction on D1 receptor and related signal pathways in rat prefrontal cortex.

PubMed

Han, Yan; Wen, Xiaosa; Rong, Fei; Chen, Xinmin; Ouyang, Ruying; Wu, Shuai; Nian, Hua; Ma, Wenling

2015-01-01

The prefrontal cortex (PFC) mediates cognitive function that is sensitive to disruption by sleep loss, and molecular mechanisms regulating neural dysfunction induced by chronic sleep restriction (CSR), particularly in the PFC, have yet to be completely understood. The aim of the present study was to investigate the effect of chronic REM sleep restriction (REM-CSR) on the D1 receptor (D1R) and key molecules in D1R' signal pathways in PFC. We employed the modified multiple platform method to create the REM-CSR rat model. The ultrastructure of PFC was observed by electron microscopy. HPLC was performed to measure the DA level in PFC. The expressions of genes and proteins of related molecules were assayed by real-time PCR and Western blot, respectively. The general state and morphology of PFC in rats were changed by CSR, and DA level and the expression of D1R in PFC were markedly decreased (P < 0.01, P < 0.05); the expression of phosphor-PKAcα was significantly lowered in CSR rats (P < 0.05). The present results suggested that the alteration of neuropathology and D1R expression in PFC may be associated with CSR induced cognitive dysfunction, and the PKA pathway of D1R may play an important role in the impairment of advanced neural function.

Effects of Chronic REM Sleep Restriction on D1 Receptor and Related Signal Pathways in Rat Prefrontal Cortex

PubMed Central

Han, Yan; Wen, Xiaosa; Rong, Fei; Chen, Xinmin; Ouyang, Ruying; Wu, Shuai; Nian, Hua; Ma, Wenling

2015-01-01

The prefrontal cortex (PFC) mediates cognitive function that is sensitive to disruption by sleep loss, and molecular mechanisms regulating neural dysfunction induced by chronic sleep restriction (CSR), particularly in the PFC, have yet to be completely understood. The aim of the present study was to investigate the effect of chronic REM sleep restriction (REM-CSR) on the D1 receptor (D1R) and key molecules in D1R' signal pathways in PFC. We employed the modified multiple platform method to create the REM-CSR rat model. The ultrastructure of PFC was observed by electron microscopy. HPLC was performed to measure the DA level in PFC. The expressions of genes and proteins of related molecules were assayed by real-time PCR and Western blot, respectively. The general state and morphology of PFC in rats were changed by CSR, and DA level and the expression of D1R in PFC were markedly decreased (P < 0.01, P < 0.05); the expression of phosphor-PKAcα was significantly lowered in CSR rats (P < 0.05). The present results suggested that the alteration of neuropathology and D1R expression in PFC may be associated with CSR induced cognitive dysfunction, and the PKA pathway of D1R may play an important role in the impairment of advanced neural function. PMID:25793215

The anticonvulsant action of AHR-11748 on kindled amygdaloid seizures in rats.

PubMed

Albertson, T E; Walby, W F

1987-03-01

The anticonvulsant effectiveness of AHR-11748 (3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) was evaluated in the kindled amygdaloid seizure model in rats. Doses of AHR-11748 that did not cause prestimulation toxicity significantly attenuated elicited afterdischarge durations and the severity of the accompanying behavioral convulsive response in previously kindled rats. AHR-11748 (25-100 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and suprathreshold (400 microA) paradigms. AHR-11748 (50-100.mg/kg) reduced suprathreshold elicited after discharges and seizure severity. Utilizing a suprathreshold kindling paradigm, the maximum anticonvulsant effectiveness for the 100 mg/kg i.p. dose of AHR-11748 was seen at 180 min. AHR-11748 significantly elevated seizure thresholds only at the 100 mg/kg dose. AHR-11748 (25-100 mg/kg) significantly reduced the severity of threshold elicited seizures. When AHR-11748 (50 and 100 mg/kg i.p.) was administered daily during kindling acquisition, the number of daily trials necessary to complete kindling significantly increased. A reduction in both the duration and the severity of the responses induced by the daily stimulations during the acquisition period was seen with AHR-11748 treatment. This study has demonstrated that AHR-11748 significantly modifies both the acquisition of kindling and the fully kindled amygdaloid seizures at doses that do not cause behavioral toxicity.

Insulin stimulated-glucose transporter Glut 4 is expressed in the retina.

PubMed

Sánchez-Chávez, Gustavo; Peña-Rangel, Ma Teresa; Riesgo-Escovar, Juan R; Martínez-Martínez, Alejandro; Salceda, Rocío

2012-01-01

The vertebrate retina is a very metabolically active tissue whose energy demands are normally met through the uptake of glucose and oxygen. Glucose metabolism in this tissue relies upon adequate glucose delivery from the systemic circulation. Therefore, glucose transport depends on the expression of glucose transporters. Here, we show retinal expression of the Glut 4 glucose transporter in frog and rat retinas. Immunohistochemistry and in situ hybridization studies showed Glut 4 expression in the three nuclear layers of the retina: the photoreceptor, inner nuclear and ganglionar cell layers. In the rat retina immunoprecipitation and Western blot analysis revealed a protein with an apparent molecular mass of 45 kDa. ¹⁴C-glucose accumulation by isolated rat retinas was significantly enhanced by physiological concentrations of insulin, an effect blocked by inhibitors of phosphatidyl-inositol 3-kinase (PI3K), a key enzyme in the insulin-signaling pathway in other tissues. Also, we observed an increase in ³H-cytochalasin binding sites in the presence of insulin, suggesting an increase in transporter recruitment at the cell surface. Besides, insulin induced phosphorylation of Akt, an effect also blocked by PI3K inhibition. Expression of Glut 4 was not modified in retinas of a type 1 diabetic rat model. To our knowledge, our results provide the first evidence of Glut4 expression in the retina, suggesting it as an insulin- responsive tissue.

Insulin Stimulated-Glucose Transporter Glut 4 Is Expressed in the Retina

PubMed Central

Sánchez-Chávez, Gustavo; Peña-Rangel, Ma. Teresa; Riesgo-Escovar, Juan R.; Martínez-Martínez, Alejandro; Salceda, Rocío

2012-01-01

The vertebrate retina is a very metabolically active tissue whose energy demands are normally met through the uptake of glucose and oxygen. Glucose metabolism in this tissue relies upon adequate glucose delivery from the systemic circulation. Therefore, glucose transport depends on the expression of glucose transporters. Here, we show retinal expression of the Glut 4 glucose transporter in frog and rat retinas. Immunohistochemistry and in situ hybridization studies showed Glut 4 expression in the three nuclear layers of the retina: the photoreceptor, inner nuclear and ganglionar cell layers. In the rat retina immunoprecipitation and Western blot analysis revealed a protein with an apparent molecular mass of 45 kDa. 14C-glucose accumulation by isolated rat retinas was significantly enhanced by physiological concentrations of insulin, an effect blocked by inhibitors of phosphatidyl-inositol 3-kinase (PI3K), a key enzyme in the insulin-signaling pathway in other tissues. Also, we observed an increase in 3H-cytochalasin binding sites in the presence of insulin, suggesting an increase in transporter recruitment at the cell surface. Besides, insulin induced phosphorylation of Akt, an effect also blocked by PI3K inhibition. Expression of Glut 4 was not modified in retinas of a type 1 diabetic rat model. To our knowledge, our results provide the first evidence of Glut4 expression in the retina, suggesting it as an insulin- responsive tissue. PMID:23285235

5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model.

PubMed

Wang, Chao-Chuan; Lin, Hui-Ching; Chan, Yun-Han; Gean, Po-Wu; Yang, Yen Kung; Chen, Po See

2013-10-01

Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addition, studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomography and computed tomography co-registration following injection of (123)I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio)-5-iodophenylamine((123)I[ADAM]). Furthermore, treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation observed in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.

QUINIDINE AND DOMPERIDONE INTERACTIONS IN THE RAT EXPERIMENTAL MODEL OF REPEATED ADMINISTRATION.

PubMed

Bamburowicz-Klimkowska, Magdalena; Szost, Tadeusz; Małkowska, Anna; Szutowski, Mirosław

2016-07-01

This study has investigated domperidone (DOM) and quinidine (QD) interaction in the Wistar rat experimental model of repeated administration. We used nonconventional administration model consistent with occasional administration method. Difference in administration was related to sequence of domperidone alone or with quinidine dosage. Expected domperidone-quinidine interactions could have its origin both in the ability of quinidine to inhibit P-glycoprotein (P-gp) activity as well as cytochrome P450-mediated metabolism of both compounds. There also were examined kinetics of acetaminophen (PAM) administered (30 mg/kg) with domperidone as an indicator of gastric emptying, showing domperidone prokinetic activity, as well as quinidine anticholinergic activity. Domperidone (30 mg/kg) with PAM and with/without quinidine (25 mg/kg) was administered orally according to the disposition regiment different for six examined rat groups. DOM and PAM concentrations in plasma were assayed by HPLC method. Following changes were observed: domperidone did not modify the duration of the uptake phase of acetaminophen; quinidine prolongs gastric emptying time (as a result of anticholinergic action); quinidine given as the fourth or fifth dose with domperidone promotes growth of its concentration in plasma; analysis of changes in the value of AUC(0-2) at the initial three weeks of experiment suggests intensity of domperidone absorption processes, the following week increase in the value AUC(4-6) suggests inhibition of domperidone hepatic biotransformation and the mechanism of induction of absorption during domperidone administration is different from the absorption - inducing effects of quinidine. Both effects are superimposed and produce large, 2, 3-fold change in domperidone's AUC(0-6).

A forced running wheel system with a microcontroller that provides high-intensity exercise training in an animal ischemic stroke model.

PubMed

Chen, C C; Chang, M W; Chang, C P; Chan, S C; Chang, W Y; Yang, C L; Lin, M T

2014-10-01

We developed a forced non-electric-shock running wheel (FNESRW) system that provides rats with high-intensity exercise training using automatic exercise training patterns that are controlled by a microcontroller. The proposed system successfully makes a breakthrough in the traditional motorized running wheel to allow rats to perform high-intensity training and to enable comparisons with the treadmill at the same exercise intensity without any electric shock. A polyvinyl chloride runway with a rough rubber surface was coated on the periphery of the wheel so as to permit automatic acceleration training, and which allowed the rats to run consistently at high speeds (30 m/min for 1 h). An animal ischemic stroke model was used to validate the proposed system. FNESRW, treadmill, control, and sham groups were studied. The FNESRW and treadmill groups underwent 3 weeks of endurance running training. After 3 weeks, the experiments of middle cerebral artery occlusion, the modified neurological severity score (mNSS), an inclined plane test, and triphenyltetrazolium chloride were performed to evaluate the effectiveness of the proposed platform. The proposed platform showed that enhancement of motor function, mNSS, and infarct volumes was significantly stronger in the FNESRW group than the control group (P<0.05) and similar to the treadmill group. The experimental data demonstrated that the proposed platform can be applied to test the benefit of exercise-preconditioning-induced neuroprotection using the animal stroke model. Additional advantages of the FNESRW system include stand-alone capability, independence of subjective human adjustment, and ease of use.

A forced running wheel system with a microcontroller that provides high-intensity exercise training in an animal ischemic stroke model

PubMed Central

Chen, C.C.; Chang, M.W.; Chang, C.P.; Chan, S.C.; Chang, W.Y.; Yang, C.L.; Lin, M.T.

2014-01-01

We developed a forced non-electric-shock running wheel (FNESRW) system that provides rats with high-intensity exercise training using automatic exercise training patterns that are controlled by a microcontroller. The proposed system successfully makes a breakthrough in the traditional motorized running wheel to allow rats to perform high-intensity training and to enable comparisons with the treadmill at the same exercise intensity without any electric shock. A polyvinyl chloride runway with a rough rubber surface was coated on the periphery of the wheel so as to permit automatic acceleration training, and which allowed the rats to run consistently at high speeds (30 m/min for 1 h). An animal ischemic stroke model was used to validate the proposed system. FNESRW, treadmill, control, and sham groups were studied. The FNESRW and treadmill groups underwent 3 weeks of endurance running training. After 3 weeks, the experiments of middle cerebral artery occlusion, the modified neurological severity score (mNSS), an inclined plane test, and triphenyltetrazolium chloride were performed to evaluate the effectiveness of the proposed platform. The proposed platform showed that enhancement of motor function, mNSS, and infarct volumes was significantly stronger in the FNESRW group than the control group (P<0.05) and similar to the treadmill group. The experimental data demonstrated that the proposed platform can be applied to test the benefit of exercise-preconditioning-induced neuroprotection using the animal stroke model. Additional advantages of the FNESRW system include stand-alone capability, independence of subjective human adjustment, and ease of use. PMID:25140816

Modifying mesoporous silica nanoparticles to avoid the metabolic deactivation of 6-mercaptopurine and methotrexate in combinatorial chemotherapy

NASA Astrophysics Data System (ADS)

Wang, Wenjing; Fang, Chenjie; Wang, Xiaozhu; Chen, Yuxi; Wang, Yaonan; Feng, Wei; Yan, Chunhua; Zhao, Ming; Peng, Shiqi

2013-06-01

Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy.Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy. Electronic supplementary information (ESI) available: Experimental details of the synthesis and in vitro and in vivo assays. See DOI: 10.1039/c3nr00227f

Biotransformation of aesculin by human gut bacteria and identification of its metabolites in rat urine.

PubMed

Ding, Wei-Jun; Deng, Yun; Feng, Hao; Liu, Wei-Wei; Hu, Rong; Li, Xiang; Gu, Zhe-Ming; Dong, Xiao-Ping

2009-03-28

To observe the biotransformation process of a Chinese compound, aesculin, by human gut bacteria, and to identify its metabolites in rat urine. Representative human gut bacteria were collected from 20 healthy volunteers, and then utilized in vitro to biotransform aesculin under anaerobic conditions. At 0, 2, 4, 8, 12, 16, 24, 48 and 72 h post-incubation, 10 mL of culture medium was collected. Metabolites of aesculin were extracted 3 x from rat urine with methanol and analyzed by HPLC. For in vivo metabolite analysis, aesculetin (100 mg/kg) was administered to rats via stomach gavage, rat urine was collected from 6 to 48 h post-administration, and metabolite analysis was performed by LC/ESI-MS and MS/MS in the positive and negative modes. Human gut bacteria could completely convert aesculin into aesculetin in vitro. The biotransformation process occurred from 8 to 24 h post-incubation, with its highest activity was seen from 8 to 12 h. The in vitro process was much slower than the in vivo process. In contrast to the in vitro model, six aesculetin metabolites were identified in rat urine, including 6-hydroxy-7-gluco-coumarin (M1), 6-hydroxy-7-sulf-coumarin (M2), 6, 7-di-gluco-coumarin (M3), 6-glc-7-gluco-coumarin (M4), 6-O-methyl-7-gluco-coumarin (M5) and 6-O-methyl-7-sulf-coumarin (M6). Of which, M2 and M6 were novel metabolites. Aesculin can be transferred into aesculetin by human gut bacteria and is further modified by the host in vivo. The diverse metabolites of aesculin may explain its pleiotropic pharmaceutical effects.

Influence of Camembert consumption on the composition and metabolism of intestinal microbiota: a study in human microbiota-associated rats.

PubMed

Lay, Christophe; Sutren, Malène; Lepercq, Pascale; Juste, Catherine; Rigottier-Gois, Lionel; Lhoste, Evelyne; Lemée, Riwanon; Le Ruyet, Pascale; Doré, Joël; Andrieux, Claude

2004-09-01

The objective of the present study was to evaluate the consequence of Camembert consumption on the composition and metabolism of human intestinal microbiota. Camembert cheese was compared with milk fermented by yoghurt starters and Lactobacillus casei as a probiotic reference. The experimental model was the human microbiota-associated (HM) rat. HM rats were fed a basal diet (HMB group), a diet containing Camembert made from pasteurised milk (HMCp group) or a diet containing fermented milk (HMfm group). The level of micro-organisms from dairy products was measured in faeces using cultures on a specific medium and PCR-temporal temperature gradient gel electrophoresis. The metabolic characteristics of the caecal microbiota were also studied: SCFA, NH3, glycosidase and reductase activities, and bile acid degradations. The results showed that micro-organisms from cheese comprised 10(5)-10(8) bacteria/g faecal sample in the HMCp group. Lactobacillus species from fermented milk were detected in HMfm rats. Consumption of cheese and fermented milk led to similar changes in bacterial metabolism: a decrease in azoreductase activity and NH3 concentration and an increase in mucolytic activities. However, specific changes were observed: in HMCp rats, the proportion of ursodeoxycholic resulting from chenodeoxycholic epimerisation was higher; in HMfm rats, alpha and beta-galactosidases were higher than in other groups and both azoreductases and nitrate reductases were lower. The results show that, as for fermented milk, Camembert consumption did not greatly modify the microbiota profile or its major metabolic activities. Ingested micro-organisms were able to survive in part during intestinal transit. These dairy products exert a potentially beneficial influence on intestinal metabolism.

Short-term treatment with nitrate is not sufficient to induce in vivo antithrombotic effects in rats and mice.

PubMed

Kramkowski, K; Leszczynska, A; Przyborowski, K; Proniewski, B; Marcinczyk, N; Rykaczewska, U; Jarmoc, D; Chabielska, E; Chlopicki, S

2017-01-01

In humans, short-term supplementation with nitrate is hypotensive and inhibits platelet aggregation via an nitric oxide (NO)-dependent mechanism. In the present work, we analyzed whether short-term treatment with nitrate induces antithrombotic effects in rats and mice. Arterial thrombosis was evoked electrically in a rat model in which renovascular hypertension was induced by partial ligation of the left renal artery. In mice expressing green fluorescent protein, laser-induced thrombosis was analyzed intravitally by using confocal microscope. Sodium nitrate (NaNO 3 ) or sodium nitrite (NaNO 2 ) was administered orally at a dose of 0.17 mmol/kg, twice per day for 3 days. Short-term nitrate treatment did not modify thrombus formation in either rats or mice, while nitrite administration led to pronounced antithrombotic activity. In hypertensive rats, nitrite treatment resulted in a significant decrease in thrombus weight (0.50 ± 0.08 mg vs. VEH 0.96 ± 0.09 mg; p < 0.01). In addition, nitrite inhibited ex vivo platelet aggregation and thromboxane B 2 (TxB 2 ) generation and prolonged prothrombin time. These effects were accompanied by significant increases in blood NOHb concentration and plasma nitrite concentration. In contrast, nitrate did not affect ex vivo platelet aggregation or prothrombin time and led to only slightly elevated nitrite plasma concentration. In mice, nitrate was also ineffective, while nitrite led to decreased platelet accumulation in the area of laser-induced endothelial injury. In conclusion, although nitrite induced profound NO-dependent antithrombotic effects in vivo, conversion of nitrates to nitrite in rats and mice over short-term 3-day treatment was not sufficient to elicit NO-dependent antiplatelet or antithrombotic effects.

Renal Response to L-Arginine in Diabetic Rats. A Possible Link between Nitric Oxide System and Aquaporin-2

PubMed Central

Ortiz, María C.; Albertoni Borghese, María F.; Balonga, Sabrina E.; Lavagna, Agustina; Filipuzzi, Ana L.; Elesgaray, Rosana; Costa, María A.; Majowicz, Mónica P.

2014-01-01

The aim of this study was to evaluate whether L-Arginine (L-Arg) supplementation modifies nitric oxide (NO) system and consequently aquaporin-2 (AQP2) expression in the renal outer medulla of streptozotocin-diabetic rats at an early time point after induction of diabetes. Male Wistar rats were divided in four groups: Control, Diabetic, Diabetic treated with L-Arginine and Control treated with L-Arginine. Nitric oxide synthase (NOS) activity was estimated by [14C] L-citrulline production in homogenates of the renal outer medulla and by NADPH-diaphorase staining in renal outer medullary tubules. Western blot was used to detect the expression of AQP2 and NOS types I and III; real time PCR was used to quantify AQP2 mRNA. The expression of both NOS isoforms, NOS I and NOS III, was decreased in the renal outer medulla of diabetic rats and L-Arg failed to prevent these decreases. However, L-Arg improved NO production, NADPH-diaphorase activity in collecting ducts and other tubular structures, and NOS activity in renal homogenates from diabetic rats. AQP2 protein and mRNA were decreased in the renal outer medulla of diabetic rats and L-Arg administration prevented these decreases. These results suggest that the decreased NOS activity in collecting ducts of the renal outer medulla may cause, at least in part, the decreased expression of AQP2 in this model of diabetes and constitute additional evidence supporting a role for NO in contributing to renal water reabsorption through the modulation of AQP2 expression in this pathological condition. However, we cannot discard that another pathway different from NOS also exists that links L-Arg to AQP2 expression. PMID:25111608

Renal response to L-arginine in diabetic rats. A possible link between nitric oxide system and aquaporin-2.

PubMed

Ortiz, María C; Albertoni Borghese, María F; Balonga, Sabrina E; Lavagna, Agustina; Filipuzzi, Ana L; Elesgaray, Rosana; Costa, María A; Majowicz, Mónica P

2014-01-01

The aim of this study was to evaluate whether L-Arginine (L-Arg) supplementation modifies nitric oxide (NO) system and consequently aquaporin-2 (AQP2) expression in the renal outer medulla of streptozotocin-diabetic rats at an early time point after induction of diabetes. Male Wistar rats were divided in four groups: Control, Diabetic, Diabetic treated with L-Arginine and Control treated with L-Arginine. Nitric oxide synthase (NOS) activity was estimated by [14C] L-citrulline production in homogenates of the renal outer medulla and by NADPH-diaphorase staining in renal outer medullary tubules. Western blot was used to detect the expression of AQP2 and NOS types I and III; real time PCR was used to quantify AQP2 mRNA. The expression of both NOS isoforms, NOS I and NOS III, was decreased in the renal outer medulla of diabetic rats and L-Arg failed to prevent these decreases. However, L-Arg improved NO production, NADPH-diaphorase activity in collecting ducts and other tubular structures, and NOS activity in renal homogenates from diabetic rats. AQP2 protein and mRNA were decreased in the renal outer medulla of diabetic rats and L-Arg administration prevented these decreases. These results suggest that the decreased NOS activity in collecting ducts of the renal outer medulla may cause, at least in part, the decreased expression of AQP2 in this model of diabetes and constitute additional evidence supporting a role for NO in contributing to renal water reabsorption through the modulation of AQP2 expression in this pathological condition. However, we cannot discard that another pathway different from NOS also exists that links L-Arg to AQP2 expression.

Diphenyl diselenide diet intake improves spatial learning and memory deficits in hypothyroid female rats.

PubMed

Dias, Glaecir Roseni Mundstock; Vieira, Francielli Araújo; Dobrachinski, Fernando; Bridi, Jéssika Cristina; Balk, Rodrigo de Souza; Soares, Félix Antunes; Nogueira, Cristina Wayne; Barbosa, Nilda Berenice de Vargas

2012-04-01

Cognitive deficits have been observed in different animal models of adult-onset hypothyroidism. Thus, this study was delineated to evaluate whether diphenyl diselenide, an organoselenium compound with neuroprotective and antioxidant properties, could afford protection against the detrimental effects of hypothyroidism on behavioral parameters. Hypothyroidism condition was induced in female rats by continuous exposure to methimazole (MTZ) at 20 mg/100 ml in the drinking water, during 3 months. MTZ-induced hypothyroid rats were fed with either standard or a diet containing 5 ppm of diphenyl diselenide for 3 months. Behavioral assessments were performed monthly, in the following order: elevated plus maze, open field and Morris water maze. The levels of thyroid hormones in the animals exposed to MTZ were lower than control until the end of experimental period. The rats exposed to MTZ had a significant weight loss from the first month, which was not modified by diphenyl diselenide supplementation. In elevated plus maze test, MTZ exposure caused a reduction on the number of entries of animals in closed arms, which was avoided by diphenyl diselenide supplementation. In Morris water maze, the parameters latency to reach the platform and distance performed to find the escape platform in the test session were significantly greater in MTZ group when compared to control. These cognitive deficits observed in MTZ-induced hypothyroid rats were restored by dietary diphenyl diselenide. The group fed with diphenyl diselenide alone exhibited a better spatial learning and memory capability in some parameters of Morris water maze when compared to the control group. In summary, our data provide evidence of the effectiveness of dietary diphenyl diselenide in improving the performance of control and hypothyroid rats in the water maze test. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

PubMed

Gallant, S; Welch, L; Martone, P; Shalev, U

2017-06-15

Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

[Study of neuron-protective effect and mechanism of neuregulin1β against cerebral ischemia reperfusion-induced injury in rats].

PubMed

Ji, Y Q; Zhang, R; Teng, L; Li, H Y; Guo, Y L

2017-07-18

Objective: Thecurrent study is to explore the neuron-protective mechanism of neuregulin1β (NRG1β) in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) through inhibiting the c-Jun phosphorylation. Methods: After 24 h of MCAO/R (referring to Longa's method), neurobehavioral function was measured by modified neurological severity score (mNSS) test; the cerebral infarction volume was detected by triphenyltetrazolium chloride (TTC) staining; the blood brain barrier (BBB) permeability was measured by Evans Blue (EB); the neuron morphology of brain tissue was observed by Nissl stain; the ultra-structures of the neurons were observed by transmission electron microscopy (TEM); the apoptotic neurons were counted by in situ cell death detection kit colocalized with NeuN; the expressions of phospho-c-Jun was determined by immunofluorescent labeling and Western blot analysis. Results: Compared with the sham-operation rats, the rats receiving MCAO/R showed increased mNSS (9.7±1.2), cerebral infarction volume (41.4±3.0)%, permeability of BBB, deformation of neurons, ischemia-induced apoptosis (0.63±0.04), and enhanced expression of phospho-c-Jun protein (0.90±0.07) (all P <0.05). Our data indicated that NRG1β attenuated neurologic deficits (6.4±0.9), decreased the cerebral infarction volume (10.4±0.5), reduced EB extravasation (1.55±0.13) and the deformation of neurons, protected the ultra-structure of neurons, blocked ischemia-induced apoptosis (0.23±0.02), through down-regulated phospho-c-Jun expression (0.40±0.03) in MCAO/R rats ( P <0.05). Conclusion: NRG1β exerts neuron-protective effects against ischemia reperfusion-induced injury in rats through inhibiting the c-Jun phosphorylation.

Attenuated plasma extravasation to sensory neuropeptides in diabetic rats.

PubMed

Mathison, R; Davison, J S

1993-01-01

The effects of either substance P (SP) or a metabolically stable SP analogue, [pGlu5,Me-Phe8,Sar9]SP(5-11), alone or in combination with calcitonin gene-related peptide (CGRP) on blood pressure (BP) and extravasation of serum albumin were examined in normal and diabetic rats. CGRP (12 ng/kg) modified neither BP nor vascular permeability in control and diabetic rats. Both SP and its analogue (74 ng/kg) produced hypotension, and increased plasma extravasation in the respiratory tissues, urinary bladder and skin. The simultaneous injection of CGRP and SP resulted in modest potentiation of the vascular permeability actions of SP in control and diabetic rats. However, extravasation induced by [pGlu5,Me-Phe8,Sar9]SP(5-11) was potentiated by CGRP in control animals, but not in diabetic rats. Defective neurogenic inflammatory responses in diabetic rats may result from decreased responses in the effector tissues of diabetic rats to the neuropeptides released from sensory nerves.

SURVEY OF HOUSE RAT INTESTINAL PARASITES FROM SURABAYA DISTRICT, EAST JAVA, INDONESIA THAT CAN CAUSE OPPORTUNISTIC INFECTIONS IN HUMANS.

PubMed

Prasetyo, R H

2016-03-01

The purpose of this study was to investigate the prevalence of house rat zoonotic intestinal parasites from Surabaya District, East Java, Indonesia that have the potential to cause opportunistic infection in humans. House rat fecal samples were collected from an area of Surabaya District with a dense rat population during May 2015. Intestinal parasites were detected microscopically using direct smear of feces stained with Lugol's iodine and modified Ziehl-Neelsen stains. The fecal samples were also cultured for Strongyloides stercoralis. Ninety-eight house rat fecal samples were examined. The potential opportunistic infection parasite densities found in those samples were Strongyloides stercoralis in 53%, Hymenolepis nana in 42%, Cryptosporidium spp in 33%, and Blastocystis spp in 6%. This is the first report of this kind in Surabaya District. Measures need to be taken to control the house rat population in the study area to reduce the risk of the public health problem. Keywords: zoonotic intestinal parasites, opportunistic infection, house rat, densely populated area, Indonesia

Comparative safety testing of genetically modified foods in a 90-day rat feeding study design allowing the distinction between primary and secondary effects of the new genetic event.

PubMed

Knudsen, Ib; Poulsen, Morten

2007-10-01

This article discusses the wider experiences regarding the usefulness of the 90-day rat feeding study for the testing of whole foods from genetically modified (GM) plant based on data from a recent EU-project [Poulsen, M., Schrøder, M., Wilcks, A., Kroghsbo, S., Lindecrona, R.H., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Shu, Q., Emami, K., Taylor, M., Gatehouse, A., Engel, K.-H., Knudsen, I., 2007a. Safety testing of GM-rice expressing PHA-E lectin using a new animal test design. Food Chem. Toxicol. 45, 364-377; Poulsen, M., Kroghsbo, S., Schrøder, M., Wilcks, A., Jacobsen, H., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Shu, Q., Emami, K., Sudhakar, D., Gatehouse, A., Engel, K.-H., Knudsen, I., 2007b. A 90-day safety in Wistar rats fed genetically modified rice expressing snowdrop lectin Galanthus nivalis (GNA). Food Chem. Toxicol. 45, 350-363; Schrøder, M., Poulsen, M., Wilcks, A., Kroghsbo, S., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Emami, K., Gatehouse, A., Shu, Q., Engel, K.-H., Knudsen, I., 2007. A 90-day safety study of genetically modified rice expressing Cry1Ab protein (Bacillus thuringiensis toxin) in Wistar rats. Food Chem. Toxicol. 45, 339-349]. The overall objective of the project has been to develop and validate the scientific methodology necessary for assessing the safety of foods from genetically modified plants in accordance with the present EU regulation. The safety assessment in the project is combining the results of the 90-day rat feeding study on the GM food with and without spiking with the pure novel gene product, with the knowledge about the identity of the genetic change, the compositional data of the GM food, the results from in-vitro/ex-vivo studies as well as the results from the preceding 28-day toxicity study with the novel gene product, before the hazard characterisation is concluded. The results demonstrated the ability of the 90-day rat feeding study to detect the biological/toxicological effects of the new gene product in the GM food. The authors consider on this basis that the 90-day, rodent feeding study with one high dose level and a dietary design based upon compositional data on the GM food and toxicity data on the gene product is sensitive and specific enough to verify the presence/absence of the biological/nutritional/toxicological effects of the novel gene insert and further by the use of spiking able to separate potentially unintended effects of the novel gene product from other unintended effects at the level of intake defined in the test and within the remit of the test. Recommendations for further work necessary in the field are given.

EMBOLIC MIDDLE CEREBRAL ARTERY OCCLUSION MODEL USING THROMBIN AND FIBRINOGEN COMPOSED CLOTS IN RAT

PubMed Central

Ren, Ming; Lin, Zi-Jing; Qian, Hai; Gourav, Choudhury Roy; liu, Ran; Liu, Hanli; Yang, Shao-Hua

2012-01-01

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model. In the present study, we modified the homologous clots formation by addition of thrombin and fibrinogen which produced even distribution of fibrin with tight cross linkage of red blood cells. We optimized the embolic MCA occlusion model in rats using different size of the mixed clots. A precise lodgment of the clots at the MCA bifurcation and highly reproducible ischemic lesion in the MCA territory were demonstrated in the embolic MCA occlusion model induced by injection of 10 pieces of 1-mm long mixed clots made in PE-60 catheter. We further tested the effect of recombinant tissue plasminogen activator (rtPA) in this embolic MCA occlusion model. rtPA induced thrombolysis, improved neurological outcome, and significantly reduced ischemic lesion volume when administered at 1 hour after embolism as compared with control. In summary, we have established a reproducible embolic MCA occlusion model using clots made of homologous blood, thrombin and fibrinogen. The mixed clots enable precise lodgment at the MCA bifurcation which is responsive to thrombolytic therapy of rtPA. PMID:22985597

Embolic middle cerebral artery occlusion model using thrombin and fibrinogen composed clots in rat.

PubMed

Ren, Ming; Lin, Zi-Jing; Qian, Hai; Choudhury, Gourav Roy; Liu, Ran; Liu, Hanli; Yang, Shao-Hua

2012-11-15

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model. In the present study, we modified the homologous clots formation by addition of thrombin and fibrinogen which produced even distribution of fibrin with tight cross linkage of red blood cells. We optimized the embolic MCA occlusion model in rats using different size of the mixed clots. A precise lodgment of the clots at the MCA bifurcation and highly reproducible ischemic lesion in the MCA territory were demonstrated in the embolic MCA occlusion model induced by injection of 10 pieces of 1-mm long mixed clots made in PE-60 catheter. We further tested the effect of recombinant tissue plasminogen activator (rtPA) in this embolic MCA occlusion model. rtPA induced thrombolysis, improved neurological outcome, and significantly reduced ischemic lesion volume when administered at 1h after embolism as compared with control. In summary, we have established a reproducible embolic MCA occlusion model using clots made of homologous blood, thrombin and fibrinogen. The mixed clots enable precise lodgment at the MCA bifurcation which is responsive to thrombolytic therapy of rtPA. Copyright © 2012 Elsevier B.V. All rights reserved.

Modulatory effect of standardised amentoflavone isolated from Juniperus communis L. agianst Freund's adjuvant induced arthritis in rats (histopathological and X Ray anaysis).

PubMed

Bais, Souravh; Abrol, Naveena; Prashar, Yash; Kumari, Renu

2017-02-01

Juniperus communis. L. is a shrub or small evergreen tree, native to Europe, South Asia, and North America, and belongs to family Cupressaceae. It has been used traditionally in unani system and in Swedish medicine as a decoction in inflammatory diseases. The main chemical constituents, which were reported in J. communis L. was α-pinene,, apigenin, sabinene, β-sitosterol, campesterol, limonene, Amentoflavone (AF), cupressuflavone, and many others. The aim of present study was to isolate the amentoflavone from the plant juniperus communis L. extracts and its protective effects against Freund's adjuvant induced arthritis in rats. Adjuvant arthritis was induced by an injection of 1mg heat killed Mycobacterium tuberculosis (CFA) into the left hind paw of rat by sub planter route (at day 0). The experiment was designed and modified as per method available in literature. The study showed that at a dose of 40mg/kg of amentoflavone (AF) from methanolic extract of Juniperus Communis L. possessed potentially useful anti-arthritic activity as it gave a positive result in controlling inflammation in the adjuvant induced experimental model. From the present experimental findings of both pharmacological and biochemical parameters observed, it had been concluded that at the doses of 20mg/kg and 40mg/kg of AF fraction from methanolic extract of Juniperus communis L. It possesses useful anti-arthritic activity since it gives a positive result in controlling inflammation in the adjuvant induced arthritic model in rats. The drug is a promising anti-arthritic agent of plant origin in the treatment of inflammatory disorders. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Worsening of memory deficit induced by energy-dense diet in a rat model of early-Alzheimer's disease is associated to neurotoxic Aβ species and independent of neuroinflammation.

PubMed

Martino Adami, Pamela V; Galeano, Pablo; Wallinger, Marina L; Quijano, Celia; Rabossi, Alejandro; Pagano, Eleonora S; Olivar, Natividad; Reyes Toso, Carlos; Cardinali, Daniel; Brusco, Luis I; Do Carmo, Sonia; Radi, Rafael; Gevorkian, Goar; Castaño, Eduardo M; Cuello, A Claudio; Morelli, Laura

2017-03-01

Diet is a modifiable risk factor for Alzheimer's disease (AD), but the mechanisms linking alterations in peripheral metabolism and cognition remain unclear. Since it is especially difficult to study long-term effects of high-energy diet in individuals at risk for AD, we addressed this question by using the McGill-R-Thy1-APP transgenic rat model (Tg(+/-)) that mimics presymptomatic AD. Wild-type and Tg(+/-) rats were exposed during 6months to a standard diet or a Western diet (WD), high in saturated fat and sugar. Results from peripheral and hippocampal biochemical analysis and in situ respirometry showed that WD induced a metabolic syndrome and decreased presynaptic bioenergetic parameters without alterations in hippocampal insulin signaling or lipid composition. Cognitive tests, ELISA multiplex, Western blot, immunohistochemistry and RT-qPCR indicated that WD worsened cognition in Tg(+/-) rats, increased hippocampal levels of monomeric Aβ isoforms and oligomeric species, promoted deposits of N-Terminal pyroglutamate-Aβ (AβN3(pE)) in CA1 pyramidal neurons and interneurons, decreased transcript levels of genes involved in neuroprotective pathways such as Sirtuin-1 and increased nitrated proteins. Our results support the concept that in the presence of early Aβ pathology, diet-induced metabolic dysfunctions may contribute as a "second hit" to impair cognition. Noteworthy, such effect is not mediated by higher microglia activation or disruption of blood brain barrier. However, it may be attributed to increased amyloidogenic processing of amyloid precursor protein, generation of AβN3(pE) and dysregulation of pathways governed by Sirtuin-1. This evidence reinforces the implementation of prophylactic interventions in individuals at risk for AD. Copyright © 2016 Elsevier B.V. All rights reserved.

Long-Term Inhibition of Xanthine Oxidase by Febuxostat Does Not Decrease Blood Pressure in Deoxycorticosterone Acetate (DOCA)-Salt Hypertensive Rats

PubMed Central

Szasz, Theodora; Davis, Robert Patrick; Garver, Hannah S.; Burnett, Robert J.; Fink, Gregory D.; Watts, Stephanie W.

2013-01-01

Xanthine oxidase and its products, uric acid and ROS, have been implicated in the pathogenesis of cardiovascular disease, such as hypertension. We have previously reported that allopurinol inhibition of XO does not alter the progression of deoxycorticosterone acetate (DOCA)-salt hypertension in rats. However other researchers have observed a reduction in blood pressure after allopurinol treatment in the same model. To resolve this controversy, in this study we used the newer and more effective XO inhibitor febuxostat, and hypothesized that a more complete XO blockade might impair hypertension development and its end-organ consequences. We used DOCA-salt hypertensive rats and administered vehicle (salt water) or febuxostat (orally, 5 mg/kg/day in salt water) in a short-term “reversal” experiment (2 weeks of treatment 3 weeks after DOCA-salt beginning) and a long-term “prevention” experiment (treatment throughout 4 weeks of DOCA-salt). We confirmed XO inhibition by febuxostat by measuring circulating and tissue levels of XO metabolites. We found an overall increase in hypoxanthine (XO substrate) and decrease in uric acid (XO product) levels following febuxostat treatment. However, despite a trend for reduced blood pressure in the last week of long-term febuxostat treatment, no statistically significant difference in hemodynamic parameters was observed in either study. Additionally, no change was observed in relative heart and kidney weight. Aortic media/lumen ratio was minimally improved by long-term febuxostat treatment. Additionally, febuxostat incubation in vitro did not modify contraction of aorta or vena cava to norepinephrine, angiotensin II or endothelin-1. We conclude that XO inhibition is insufficient to attenuate hypertension in the rat DOCA-salt model, although beneficial vascular effects are possible. PMID:23393607

The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model.

PubMed

Hayami, Tadashi; Pickarski, Maureen; Wesolowski, Gregg A; McLane, Julia; Bone, Ashleigh; Destefano, James; Rodan, Gideon A; Duong, Le T

2004-04-01

It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 microg/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor beta (TGF beta), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF beta. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dose-dependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF beta, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.

Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats.

PubMed

Okuda, Keiji; Fu, Hai Ying; Matsuzaki, Takashi; Araki, Ryo; Tsuchida, Shota; Thanikachalam, Punniyakoti V; Fukuta, Tatsuya; Asai, Tomohiro; Yamato, Masaki; Sanada, Shoji; Asanuma, Hiroshi; Asano, Yoshihiro; Asakura, Masanori; Hanawa, Haruo; Hao, Hiroyuki; Oku, Naoto; Takashima, Seiji; Kitakaze, Masafumi; Sakata, Yasushi; Minamino, Tetsuo

2016-01-01

Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.

In vivo quantification of liver stiffness in a rat model of hepatic fibrosis with acoustic radiation force.

PubMed

Wang, Michael H; Palmeri, Mark L; Guy, Cynthia D; Yang, Liu; Hedlund, Laurence W; Diehl, Anna Mae; Nightingale, Kathryn R

2009-10-01

Liver fibrosis is currently staged using needle biopsy, a highly invasive procedure with a number of disadvantages. Measurement of liver stiffness changes that accompany progression of the disease may provide a quantitative and noninvasive method to assess the health of the liver. The purpose of this study is to investigate the correlation between liver stiffness measured by radiation force induced shear waves and disease related changes in the liver. An additional aim is to present initial findings on the effects of liver viscosity on radiation force induced shear wave morphology. Liver fibrosis was induced in 10 rats using carbon tetrachloride (CCl(4)), while five rats acted as controls. Liver stiffness was measured in vivo in all rats after a treatment period of 8 weeks using a modified Siemens SONOLINE Antares scanner (Siemens Medical Solutions USA, Ultrasound Division, Issaquah, WA, USA). The spatial coherence of radiation force induced shear waves propagating in the viscoelastic rat liver decreased significantly with propagation distance, compared with shear waves in an elastic phantom and a finite element model of a purely elastic medium. Animals were sacrificed after imaging and liver samples were taken for histopathologic analysis and collagen quantification using picrosirius red staining and hydroxyproline assay. At the end of the treatment period, five rats had healthy livers (stage F0), while six had severe fibrosis (F3) and the rest had light to moderate fibrosis (F1 and F2). The measured liver stiffness for the F0 group was 1.5+/-0.1 kPa (mean+/-95% confidence interval) and for F3 livers was 1.8+/-0.2 kPa. In this study, liver stiffness was found to be linearly correlated with the amount of collagen in the liver measured by picrosirius red staining (r(2)=0.43, p=0.008). In addition, stiffness spatial heterogeneity was also linearly correlated with liver collagen content (r(2)=0.58, p=0.001) by picrosirius red staining. These results are consistent with those obtained by Salameh et al. (2007) and Yin et al. (2007b) using animal models of liver fibrosis and MR elastography. This suggests that stiffness measurement using acoustic radiation force can provide a quantitative assessment of the extent of fibrosis in the liver and can be potentially used for the diagnosis, management and study of liver fibrosis.

Peri-implant bone formation and implant integration strength of peptide-modified p(AAM-co-EG/AAC) interpenetrating polymer network-coated titanium implants.

PubMed

Barber, Thomas A; Ho, James E; De Ranieri, Aladino; Virdi, Amarjit S; Sumner, Dale R; Healy, Kevin E

2007-02-01

Interpenetrating polymer networks (IPNs) of poly (acrylamide-co-ethylene glycol/acrylic acid) functionalized with an -Arg-Gly-Asp- (RGD) containing 15 amino acid peptides, derived from rat bone sialoprotein (bsp-RGD(15), were grafted to titanium implants in an effort to modulate bone formation in the peri-implant region in the rat femoral ablation model. Bone-implant contact (BIC) and bone formation within the medullary canal were determined using microcomputed tomography at 2 and 4 weeks postimplantation. BIC for bsp-RGD(15)-IPN implants was enhanced relative to hydroxyapatite tricalcium phosphate (HA-TCP) coated implants, but was similar to all other groups. Aggregate bone formation neither indicated a dose-dependent effect of bsp-RGD(15) nor a meaningful trend. Mechanical testing of implant fixation revealed that only the HA-TCP coated implants supported significant (>1 MPa) interfacial shear strength, despite exhibiting lower overall BIC, an indication that bone ingrowth into the rougher coating was the primary mode of implant fixation. While no evidence was found to support the hypothesis that bsp-RGD(15)-modified IPN coated implants significantly impacted bone-implant bonding, these results point to the lack of correlation between in vitro studies employing primary osteoblasts and in vivo wound healing in the peri-implant region. Copyright 2006 Wiley Periodicals, Inc.

The effects of cocoa on the immune system.

PubMed

Pérez-Cano, Francisco J; Massot-Cladera, Malen; Franch, Angels; Castellote, Cristina; Castell, Margarida

2013-01-01

Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant. Due to its activity as an antioxidant, as well as through other mechanisms, cocoa consumption has been reported to be beneficial for cardiovascular health, brain functions, and cancer prevention. Furthermore, cocoa influences the immune system, in particular the inflammatory innate response and the systemic and intestinal adaptive immune response. Preclinical studies have demonstrated that a cocoa-enriched diet modifies T cell functions that conduce to a modulation of the synthesis of systemic and gut antibodies. In this regard, it seems that a cocoa diet in rats produces changes in the lymphocyte composition of secondary lymphoid tissues and the cytokines secreted by T cells. These results suggest that it is possible that cocoa could inhibit the function of T helper type 2 cells, and in line with this, the preventive effect of cocoa on IgE synthesis in a rat allergy model has been reported, which opens up new perspectives when considering the beneficial effects of cocoa compounds. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota. The mechanisms involved in these influences are discussed here. Further research may elucidate the cocoa compounds involved in such an effect and also the possible medical approaches to these repercussions.

The effects of cocoa on the immune system

PubMed Central

Pérez-Cano, Francisco J.; Massot-Cladera, Malen; Franch, Àngels; Castellote, Cristina; Castell, Margarida

2013-01-01

Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant. Due to its activity as an antioxidant, as well as through other mechanisms, cocoa consumption has been reported to be beneficial for cardiovascular health, brain functions, and cancer prevention. Furthermore, cocoa influences the immune system, in particular the inflammatory innate response and the systemic and intestinal adaptive immune response. Preclinical studies have demonstrated that a cocoa-enriched diet modifies T cell functions that conduce to a modulation of the synthesis of systemic and gut antibodies. In this regard, it seems that a cocoa diet in rats produces changes in the lymphocyte composition of secondary lymphoid tissues and the cytokines secreted by T cells. These results suggest that it is possible that cocoa could inhibit the function of T helper type 2 cells, and in line with this, the preventive effect of cocoa on IgE synthesis in a rat allergy model has been reported, which opens up new perspectives when considering the beneficial effects of cocoa compounds. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota. The mechanisms involved in these influences are discussed here. Further research may elucidate the cocoa compounds involved in such an effect and also the possible medical approaches to these repercussions. PMID:23759861

Metabolomic Fingerprinting in the Comprehensive Study of Liver Changes Associated with Onion Supplementation in Hypercholesterolemic Wistar Rats

PubMed Central

González-Peña, Diana; Dudzik, Danuta; García, Antonia; de Ancos, Begoña; Barbas, Coral; Sánchez-Moreno, Concepción

2017-01-01

The consumption of functional ingredients has been suggested to be a complementary tool for the prevention and management of liver disease. In this light, processed onion can be considered as a source of multiple bioactive compounds with hepatoprotective properties. The liver fingerprint of male Wistar rats (n = 24) fed with three experimental diets (control (C), high-cholesterol (HC), and high-cholesterol enriched with onion (HCO) diets) was obtained through a non-targeted, multiplatform metabolomics approach to produce broad metabolite coverage. LC-MS, CE-MS and GC-MS results were subjected to univariate and multivariate analyses, providing a list of significant metabolites. All data were merged in order to figure out the most relevant metabolites that were modified by the onion ingredient. Several relevant metabolic changes and related metabolic pathways were found to be impacted by both HC and HCO diet. The model highlighted several metabolites (such as hydroxybutyryl carnitine and palmitoyl carnitine) modified by the HCO diet. These findings could suggest potential impairments in the energy−lipid metabolism, perturbations in the tricarboxylic acid cycle (TCA) cycle and β-oxidation modulated by the onion supplementation in the core of hepatic dysfunction. Metabolomics shows to be a valuable tool to evaluate the effects of complementary dietetic approaches directed to hepatic damage amelioration or non-alcoholic fatty liver disease (NAFLD) prevention. PMID:28134852

Detection of fluorescent organic nanoparticles by confocal laser endomicroscopy in a rat model of Barrett’s esophageal adenocarcinoma

PubMed Central

Dassie, Elisa; Arcidiacono, Diletta; Wasiak, Iga; Damiano, Nunzio; Dall’Olmo, Luigi; Giacometti, Cinzia; Facchin, Sonia; Cassaro, Mauro; Guido, Ennio; De Lazzari, Franca; Marin, Oriano; Ciach, Tomasz; Fery-Forgues, Suzanne; Alberti, Alfredo; Battaglia, Giorgio; Realdon, Stefano

2015-01-01

For many years, novel strategies for cancer detection and treatment using nanoparticles (NPs) have been developed. Esophageal adenocarcinoma is the sixth leading cause of cancer-related deaths in Western countries, and despite recent advances in early detection and treatment, its prognosis is still very poor. This study investigated the use of fluorescent organic NPs as potential diagnostic tool in an experimental in vivo model of Barrett’s esophageal adenocarcinoma. NPs were made of modified polysaccharides loaded with [4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran] (DCM), a well-known fluorescent dye. The NP periphery might or might not be decorated with ASYNYDA peptide that has an affinity for esophageal cancer cells. Non-operated and operated rats in which gastroesophageal reflux was surgically induced received both types of NPs (NP-DCM and NP-DCM-ASYNYDA) by intravenous route. Localization of mucosal NPs was assessed in vivo by confocal laser endomicroscopy, a technique which enables a “real time” and in situ visualization of the tissue at a cellular level. After injection of NP-DCM and NP-DCM-ASYNYDA, fluorescence was observed in rats affected by esophageal cancer, whereas no signal was observed in control non-operated rats, or in rats with simple esophagitis or Barrett’s esophagus mucosa. Fluorescence was observable in vivo 30 minutes after the administration of NPs. Interestingly, NP-DCM-ASYNYDA induced strong fluorescence intensity 24 hours after administration. These observations suggested that NPs could reach the tumor cells, likely by enhanced permeability and retention effect, and the peptide ASYNYDA gave them high specificity for esophageal cancer cells. Thus, the combination of NP platform and confocal laser endomicroscopy could play an important role for highlighting esophageal cancer conditions. This result supports the potential of this strategy as a targeted carrier for photoactive and bioactive molecules in esophageal cancer diagnosis and treatment. PMID:26586943

Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD

PubMed Central

Di Marco, Giovana Seno; Reuter, Stefan; Kentrup, Dominik; Grabner, Alexander; Amaral, Ansel Philip; Fobker, Manfred; Stypmann, Jörg; Pavenstädt, Hermann; Wolf, Myles; Faul, Christian; Brand, Marcus

2014-01-01

Background Activation of fibroblast growth factor receptor (FGFR)-dependent signalling by FGF23 may contribute to the complex pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease (CKD). Pan FGFR blockade by PD173074 prevented development of LVH in the 5/6 nephrectomy rat model of CKD, but its ability to treat and reverse established LVH is unknown. Methods CKD was induced in rats by 5/6 nephrectomy. Two weeks later, rats began treatment with vehicle (0.9% NaCl) or PD173074, 1 mg/kg once-daily for 3 weeks. Renal function was determined by urine and blood analyses. Left ventricular (LV) structure and function were determined by echocardiography, histopathology, staining for myocardial fibrosis (Sirius-Red) and investigating cardiac gene expression profiles by real-time PCR. Results Two weeks after inducing CKD by 5/6 nephrectomy, rats manifested higher (mean ± SEM) systolic blood pressure (208 ± 4 versus 139 ± 3 mmHg; P < 0.01), serum FGF23 levels (1023 ± 225 versus 199 ± 9 pg/mL; P < 0.01) and LV mass (292 ± 9 versus 220 ± 3 mg; P < 0.01) when compared with sham-operated animals. Thereafter, 3 weeks of treatment with PD173074 compared with vehicle did not significantly change blood pressure, kidney function or metabolic parameters, but significantly reduced LV mass (230 ± 14 versus 341 ± 33 mg; P < 0.01), myocardial fibrosis (2.5 ± 0.7 versus 5.4 ± 0.95% staining/field; P < 0.01) and cardiac expression of genes associated with pathological LVH, while significantly increasing ejection fraction (18 versus 2.5% post-treatment increase; P < 0.05). Conclusions FGFR blockade improved cardiac structure and function in 5/6 nephrectomy rats with previously established LVH. These data support FGFR activation as a potentially modifiable, blood pressure-independent molecular mechanism of LVH in CKD. PMID:24875663

Buspirone anti-dyskinetic effect is correlated with temporal normalization of dysregulated striatal DRD1 signalling in L-DOPA-treated rats.

PubMed

Azkona, Garikoitz; Sagarduy, Ainhoa; Aristieta, Asier; Vazquez, Nerea; Zubillaga, Verónica; Ruíz-Ortega, José Angel; Pérez-Navarro, Esther; Ugedo, Luisa; Sánchez-Pernaute, Rosario

2014-04-01

Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood. In this study, we used a well-characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias. We then investigated the molecular substrates implicated in the anti-dyskinetic effect of buspirone, a 5HT1A partial agonist. Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor (DR)D3, ΔFosB and phospho (p)CREB, as well as an over-activation of the DRD1 signalling pathway, reflected by elevated ratios of phosphorylated DARPP32 and ERK2. Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose-dependent fashion. Buspirone (4 mg/kg) dramatically reduced the presence and severity of dyskinesias (by 83%) and normalized DARPP32 and ERK2 phosphorylation ratios, while the increases in DRD3, ΔFosB and pCREB observed in dyskinetic rats were not modified. Pharmacological experiments combining buspirone with 5HT1A and DRD3 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required, but not sufficient, for blocking dyskinesias. The correlation between pDARPP32 ratio and dyskinesias was significant but not strong, pointing to the involvement of convergent factors and signalling pathways. Our results suggest that in dyskinetic rats DRD3 striatal over-expression could be instrumental in the activation of DRD1-downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with DRD1 pathway normalization. Copyright © 2013 Elsevier Ltd. All rights reserved.

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis.

PubMed

Sagar, Devi Rani; Ashraf, Sadaf; Xu, Luting; Burston, James J; Menhinick, Matthew R; Poulter, Caroline L; Bennett, Andrew J; Walsh, David A; Chapman, Victoria

2014-08-01

Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Our data suggest that early targeting of osteoclasts may reduce pain associated with OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Detection of fluorescent organic nanoparticles by confocal laser endomicroscopy in a rat model of Barrett's esophageal adenocarcinoma.

PubMed

Dassie, Elisa; Arcidiacono, Diletta; Wasiak, Iga; Damiano, Nunzio; Dall'Olmo, Luigi; Giacometti, Cinzia; Facchin, Sonia; Cassaro, Mauro; Guido, Ennio; De Lazzari, Franca; Marin, Oriano; Ciach, Tomasz; Fery-Forgues, Suzanne; Alberti, Alfredo; Battaglia, Giorgio; Realdon, Stefano

2015-01-01

For many years, novel strategies for cancer detection and treatment using nanoparticles (NPs) have been developed. Esophageal adenocarcinoma is the sixth leading cause of cancer-related deaths in Western countries, and despite recent advances in early detection and treatment, its prognosis is still very poor. This study investigated the use of fluorescent organic NPs as potential diagnostic tool in an experimental in vivo model of Barrett's esophageal adenocarcinoma. NPs were made of modified polysaccharides loaded with [4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran] (DCM), a well-known fluorescent dye. The NP periphery might or might not be decorated with ASYNYDA peptide that has an affinity for esophageal cancer cells. Non-operated and operated rats in which gastroesophageal reflux was surgically induced received both types of NPs (NP-DCM and NP-DCM-ASYNYDA) by intravenous route. Localization of mucosal NPs was assessed in vivo by confocal laser endomicroscopy, a technique which enables a "real time" and in situ visualization of the tissue at a cellular level. After injection of NP-DCM and NP-DCM-ASYNYDA, fluorescence was observed in rats affected by esophageal cancer, whereas no signal was observed in control non-operated rats, or in rats with simple esophagitis or Barrett's esophagus mucosa. Fluorescence was observable in vivo 30 minutes after the administration of NPs. Interestingly, NP-DCM-ASYNYDA induced strong fluorescence intensity 24 hours after administration. These observations suggested that NPs could reach the tumor cells, likely by enhanced permeability and retention effect, and the peptide ASYNYDA gave them high specificity for esophageal cancer cells. Thus, the combination of NP platform and confocal laser endomicroscopy could play an important role for highlighting esophageal cancer conditions. This result supports the potential of this strategy as a targeted carrier for photoactive and bioactive molecules in esophageal cancer diagnosis and treatment.

Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction.

PubMed

Paul, Arghya; Nayan, Madhur; Khan, Afshan Afsar; Shum-Tim, Dominique; Prakash, Satya

2012-01-01

The objective of this study was to develop angiopoietin-1 (Ang1)-expressing genetically modified human adipose tissue derived stem cells (hASCs) for myocardial therapy. For this, an efficient gene delivery system using recombinant baculovirus complexed with cell penetrating transactivating transcriptional activator TAT peptide/deoxyribonucleic acid nanoparticles (Bac-NP), through ionic interactions, was used. It was hypothesized that the hybrid Bac- NP(Ang1) system can efficiently transduce hASCs and induces favorable therapeutic effects when transplanted in vivo. To evaluate this hypothesis, a rat model with acute myocardial infarction and intramyocardially transplanted Ang1-expressing hASCs (hASC-Ang1), genetically modified by Bac-NP(Ang1), was used. Ang1 is a crucial pro-angiogenic factor for vascular maturation and neovasculogenesis. The released hAng1 from hASC-Ang1 demonstrated profound mitotic and anti-apoptotic activities on endothelial cells and cardiomyocytes. The transplanted hASC-Ang1 group showed higher cell retention compared to hASC and control groups. A significant increase in capillary density and reduction in infarct sizes were noted in the infarcted hearts with hASC-Ang1 treatment compared to infarcted hearts treated with hASC or the untreated group. Furthermore, the hASC-Ang1 group showed significantly higher cardiac performance in echocardiography (ejection fraction 46.28% ± 6.3%, P < 0.001 versus control, n = 8) than the hASC group (36.35% ± 5.7%, P < 0.01, n = 8), 28 days post-infarction. The study identified Bac-NP complex as an advanced gene delivery vehicle for stem cells and demonstrated its potential to treat ischemic heart disease with high therapeutic index for combined stem cell-gene therapy strategy.

Anxiolytic-like Effect of Testosterone in Male Rats: GABAC Receptors Are Not Involved

PubMed Central

Roohbakhsh, Ali; Moghaddam, Akbar Hajizadeh; Delfan, Karim Mahmoodi

2011-01-01

Objective(s) The effect of testosterone on anxiety-like behaviors has been the subject of some studies. There is evidence that testosterone modulates anxiety via GABA (gama aminobutyric acid) and GABAergic system. The involvement of GABAC receptors in those effects of testosterone on anxiety-like behaviors of the rats was investigated in the present study. Materials and Methods A group of rats received subcutaneous injections of testosterone (5, 10 and 20 mg/kg). Two groups of rats received intracerebroventricular injections of either CACA (GABAC agonist, 0.125 μg/rat) or TPMPA (GABAC antagonist, 3 microg/rat) following administration of testosterone (5, 10 and 20 mg/kg). After the injections, the rats were submitted to the elevated plus-maze test of anxiety. Results The rats received testosterone alone, showed a decreased in anxiety-like behaviors (P< 0.01). Administration of either CACA or TPMPA did not modify animals’ behavior compared to the rats received testosterone alone. Conclusion The results of the present study showed that administration of testosterone induces anxiolytic-like behaviors in the rats and GABAC receptors possibly are not involved in the anxiolytic effect of testosterone. PMID:23493519

Decrease of hyperglycemia by syringaldehyde in diabetic rats.

PubMed

Kuo, S C; Chung, H H; Huang, C H; Cheng, J T

2014-01-01

Syringaldehyde is one of the active principles from the stems of Hibiscus taiwanensis (Malvaceae) that has been mentioned to lower hyperglycemia. However, the potential mechanisms for this action of syringaldehyde remain obscure. In the present study, we used streptozotocin to induce diabetic rats (STZ-diabetic rats) as type 1-like diabetic rats and fed fructose-rich chow to rats as type 2-like diabetic rats. Then, we performed the postprandial glucose test and applied the hyperinsulinemic euglycemic clamp to investigate the actions of syringaldehyde. Also, the changes of gene expressions of enzyme relating to glucose homeostasis in muscle and liver were characterized. Syringaldehyde significantly decreased the postprandial plasma glucose in rats, while the plasma insulin was not modified by syringaldehyde. The glucose infusion rate (GIR) in fructose chow-fed rats using hyperinsulinemic euglycemic clamp was markedly improved by syringaldehyde. Additionally, repeated administration of syringaldehyde for 3 days in STZ-diabetic rats resulted in a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. Our results suggest that syringaldehyde may increase glucose utilization to lower hyperglycemia in diabetic rats. © Georg Thieme Verlag KG Stuttgart · New York.

[Crabtree effect caused by ketoses in isolated rat hepatocytes].

PubMed

Martínez, P; Carrascosa, J M; Núñez de Castro, I

1982-01-01

Oxygen uptake and glycolytic activity were studied in hepatocytes isolated from fed rats. The addition of fructose or tagatose resulted in a 38% and 31% inhibition of cellular respiration respectively. The addition of 10 mM D-glyceraldehyde caused a slight Crabtree effect. Glucose, L-sorbose, or glycerol failed to modify oxygen consumption. Only incubation in the presence of fructose showed a high aerobic glycolysis measured by lactate production.

Pretreatment with CP-154526 blocks the modifying effects of alarm pheromone on components of sexual behavior in male, but not in female, rats.

PubMed

Kobayashi, Tatsuya; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji

2011-09-01

We previously demonstrated that an alarm pheromone released from male donor Wistar rats evoked several physiological and behavioral responses in recipient rats. However, the pheromone effects on social behavior were not analyzed. In the present study, we examined whether the alarm pheromone affects sexual behavior in male or female rats. When a pair of male and female subjects was exposed to the alarm pheromone during sexual behavior, the ejaculation latency was elongated, the number of mounts was increased, and the hit rate (number of intromissions/number of mounts and intromissions) was decreased in the male subject. In contrast, female sexual behavior was not affected by the alarm pheromone. When we exposed only the male or female subject of the pair to the pheromone just before sexual behavior, the results were similar: the pheromone effects were evident in male, but not in female, subjects. In addition, when we pretreated with corticotropin-releasing factor (CRF) antagonist (CP-154526) before exposing the male subject to the alarm pheromone, the pheromone effects were attenuated in a dose-dependent manner. These results indicate that the alarm pheromone modifies male, but not female, components of sexual behavior and that CRF participates in the effects.

Influence of Hesperidin on the Systemic and Intestinal Rat Immune Response.

PubMed

Camps-Bossacoma, Mariona; Franch, Àngels; Pérez-Cano, Francisco J; Castell, Margarida

2017-06-06

Polyphenols, widely found in edible plants, influence the immune system. Nevertheless, the immunomodulatory properties of hesperidin, the predominant flavanone in oranges, have not been deeply studied. To establish the effect of hesperidin on in vivo immune response, two different conditions of immune system stimulations in Lewis rats were applied. In the first experimental design, rats were intraperitoneally immunized with ovalbumin (OVA) plus Bordetella pertussis toxin and alum as the adjuvants, and orally given 100 or 200 mg/kg hesperidin. In the second experimental design, rats were orally sensitized with OVA together with cholera toxin and fed a diet containing 0.5% hesperidin. In the first approach, hesperidin administration changed mesenteric lymph node lymphocyte (MLNL) composition, increasing the TCRαβ+ cell percentage and decreasing that of B lymphocytes. Furthermore, hesperidin enhanced the interferon (IFN)-γ production in stimulated MLNL. In the second approach, hesperidin intake modified the lymphocyte composition in the intestinal epithelium (TCRγδ+ cells) and the lamina propria (TCRγδ+, CD45RA+, natural killer, natural killer T, TCRαβ+CD4+, and TCRαβ+CD8+ cells). Nevertheless, hesperidin did not modify the level of serum anti-OVA antibodies in either study. In conclusion, hesperidin does possess immunoregulatory properties in the intestinal immune response, but this effect is not able to influence the synthesis of specific antibodies.

A C8-Modified Graphene@mSiO2 Composites Based Method for Quantification of Gallic Acid in Rat Plasma after Oral Administration of Changtai Granule and Its Application to Pharmacokinetics.

PubMed

Xu, Chen; Yu, Yingjia; Ling, Li; Wang, Yang; Zhang, Jundong; Li, Yan; Duan, Gengli

2017-01-01

A rapid, effective extraction technique has been established for measuring the gallic acid in rat plasma by using sandwich-structured graphene/mesoporous silica composites with C 8 -modified interior pore-walls as adsorbent. The unique characteristics of the graphene-silica composites excluded large molecules, like proteins, from the mesopore channels as a result of size exclusion effect, leading to a direct extraction of drug molecules from protein-rich biological samples such as plasma without any other pretreatment procedure. Followed by elution and centrifugation, the gallic acid-absorbed composites were rapidly isolated before LC-MS/MS. Serving as a reliable tool for analysis of Traditional Chinese Medicine: Changtai Granule, the newly developed method was fully validated and successfully applied in the pharmacokinetic study of gallic acid in rat plasma. Extraction recovery, matrix effect and stability were satisfactory in rat plasma. According to the results of pharmacokinetic studies, Changtai Granule exhibited greater adsorption, distribution and clearance properties of gallic acid in the treatment of ulcerative colitis. Hence, this study may offer a valuable alternative to simplify and speed up sample preparation, and be useful for clinical studies of related preparations.

High-frequency attenuation and backscatter measurements of rat blood between 30 and 60 MHz.

PubMed

Huang, Chih-Chung

2010-10-07

There has recently been a great deal of interest in noninvasive high-frequency ultrasound imaging of small animals such as rats due to their being the preferred animal model for gene therapy and cancer research. Improving the interpretation of the obtained images and furthering the development of the imaging devices require a detailed knowledge of the ultrasound attenuation and backscattering of biological tissue (e.g. blood) at high frequencies. In the present study, the attenuation and backscattering coefficients of the rat red blood cell (RBC) suspensions and whole blood with hematocrits ranging from 6% to 40% were measured between 30 and 60 MHz using a modified substitution approach. The acoustic parameters of porcine blood under the same conditions were also measured in order to compare differences in the blood properties between these two animals. For porcine blood, both whole blood and RBC suspension were stirred at a rotation speed of 200 rpm. Three different rotation speeds of 100, 200 and 300 rpm were carried out for rat blood experiments. The attenuation coefficients of both rat and porcine blood were found to increase linearly with frequency and hematocrit (the values of coefficients of determination (r(2)) are around 0.82-0.97 for all cases). The average attenuation coefficient of rat whole blood with a hematocrit of 40% increased from 0.26 Nepers mm(-1) at 30 MHz to 0.47 Nepers mm(-1) at 60 MHz. The maximum backscattering coefficients of both rat and porcine RBC suspensions were between 10% and 15% hematocrits at all frequencies. The fourth-power dependence of backscatter on frequency was approximately valid for rat RBC suspensions with hematocrits between 6% and 40%. However, the frequency dependence of the backscatter estimate deviates from a fourth-power law for porcine RBC suspension with hematocrit higher than 20%. The backscattering coefficient plateaued for hematocrits higher than 15% in porcine blood, but for rat blood it was maximal around a hematocrit of 20% at the same rotation speed, and shifted to a hematocrit of 10% at a higher speed. The backscattering properties of rat RBCs in plasma are similar to those of RBCs in saline at a higher rotation speed. The differences in attenuation and backscattering between rat and porcine blood may be attributed to RBCs' being smaller and the RBC aggregation level being lower for rat blood than for porcine blood.

The effects of the covalent attachment of 3-(4-hydroxy-3,5-di-tert-butylphenyl) propyl amine to glutaraldehyde pretreated bovine pericardium on structural degeneration, oxidative modification, and calcification of rat subdermal implants.

PubMed

Christian, Abigail J; Alferiev, Ivan S; Connolly, Jeanne M; Ischiropoulos, Harry; Levy, Robert J

2015-07-01

Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft materials, porcine aortic valves or bovine pericardium (BP), are widely used in cardiac surgery. BHV progressively fail in clinical use due to structural degeneration. Previously we reported that dityrosine, an oxidized amino acid, was present in failed clinical BP-BHV explants; unimplanted BP had no detectable dityrosine. In the same studies BP were demonstrated in vitro to be susceptible to oxidative damage, that could be mitigated with BP covalently modified with the antioxidant, 3-(4-hydroxy-3,5-di-tert-butylphenyl)propyl amine (DBP). The present studies compared in rat subdermal implants glutaraldehyde pretreated BP to BP modified with either DBP or the chemical reactions used to link DBP. All BP explants regardless of DBP demonstrated reduced hydroxyproline and increased digestibility by collagenase. However, the DBP-BP explants showed significant inhibition of reduced explant shrink temperatures (an index of crosslinking) as compared with control BP. Significant mitigation of calcification was observed in both the BP-DBP and chemically modified explants as compared with BP. Dityrosine was not detectable in the 90 day explants. It is concluded that rat subdermal BP implants undergo both calcific and noncalcific structural degeneration, but without the formation of dityrosine, unlike clinical BP explants. © 2014 Wiley Periodicals, Inc.

The effects of the covalent attachment of 3-(4-hydroxy-3,5-di-tert-butylphenyl)propyl amine to glutaraldehyde pre-treated bovine pericardium on structural degeneration, oxidative modification and calcification of rat subdermal implants

PubMed Central

Christian, Abigail J.; Alferiev, Ivan S.; Connolly, Jeanne M.; Ischiropoulos, Harry; Levy, Robert J.

2014-01-01

Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft materials, porcine aortic valves or bovine pericardium (BP), are widely used in cardiac surgery. BHV progressively fail in clinical use due to structural degeneration. Previously we reported that dityrosine, an oxidized amino acid, was present in failed clinical BP-BHV explants; unimplanted BP had no detectable dityrosine. In the same studies BP were demonstrated in vitro to be susceptible to oxidative damage, that could be mitigated with BP covalently modified with the antioxidant, 3-(4-hydroxy-3,5-di-tert-butylphenyl)propyl amine (DBP). The present studies compared in rat subdermal implants glutaraldehyde pretreated BP to BP modified with either DBP or the chemical reactions used to link DBP. All BP explants regardless of DBP demonstrated reduced hydroxyproline and increased digestibility by collagenase. However, the DBP-BP explants showed significant inhibition of reduced explant shrink temperatures (an index of crosslinking) compared to control BP. Significant mitigation of calcification was observed in both the BP-DBP and chemically modified explants compared to BP. Dityrosine was not detectable in the 90 day explants. It is concluded that rat subdermal BP implants undergo both calcific and non-calcific structural degeneration, but without the formation of dityrosine, unlike clinical BP explants. PMID:25546235

Proliferation and osteogenic differentiation of rat BMSCs on a novel Ti/SiC metal matrix nanocomposite modified by friction stir processing

PubMed Central

Zhu, Chenyuan; Lv, Yuting; Qian, Chao; Qian, Haixin; Jiao, Ting; Wang, Liqiang; Zhang, Fuqiang

2016-01-01

The aims of this study were to fabricate a novel titanium/silicon carbide (Ti/SiC) metal matrix nanocomposite (MMNC) by friction stir processing (FSP) and to investigate its microstructure and mechanical properties. In addition, the adhesion, proliferation and osteogenic differentiation of rat bone marrow stromal cells (BMSCs) on the nanocomposite surface were investigated. The MMNC microstructure was observed by both scanning and transmission electron microscopy. Mechanical properties were characterized by nanoindentation and Vickers hardness testing. Integrin β1 immunofluorescence, cell adhesion, and MTT assays were used to evaluate the effects of the nanocomposite on cell adhesion and proliferation. Osteogenic and angiogenic differentiation were evaluated by alkaline phosphatase (ALP) staining, ALP activity, PCR and osteocalcin immunofluorescence. The observed microstructures and mechanical properties clearly indicated that FSP is a very effective technique for modifying Ti/SiC MMNC to contain uniformly distributed nanoparticles. In the interiors of recrystallized grains, characteristics including twins, fine recrystallized grains, and dislocations formed concurrently. Adhesion, proliferation, and osteogenic and angiogenic differentiation of rat BMSCs were all enhanced on the novel Ti/SiC MMNC surface. In conclusion, nanocomposites modified using FSP technology not only have superior mechanical properties under stress-bearing conditions but also provide improved surface and physicochemical properties for cell attachment and osseointegration. PMID:27958394

Electroacupuncture modulates stromal cell-derived factor-1α expression and mobilization of bone marrow endothelial progenitor cells in focal cerebral ischemia/reperfusion model rats.

PubMed

Xie, Chenchen; Gao, Xiang; Luo, Yong; Pang, Yueshan; Li, Man

2016-10-01

Stromal cell-derived factor-1α(SDF-1α) plays a crucial role in regulating the mobilization, migration and homing of endothelial progenitor cells(EPCs). Electroacupuncture(EA), a modern version of Traditional Chinese Medicine, can improve neurological recovery and angiogenesis in cerebral ischemic area. This study aimed to investigate the effects of electroacupuncture(EA) on the mobilization and migration of bone marrow EPCs and neurological functional recovery in rats model after focal cerebral ischemia/reperfusion and the potentially involved mechanisms. Sprague-Dawley rats received filament occlusion of the right middle cerebral artery for 2h followed by reperfusion for 12h, 1d, 2d, 3d, 7d respectively. Rats were randomly divided into sham group, model group and EA group. After 2h of the reperfusion, EA was given at the "Baihui" (GV 20)/Siguan ("Hegu" (LI 4)/"Taichong" (LR 3)) acupoints in the EA group. Modified neurological severity score (mNSS) was used to assess the neurological functional recovery. EPCs number and SDF-1α level in bone marrow(BM) and peripheral blood(PB) were detected by using fluorescence-activated cell sorting (FACS) analysis and quantitative real time polymerase chain reaction (qRT-PCR) respectively. An mNSS test showed that EA treatment significantly improved the neurological functional outcome. EPCs number in PB and BM were obviously increased in the EA group. After cerebral ischemia, the SDF-1α level was decreased in BM while it was increased in PB, which implied a gradient of SDF-1α among BM and PB after ischemia. It suggested that the forming of SDF-1α concentration gradient can induce the mobilization and homing of EPCs. Eletroacupuncture as a treatment can accelerate and increase the forming of SDF-1α concentration gradient to further induce the mobilization of EPCs and angiogenesis in ischemic brain and improve the neurological function recovery. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of orbitofrontal cortex lesions on autoshaped lever pressing and reversal learning.

PubMed

Chang, Stephen E

2014-10-15

A cue associated with a rewarding event can trigger behavior towards the cue itself due to the cue acquiring incentive value through its pairing with the rewarding outcome (i.e., sign-tracking). For example, rats will approach, press, and attempt to "consume" a retractable lever conditioned stimulus (CS) that signals delivery of a food unconditioned stimulus (US). Attending to food-predictive CSs is important when seeking out food, and it is just as important to be able to modify one's behavior when the relationships between CSs and USs are changed. Using a discriminative autoshaping procedure with lever CSs, the present study investigated the effects of orbitofrontal cortex (OFC) lesions on sign-tracking and reversal learning. Insertion of one lever was followed by sucrose delivery upon retraction, and insertion of another lever was followed by nothing. After the acquisition phase, the contingencies between the levers and outcomes were reversed. Bilateral OFC lesions had no effect on the acquisition of sign-tracking. However, OFC-lesioned rats showed substantial deficits in acquiring sign-tracking compared to sham-lesioned rats once the stimulus-outcome contingencies were reversed. Over the course of reversal learning, OFC-lesioned rats were able to reach comparable levels of sign-tracking as sham-lesioned rats. These findings suggest that OFC is not necessary for the ability of a CS to acquire incentive value and provide more evidence that OFC is critical for modifying behavior appropriately following a change in stimulus-outcome contingencies. Copyright © 2014 Elsevier B.V. All rights reserved.

Review of Surgical Techniques of Experimental Renal Transplantation in Rats.

PubMed

Shrestha, Badri; Haylor, John

2017-08-01

Microvascular surgical techniques of renal transplant in rats have evolved over the past 5 decades to achieve successful rat renal transplant; these modifications have included surgical techniques to address the anatomic variations in the renal blood vessels and those to reduce ischemic and operation durations. Here, we review the surgical techniques of renal transplant in rats and evaluate the advantages and disadvantages of individual techniques of vascular and ureteric anastomoses. For this review, we performed a systematic literature search using relevant medical subject heading terms and included appropriate publications in the review. Since the first description of a rat model of renal transplant by Bernard Fisher and his colleagues in 1965, which used end-to-side anastomosis between the renal vein and renal artery to the recipient inferior vena cava and aorta, several vascular and ureteric anastomosis techniques have been modified. Vascular anastomosis techniques now include end-to-end anastomosis, use of donor aortic and inferior vena cava conduits, sleeve and cuff anastomoses, and application of fibrin glue. Likewise, restoration of the urinary tract can now be achieved by direct anastomosis of the donor ureter to the recipient bladder, end-to-end anastomosis between the donor and recipient ureters, and donor bladder cuff to the recipient bladder. There are advantages and disadvantages attributable to individual techniques. The range of vascular and ureteric anastomosis techniques that has emerged reflects the need for mastering more than one technique to suit the vascular anatomy of individual animals and to reduce operating time for achieving successful outcomes after renal transplant.

In vivo genotoxicity assessment in rats exposed to Prestige-like oil by inhalation.

PubMed

Valdiglesias, Vanessa; Kiliç, Gözde; Costa, Carla; Amor-Carro, Óscar; Mariñas-Pardo, Luis; Ramos-Barbón, David; Méndez, Josefina; Pásaro, Eduardo; Laffon, Blanca

2012-01-01

One of the largest oil spill disasters in recent times was the accident of the oil tanker Prestige in front of the Galician coast in 2002. Thousands of people participated in the cleanup of the contaminated areas, being exposed to a complex mixture of toxic substances. Acute and prolonged respiratory symptoms and genotoxic effects were reported, although environmental exposure measurements were restricted to current determinations, such that attribution of effects observed to oil exposure is difficult to establish. The aim of this study was to analyze peripheral blood leukocytes (PBL) harvested from a rat model of subchronic exposure to a fuel oil with similar characteristics to that spilled by the Prestige tanker, in order to determine potential genotoxic effects under strictly controlled, in vivo exposure. Wistar Han and Brown Norway rats were exposed to the oil for 3 wk, and micronucleus test (MN) and comet assay, standard and modified with 8-oxoguanine DNA glycosylase (OGG1) enzyme, were employed to assess genotoxicity 72 h and 15 d after the last exposure. In addition, the potential effects of oil exposure on DNA repair capacity were determined by means of mutagen sensitivity assay. Results obtained from this study showed that inhalation oil exposure induced DNA damage in both Brown Norway and Wistar Han rats, especially in those animals evaluated 15 d after exposure. Although alterations in the DNA repair responses were noted, the sensitivity to oil substances varied depending on rat strain. Data support previous positive genotoxicity results reported in humans exposed to Prestige oil during cleanup tasks.

Effect of Hawthorn (Crataegus aronia syn. Azarolus (L)) on platelet function in albino Wistar rats.

PubMed

Shatoor, Abdullah S; Soliman, Hesham; Al-Hashem, Fahaid; Gamal, Basiouny El-; Othman, Adel; El-Menshawy, Nadia

2012-07-01

This study was designed to investigate the possible antiplatelet effect of aqueous whole-plant C. aronia syn: Azarolus (L) extract using Wistar albino rats as a model. Forty-two male albino Wistar rats weighing 200 to 250 g were divided into seven groups with six rats in each group. Group 1 served as the control and received equal volumes of distilled water. Groups 2-6 served as the experimental groups and were given C. aronia extract at doses of 100, 200, 500, 1,000, and 2,000 mg/kg, while group 7 served as a positive control and was given aspirin (25mg/kg). All the doses were administered orally once a day and the treatment was continued for seven days. In all groups, at the end of the experimental procedure, blood samples were obtained for platelet function measurements, including PFA-100, thromboxane B2 levels, platelet count, and haematocrit. The bleeding time was determined using a modified tail cutting method described previously. The aqueous C. aronia syn. Azarolus (L) extract significantly altered the bleeding time and the closure time, as determined by the PFA-100 and thromboxane B2 levels, suggesting significant platelet function inhibition. These effects were observed with C. aronia doses between 100 - 500 mg/kg, which yielded thromboxane B2 levels of 1,000 mg/kg, whereas the higher dose (2,000 mg/kg) produced opposite effects on these parameters. C. aronia syn. Azarolus (L) aqueous extract has antiplatelet effects in Wistar albino rats. Copyright © 2012 Elsevier Ltd. All rights reserved.

Binge ethanol exposure increases the Krüppel-like factor 11-monoamine oxidase (MAO) pathway in rats: Examining the use of MAO inhibitors to prevent ethanol-induced brain injury

PubMed Central

Duncan, Jeremy W.; Zhang, Xiao; Wang, Niping; Johnson, Shakevia; Harris, Sharonda; Udemgba, Chinelo; Ou, Xiao-Ming; Youdim, Moussa B.; Stockmeier, Craig A.; Wang, Jun Ming

2016-01-01

Binge drinking induces several neurotoxic consequences including oxidative stress and neurodegeneration. Because of these effects, drugs which prevent ethanol-induced damage to the brain may be clinically beneficial. In this study, we investigated the ethanol-mediated KLF11-MAO cell death cascade in the frontal cortex of Sprague–Dawley rats exposed to a modified Majchowicz 4-day binge ethanol model and control rats. Moreover, MAO inhibitors (MAOIs) were investigated for neuroprotective activity against binge ethanol. Binge ethanol-treated rats demonstrated a significant increase in KLF11, both MAO isoforms, protein oxidation and caspase-3, as well as a reduction in BDNF expression in the frontal cortex compared to control rats. MAOIs prevented these binge ethanol-induced changes, suggesting a neuroprotective benefit. Neither binge ethanol nor MAOI treatment significantly affected protein expression levels of the oxidative stress enzymes, SOD2 or catalase. Furthermore, ethanol-induced antinociception was enhanced following exposure to the 4-day ethanol binge. These results demonstrate that the KLF11-MAO pathway is activated by binge ethanol exposure and MAOIs are neuroprotective by preventing the binge ethanol-induced changes associated with this cell death cascade. This study supports KLF11-MAO as a mechanism of ethanol-induced neurotoxicity and cell death that could be targeted with MAOI drug therapy to alleviate alcohol-related brain injury. Further examination of MAOIs to reduce alcohol use disorder-related brain injury could provide pivotal insight to future pharmacotherapeutic opportunities. PMID:26805422

Comparison of transplantation of bone marrow stromal cells (BMSC) and stem cell mobilization by granulocyte colony stimulating factor after traumatic brain injury in rat.

PubMed

Bakhtiary, Mehrdad; Marzban, Mohsen; Mehdizadeh, Mehdi; Joghataei, Mohammad Taghi; Khoei, Samideh; Pirhajati Mahabadi, Vahid; Laribi, Bahareh; Tondar, Mahdi; Moshkforoush, Arash

2010-10-01

Recent clinical studies of treating traumatic brain injury (TBI) with autologous adult stem cells led us to compare effect of intravenous injection of bone marrow mesenchymal stem cells (BMSC) and bone marrow hematopoietic stem cell mobilization, induced by granulocyte colony stimulating factor (G-CSF), in rats with a cortical compact device. Forty adult male Wistar rats were injured with controlled cortical impact device and divided randomly into four groups. The treatment groups were injected with 2 × 106 intravenous bone marrow stromal stem cell (n = 10) and also with subcutaneous G-CSF (n = 10) and sham-operation group (n = 10) received PBS and "bromodeoxyuridine (Brdu)" alone, i.p. All injections were performed 1 day after injury into the tail veins of rats. All cells were labeled with Brdu before injection into the tail veins of rats. Functional neurological evaluation of animals was performed before and after injury using modified neurological severity scores (mNSS). Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry. Statistically, significant improvement in functional outcome was observed in treatment groups compared with control group (P<0.01). mNSS showed no significant difference between the BMSC and G-CSF-treated groups during the study period (end of the trial). Histological analyses showed that Brdu-labeled (MSC) were present in the lesion boundary zone at 42nd day in all injected animals. In our study, we found that administration of a bone marrow-stimulating factor (G-CSF) and BMSC in a TBI model provides functional benefits.

Involvement of spinal orexin A in the electroacupuncture analgesia in a rat model of post-laparotomy pain.

PubMed

Feng, Xiao-Ming; Mi, Wen-Li; Xia, Fang; Mao-Ying, Qi-Liang; Jiang, Jian-Wei; Xiao, Sheng; Wang, Zhi-Fu; Wang, Yan-Qing; Wu, Gen-Cheng

2012-11-22

Orexin A (OXA, hypocretin/hcrt 1) is a newly discovered potential analgesic substance. However, whether OXA is involved in acupuncture analgesia remains unknown. The present study was designed to investigate the involvement of spinal OXA in electroacupuncture (EA) analgesia. A modified rat model of post-laparotomy pain was adopted and evaluated. Von Frey filaments were used to measure mechanical allodynia of the hind paw and abdomen. EA at 2/15 Hz or 2/100 Hz was performed once on the bilateral ST36 and SP6 for 30 min perioperatively. SB-334867, a selective orexin 1 receptor (OX1R) antagonist with a higher affinity for OXA than OXB, was intrathecally injected to observe its effect on EA analgesia. OXA at 0.3 nmol and EA at 2/15 Hz produced respective analgesic effects on the model (P<0.05). Pre-surgical intrathecal administered of SB-334867 30 nmol antagonized OXA analgesia and attenuated the analgesic effect of EA (P<0.05). However, SB-334867 did not block fentanyl-induced analgesia (P>0.05). In addition, naloxone, a selective opioid receptor antagonist, failed to antagonize OXA-induced analgesia (P>0.05). The results of the present study indicate the involvement of OXA in EA analgesia via OX1R in an opioid-independent way.

Evaluating the Small-World-Ness of a Sampled Network: Functional Connectivity of Entorhinal-Hippocampal Circuitry

NASA Astrophysics Data System (ADS)

She, Qi; Chen, Guanrong; Chan, Rosa H. M.

2016-02-01

The amount of publicly accessible experimental data has gradually increased in recent years, which makes it possible to reconsider many longstanding questions in neuroscience. In this paper, an efficient framework is presented for reconstructing functional connectivity using experimental spike-train data. A modified generalized linear model (GLM) with L1-norm penalty was used to investigate 10 datasets. These datasets contain spike-train data collected from the entorhinal-hippocampal region in the brains of rats performing different tasks. The analysis shows that entorhinal-hippocampal network of well-trained rats demonstrated significant small-world features. It is found that the connectivity structure generated by distance-dependent models is responsible for the observed small-world features of the reconstructed networks. The models are utilized to simulate a subset of units recorded from a large biological neural network using multiple electrodes. Two metrics for quantifying the small-world-ness both suggest that the reconstructed network from the sampled nodes estimates a more prominent small-world-ness feature than that of the original unknown network when the number of recorded neurons is small. Finally, this study shows that it is feasible to adjust the estimated small-world-ness results based on the number of neurons recorded to provide a more accurate reference of the network property.

[Contractile properties of skeletal muscles of rats after flight on "Kosmos-1887"].

PubMed

Oganov, V S; Skuratova, S A; Murashko, L M

1991-01-01

Contractile properties of skeletal muscles of rats were investigated using glycerinated muscle preparations that were obtained from Cosmos-1887 animals flown for 13 days (plus 2 days on the ground) and from rats that remained hypokinetic for 13 days on the ground. In the flow rats, the absolute mass of postural muscles remained unchanged while their relative mass increased; this may be attributed to their enhanced hydration which developed during the first 2 days after landing. Strength losses of the postural muscles were less significant than after previous flights. Comparison of the Cosmos-1887 and hypokinesia control data has shown that even 2-day exposure to 1 G after 13-day flight can modify drastically flight-induced changes.

Effects of "nourishing liver and kidney" acupuncture therapy on expression of brain derived neurotrophic factor and synaptophysin after cerebral ischemia reperfusion in rats.

PubMed

Xia, Wen-Guang; Zheng, Chan-Juan; Zhang, Xuan; Wang, Juan

2017-04-01

The aim of the present study was to investigate the effect of "nourishing liver and kidney" acupuncture therapy on motor and cognitive deficits, and the underlying mechanism following cerebral ischemia-reperfusion (I/R) via increasing the expression of brain derived neurotrophic factor (BDNF) and synaptophysin (SYN) in the hippocampus. Healthy adult male SD rats were randomly divided into sham operation group (n=51), model group (n=51), acupuncture group (n=51) and acupuncture control group (n=51). The middle cerebral I/R model was established. Acupunctures were performed in the acupuncture group and acupuncture control group at acupoints of Taixi (K103), Taichong (ST09) of both sides, for 30 min once daily every morning. The animals in the sham operation group and model group were conventionally fed in the cage, without any intervention therapy. The rats of each group were assessed with modified neurological severity scores (mNSS). The expression of BDNF and SYN in the hippocampus was detected by immunohistochemical SP method and the synaptic structure in hippocampus area was assessed morphologically and quantitatively at the 3rd, 7th and 14th day. The Morris water Maze (MWM) test was used to evaluate the rats' learning and memory abilities on the 15th day after acupuncture. The animals in the acupuncture control group and sham operation group presented no neurological deficit. In the acupuncture group, the nerve functional recovery was significantly better than that in the model group at the 7th and 14th day after modeling. The average MWM escape latency in the acupuncture group was shorter than that in the model group at the 3rd, 4th and 5th day. The number of crossings of the platform quadrant in the acupuncture group was significantly more than that in the model group. At the each time point, the expression levels of BDNF and SYN in the hippocampal regions increased significantly in the model group as compared with the sham operation group and the acupuncture control group. In the acupuncture group, the expression levels of BDNF at the 7th and 14th day increased more significantly than those in the model group. In the acupuncture group, the expression levels of SYN at the each time point increased more significantly than those in the model group. The post-synaptic density (PSD) was significantly increased and the synapse cleft width was narrowed in the acupuncture group as compared with other groups. The synaptic curvatures were improved obviously in the acupuncture group in contrast to the model group. It was concluded that the "nourishing liver and kidney" acupuncture therapy has positive effects on behavioral recovery, as well as learning and memory abilities, probably by promoting the expression of BDNF and SYN, and synaptic structure reconstruction in the ipsilateral hippocampus after I/R in rats. The "nourishing liver and kidney" acupuncture therapy can promote the functional recovery in rats after cerebral ischemia injury.

Pulmonary preservation studies: effects on endothelial function and pulmonary adenine nucleotides.

PubMed

Paik, Hyo Chae; Hoffmann, Steven C; Egan, Thomas M

2003-02-27

Lung transplantation is an effective therapy plagued by a high incidence of early graft dysfunction, in part because of reperfusion injury. The optimal preservation solution for lung transplantation is unknown. We performed experiments using an isolated perfused rat lung model to test the effect of lung preservation with three solutions commonly used in clinical practice. Lungs were retrieved from Sprague-Dawley rats and flushed with one of three solutions: modified Euro-Collins (MEC), University of Wisconsin (UW), or low potassium dextran and glucose (LPDG), then stored cold for varying periods before reperfusion with Earle's balanced salt solution using the isolated perfused rat lung model. Outcome measures were capillary filtration coefficient (Kfc), wet-to-dry weight ratio, and lung tissue levels of adenine nucleotides and cyclic AMP. All lungs functioned well after 4 hr of storage. By 6 hr, UW-flushed lungs had a lower Kfc than LPDG-flushed lungs. After 8 hr of storage, only UW-flushed lungs had a measurable Kfc. Adenine nucleotide levels were higher in UW-flushed lungs after prolonged storage. Cyclic AMP levels correlated with Kfc in all groups. Early changes in endothelial permeability seemed to be better attenuated in lungs flushed with UW compared with LPDG or MEC; this was associated with higher amounts of adenine nucleotides. MEC-flushed lungs failed earlier than LPDG-flushed or UW-flushed lungs. The content of the solution may be more important for lung preservation than whether the ionic composition is intracellular or extracellular.

Cannabinoid receptor 2 activation restricts fibrosis and alleviates hydrocephalus after intraventricular hemorrhage.

PubMed

Tan, Qiang; Chen, Qianwei; Feng, Zhou; Shi, Xia; Tang, Jun; Tao, Yihao; Jiang, Bing; Tan, Liang; Feng, Hua; Zhu, Gang; Yang, Yunfeng; Chen, Zhi

2017-01-01

Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH). The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases. However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model. Autologous non-anticoagulative blood injection model was induced to mimic ventricular extension of hemorrhage in adult Sprague-Dawley rats. Rats were randomized to receive JWH-133(CB2 agonist), SR144528 (CB2 antagonist) or saline. The lateral ventricular volumes, fibrosis in the subarachnoid space and ventricular wall, transforming growth factor-β 1(TGF-β1) in cerebrospinal fluid and brain tissue, and animal neurological scores were measured to evaluate the effects of CB2 in hydrocephalus following IVH. CB2 agonist JWH-133 significantly decreased the lateral ventricular volumes, improved the associated neurological deficits, down-regulated TGF-β1 expression, and alleviated fibrosis in the subarachnoid space and ventricular wall after IVH. All of these effects were reversed by SR144528. In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1. Copyright © 2016 Elsevier B.V. All rights reserved.

Influence of physicochemical properties of laser-modified polystyrene on bovine serum albumin adsorption and rat C6 glioma cell behavior.

PubMed

Wang, Xuefeng; Ohlin, C André; Lu, Qinghua; Hu, Jun

2006-09-15

Biomaterial surface modification is an efficient way of improving cell-material interactions. In this study, sub-micrometer laser-induced periodic surface structures (LIPSS) were produced on polystyrene by laser irradiation. FT-IR analysis confirmed that this treatment also led to surface oxidation and anisotropic orientation of the produced carbonyl groups. As a consequence, the surface energy of the laser-treated polystyrene was 1.45 times that of the untreated polystyrene, as measured by contact-angle goniometry. Protein adsorption and rat C6 glioma cell behavior on the two substrates were investigated, showing that the changed physicochemical properties of laser-modified polystyrene surface led to an increase in the quantity of adsorbed bovine serum albumin and significantly affected the behavior of rat C6 glioma cells. In the early stages of cell spreading, cells explored their microenvironment using filopodium as the main sensor. Moreover, cells actively aligned themselves along the direction of LIPSS gradually and cell attachment and proliferation were significantly enhanced. 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006.

Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats.

PubMed

Urakawa, Susumu; Takamoto, Kouich; Hori, Etsuro; Sakai, Natsuko; Ono, Taketoshi; Nishijo, Hisao

2013-01-25

Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive neurons in the basolateral amygdala and anxiety-like behavior. Three-week-old male rats were divided into two groups: those reared in an enriched environment (EE rats) and those reared in standard cages (SE rats). After 5 weeks of rearing, the EE rats showed decreased anxiety-like behavior in an open field than the SE rats. Under another anxiogenic situation, in a beam walking test, the EE rats more quickly traversed an elevated narrow beam. Anxiety-like behavior in the open field was significantly and negatively correlated with walking time in the beam-walking test. Immunohistochemical tests revealed that the number of parvalbumin-positive neurons significantly increased in the basolateral amygdala of the EE rats than that of the SE rats, while the number of calbindin-D28k-positive neurons did not change. These parvalbumin-positive neurons had small, rounded soma and co-expressed the glutamate decarboxylase (GAD67). Furthermore, the number of parvalbumin-positive small cells in the basolateral amygdala tended to positively correlate with emergence in the center arena of the open field and negatively correlated with walking time in the beam walking test. Rearing in the enriched environment augmented the number of parvalbumin-containing specific inhibitory neuron in the basolateral amygdala, but not that of calbindin-containing neuronal phenotype. Furthermore, the number of parvalbumin-positive small neurons in the basolateral amygdala was negatively correlated with walking time in the beam walking test and tended to be positively correlated with activity in the center arena in the open field test. The results suggest that rearing in the enriched environment augmented parvalbumin-positive specific neurons in the basolateral amygdala, which induced behavioral plasticity that was reflected by a decrease in anxiety-like behavior in anxiogenic situations.

Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats

PubMed Central

2013-01-01

Background Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive neurons in the basolateral amygdala and anxiety-like behavior. Results Three-week-old male rats were divided into two groups: those reared in an enriched environment (EE rats) and those reared in standard cages (SE rats). After 5 weeks of rearing, the EE rats showed decreased anxiety-like behavior in an open field than the SE rats. Under another anxiogenic situation, in a beam walking test, the EE rats more quickly traversed an elevated narrow beam. Anxiety-like behavior in the open field was significantly and negatively correlated with walking time in the beam-walking test. Immunohistochemical tests revealed that the number of parvalbumin-positive neurons significantly increased in the basolateral amygdala of the EE rats than that of the SE rats, while the number of calbindin-D28k-positive neurons did not change. These parvalbumin-positive neurons had small, rounded soma and co-expressed the glutamate decarboxylase (GAD67). Furthermore, the number of parvalbumin-positive small cells in the basolateral amygdala tended to positively correlate with emergence in the center arena of the open field and negatively correlated with walking time in the beam walking test. Conclusion Rearing in the enriched environment augmented the number of parvalbumin-containing specific inhibitory neuron in the basolateral amygdala, but not that of calbindin-containing neuronal phenotype. Furthermore, the number of parvalbumin-positive small neurons in the basolateral amygdala was negatively correlated with walking time in the beam walking test and tended to be positively correlated with activity in the center arena in the open field test. The results suggest that rearing in the enriched environment augmented parvalbumin-positive specific neurons in the basolateral amygdala, which induced behavioral plasticity that was reflected by a decrease in anxiety-like behavior in anxiogenic situations. PMID:23347699

Humoral and cellular immune response in Wistar Han RCC rats fed two genetically modified maize MON810 varieties for 90 days (EU 7th Framework Programme project GRACE).

PubMed

Tulinská, Jana; Adel-Patient, Karine; Bernard, Hervé; Líšková, Aurélia; Kuricová, Miroslava; Ilavská, Silvia; Horváthová, Mira; Kebis, Anton; Rollerová, Eva; Babincová, Júlia; Aláčová, Radka; Wal, Jean-Michel; Schmidt, Kerstin; Schmidtke, Jörg; Schmidt, Paul; Kohl, Christian; Wilhelm, Ralf; Schiemann, Joachim; Steinberg, Pablo

2018-07-01

The genetically modified maize event MON810 expresses a Bacillus thuringiensis-derived gene, which encodes the insecticidal protein Cry1Ab to control some lepidopteran insect pests such as the European corn borer. It has been claimed that the immune system may be affected following the oral/intragastric administration of the MON810 maize in various different animal species. In the frame of the EU-funded project GRACE, two 90-day feeding trials, the so-called studies D and E, were performed to analyze the humoral and cellular immune responses of male and female Wistar Han RCC rats fed the MON810 maize. A MON810 maize variety of Monsanto was used in the study D and a MON810 maize variety of Pioneer Hi-Bred was used in the study E. The total as well as the maize protein- and Cry1Ab-serum-specific IgG, IgM, IgA and IgE levels, the proliferative activity of the lymphocytes, the phagocytic activity of the granulocytes and monocytes, the respiratory burst of the phagocytes, a phenotypic analysis of spleen, thymus and lymph node cells as well as the in vitro production of cytokines by spleen cells were analyzed. No specific Cry1Ab immune response was observed in MON810 rats, and anti-maize protein antibody responses were similar in MON810 and control rats. Single parameters were sporadically altered in rats fed the MON810 maize when compared to control rats, but these alterations are considered to be of no immunotoxicological significance.

The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats.

PubMed

Zaru, Alessandro; Maccioni, Paola; Colombo, Giancarlo; Gessa, Gian Luigi

2013-10-01

Craving for chocolate is a common phenomenon, which may evolve to an addictive-like behaviour and contribute to obesity. Nepicastat is a selective dopamine β-hydroxylase (DBH) inhibitor that suppresses cocaine-primed reinstatement of cocaine seeking in rats. We verified whether nepicastat was able to modify the reinforcing and motivational properties of a chocolate solution and to prevent the reinstatement of chocolate seeking in rats. Nepicastat (25, 50 and 100 mg/kg, intraperitoneal) produced a dose-related inhibition of operant self-administration of the chocolate solution in rats under fixed-ratio 10 (FR10) and progressive-ratio schedules of reinforcement, measures of the reinforcing and motivational properties of the chocolate solution, respectively. The effect of nepicastat on the reinstatement of chocolate seeking was studied in rats in which lever-responding had been extinguished by removing the chocolate solution for approximately 8 d. Nepicastat dose-dependently suppressed the reinstatement of lever-responding triggered by a 'priming' of the chocolate solution together with cues previously associated with the availability of the reward. In a separate group of food-restricted rats trained to lever-respond for regular food pellets, nepicastat reduced FR10 lever-responding with the same potency as for the chocolate solution. Spontaneous locomotor activity was not modified by nepicastat doses that reduced self-administration of the chocolate solution and regular food pellets and suppressed the reinstatement of chocolate seeking. The results indicate that nepicastat reduces motivation to food consumption sustained by appetite or palatability. Moreover, the results suggest that DBH inhibitors may be a new class of pharmacological agents potentially useful in the prevention of relapse to food seeking in human dieters.

The Effect of Chemically Modified Tetracycline-3 on the Progression of Dental Caries in Rats.

PubMed

Xu, Jun; Miao, Congcong; Tian, Zhenchuan; Li, Jinlu; Zhang, Chunmei; Yang, Dongmei

2018-02-07

Matrix metalloproteinases (MMPs) exist in human saliva and dentin and play an important role in the degradation of organic matrix in teeth. Chemically modified tetracycline-3 (CMT-3) is an inhibitor of MMPs. CMT-3 has been used experimentally to treat caries since 1999, but no distinction between dental caries prevalence and dentin caries prevalence has been described. A total of 65 Sprague-Dawley rats were randomly divided into three groups. The positive control group (25 rats) was inoculated with Streptococcus mutans (ATCC700610) and fed the cariogenic feed of improved Keyes Diet 2000. The CMT-3 group (25 rats) was also inoculated with S. mutans and fed the cariogenic feed of improved Keyes Diet 2000; the surfaces of rats' molars were daily treated with 0.02% CMT-3. The negative control group (15 rats) was only fed the standard rodent chow. At the end of the 10th week, the dental caries prevalence and dentin caries prevalence of each group were calculated, and the regions of caries were assessed. No caries was found in the negative control group. The dental caries prevalence of the CMT-3 and the positive control group was 75.0 and 83.3%, respectively (p > 0.05, Table 2). The dentin caries prevalence of the CMT-3 and the positive control group was 33.3 and 70.8%, respectively (p < 0.05, Table 2). The Keyes scoring of dentin caries in the CMT-3 group was significantly lower than that in the positive control group (p < 0.05, Table 3). CMT-3 had no effect on the prevalence of dental caries, but could lower the prevalence and slow down the progression of dentin caries. © 2018 S. Karger AG, Basel.

Brain-Derived Neurotrophic Factor Increases Synaptic Protein Levels via the MAPK/Erk Signaling Pathway and Nrf2/Trx Axis Following the Transplantation of Neural Stem Cells in a Rat Model of Traumatic Brain Injury.

PubMed

Chen, Tao; Wu, Yu; Wang, Yuzi; Zhu, Jigao; Chu, Haiying; Kong, Li; Yin, Liangwei; Ma, Haiying

2017-11-01

Brain-derived neurotrophic factor (BDNF) plays an important role in promoting the growth, differentiation, survival and synaptic stability of neurons. Presently, the transplantation of neural stem cells (NSCs) is known to induce neural repair to some extent after injury or disease. In this study, to investigate whether NSCs genetically modified to encode the BDNF gene (BDNF/NSCs) would further enhance synaptogenesis, BDNF/NSCs or naive NSCs were directly engrafted into lesions in a rat model of traumatic brain injury (TBI). Immunohistochemistry, western blotting and RT-PCR were performed to detect synaptic proteins, BDNF-TrkB and its downstream signaling pathways, at 1, 2, 3 or 4 weeks after transplantation. Our results showed that BDNF significantly increased the expression levels of the TrkB receptor gene and the phosphorylation of the TrkB protein in the lesions. The expression levels of Ras, phosphorylated Erk1/2 and postsynaptic density protein-95 were elevated in the BDNF/NSCs-transplanted groups compared with those in the NSCs-transplanted groups throughout the experimental period. Moreover, the nuclear factor (erythroid-derived 2)-like 2/Thioredoxin (Nrf2/Trx) axis, which is a specific therapeutic target for the treatment of injury or cell death, was upregulated by BDNF overexpression. Therefore, we determined that the increased synaptic proteins level implicated in synaptogenesis might be associated with the activation of the MAPK/Erk1/2 signaling pathway and the upregulation of the antioxidant agent Trx modified by BDNF-TrkB following the BDNF/NSCs transplantation after TBI.

Stress disrupts intestinal mucus barrier in rats via mucin O-glycosylation shift: prevention by a probiotic treatment.

PubMed

Da Silva, Stéphanie; Robbe-Masselot, Catherine; Ait-Belgnaoui, Afifa; Mancuso, Alessandro; Mercade-Loubière, Myriam; Salvador-Cartier, Christel; Gillet, Marion; Ferrier, Laurent; Loubière, Pascal; Dague, Etienne; Theodorou, Vassilia; Mercier-Bonin, Muriel

2014-08-15

Despite well-known intestinal epithelial barrier impairment and visceral hypersensitivity in irritable bowel syndrome (IBS) patients and IBS-like models, structural and physical changes in the mucus layer remain poorly understood. Using a water avoidance stress (WAS) model, we aimed at evaluating whether 1) WAS modified gut permeability, visceral sensitivity, mucin expression, biochemical structure of O-glycans, and related mucus physical properties, and 2) whether Lactobacillus farciminis treatment prevented these alterations. Wistar rats received orally L. farciminis or vehicle for 14 days; at day 10, they were submitted to either sham or 4-day WAS. Intestinal paracellular permeability and visceral sensitivity were measured in vivo. The number of goblet cells and Muc2 expression were evaluated by histology and immunohistochemistry, respectively. Mucosal adhesion of L. farciminis was determined ex situ. The mucin O-glycosylation profile was obtained by mass spectrometry. Surface imaging of intestinal mucus was performed at nanoscale by atomic force microscopy. WAS induced gut hyperpermeability and visceral hypersensitivity but did not modify either the number of intestinal goblet cells or Muc2 expression. In contrast, O-glycosylation of mucins was strongly affected, with the appearance of elongated polylactosaminic chain containing O-glycan structures, associated with flattening and loss of the mucus layer cohesive properties. L. farciminis bound to intestinal Muc2 and prevented WAS-induced functional alterations and changes in mucin O-glycosylation and mucus physical properties. WAS-induced functional changes were associated with mucus alterations resulting from a shift in O-glycosylation rather than from changes in mucin expression. L. farciminis treatment prevented these alterations, conferring epithelial and mucus barrier strengthening. Copyright © 2014 the American Physiological Society.

Chronic Sarpogrelate Treatment Reveals 5-HT7 Receptor in the Serotonergic Inhibition of the Rat Vagal Bradycardia.

PubMed

García-Pedraza, José Ángel; García, Mónica; Martín, María Luisa; Eleno, Nélida; Morán, Asunción

2017-01-01

5-Hydroxytryptamine (5-HT) modulates the cardiac parasympathetic neurotransmission, inhibiting the bradyarrhythmia by 5-HT2 receptor activation. We aimed to determine whether the chronic selective 5-HT2 blockade (sarpogrelate) could modify the serotonergic modulation on vagal cardiac outflow in pithed rat. Bradycardic responses in rats treated with sarpogrelate (30 mg·kg·d; orally) were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or intravenous (IV) injections of acetylcholine (1, 5, and 10 μg/kg). 5-HT7 receptor expression was quantified by Western blot in vagus nerve and right atrium. The IV administration of 5-HT (10-200 μg/kg) dose dependently decreased the vagally induced bradycardia, and agonists 5-CT (5-HT1/7), 8-OH-DPAT (5-HT1A), or AS-19 (5-HT7) (50 μg/kg each) mimicked the 5-HT-induced inhibitory effect. Neither agonists CGS-12066B (5-HT1B), L-694,247 (5-HT1D), nor 1-phenylbiguanide (5-HT3) modified the electrically-induced bradycardic responses. Moreover, SB-258719 (5-HT7 antagonist) abolished the 5-HT-, 5-CT-, 8-OH-DPAT-, and AS-19-induced bradycardia inhibition; 5-HT or AS-19 did not modify the bradycardia induced by IV acetylcholine; and 5-HT7 receptor was expressed in both the vagus nerve and the right atrium. Our outcomes suggest that blocking chronically 5-HT2 receptors modifies the serotonergic influence on cardiac vagal neurotransmission exhibiting 5-HT as an exclusively inhibitory agent via prejunctional 5-HT7 receptor.

The proliferative effect of synthetic N-POMC(1-28) peptides in rat adrenal cortex: a possible role for cyclin E.

PubMed

Mendonça, Pedro O R de; Lotfi, Claudimara F P

2011-04-10

Modified synthetic N-POMC(1-28) without disulfide bridges has been shown to act as an adrenal mitogen. Cyclins and their inhibitors are the major cell cycle controls, but in the adrenal cortex the effect of ACTH and N-POMC on the expression of these proteins remains unclear. In this work, we evaluate the effect of different synthetic N-POMC peptides on the S-phase of the cell cycle. In addition, we examine the cyclin E expression in rat adrenal cortex. Rats treated with dexamethasone were injected with ACTH and/or synthetic modified N-POMC and/or synthetic N-POMC with disulfide bridges. DNA synthesis was determined by BrdU incorporation and protein expression was analyzed by immunoblotting and immunohistochemistry. The results showed that similarly to modified N-POMC without disulfide bridges, administration of synthetic N-POMC with disulfide bridges and the combination of ACTH and N-POMC promoted an increase of BrdU-positive nuclei in adrenal cortex. However, the proliferative effect of N-POMC was comparable to that of ACTH only in the zona glomerulosa. An increase in cyclin E expression was observed 6 h after N-POMC treatment in the outer fraction of the adrenal cortex, in agreement with immunohistochemical findings in the zona glomerulosa. In summary, the effect of synthetic N-POMC with disulfide bridges was similar to modified synthetic N-POMC, increasing proliferation in the adrenal cortex, confirming previous evidence that disulfide bridges are not essential to the N-POMC mitogenic effect. Moreover, cyclin E appears to be involved in the N-POMC- and ACTH-stimulated proliferation in the zona glomerulosa of the adrenal cortex. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Detection of Sequence-Specific Tyrosine Nitration of Manganese SOD and SERCA in Cardiovascular Disease and Aging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Shanqin; Ying, Jia; Jiang, Bingbing

2006-06-01

Nitration of protein tyrosine residues (nY) is a marker of oxidative stress and may alter the biological activity of the modified proteins. The aim of this study was to develop antibodies towards site-specific nY-modified proteins and to use histochemical and immunoblotting to demonstrate protein nitration in tissues. Affinity-purified polyclonal antibodies towards peptides with known nY sites in MnSOD nY-34 and of two adjacent nY in the sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA2 di-nY-294,295) were developed. Kidneys from rats infused with angiotensin II with known MnSOD nY and aorta from atherosclerotic rabbits and aging rat skeletal and cardiac sarcoplasmic reticulum withmore » known SERCA di-nY were used for positive controls. Staining for MnSOD nY-34 was most intense in distal renal tubules and collecting ducts. Staining of atherosclerotic aorta for SERCA2 di-nY was most intense in atherosclerotic plaques. Aging rat skeletal muscle and atherosclerotic aorta and cardiac atrium from human diabetic patients also stained positively. Staining was decreased by sodium dithionite that chemically reduces nitrotyrosine to aminotyrosine, and the antigenic nY-peptide blocked staining for each respective nY site, but not for the other. As previously demonstrated, immunoblotting failed to detect these modified proteins in whole tissue lysates, but did when the proteins were concentrated. Immunohistochemical staining for specific nY-modified tyrosine residues offers the ability to assess the effects of oxidant stress associated with pathological conditions on individual proteins whose function may be affected in specific tissue sites.« less

Novel Curcumin Diclofenac Conjugate Enhanced Curcumin Bioavailability and Efficacy in Streptococcal Cell Wall-induced Arthritis.

PubMed

Jain, S K; Gill, M S; Pawar, H S; Suresh, Sarasija

2014-09-01

Curcumin-diclofenac conjugate as been synthesized by esterification of phenolic group of curcumin with the acid moiety of diclofenac, and characterized by mass spectrometry, NMR, FTIR, DSC, thermogravimetric analysis and X-ray diffraction analysis. The relative solubility of curcumin-diclofenac conjugate, curcumin and diclofenac; stability of curcumin-diclofenac conjugate in intestinal extract; permeability study of curcumin-diclofenac conjugate using the everted rat intestinal sac method; stability of curcumin-diclofenac conjugate in gastrointestinal fluids and in vitro efficacy have been evaluated. In vivo bioavailability of curcumin-diclofenac conjugate and curcumin in Sprague-Dawley rats, and antiarthritic activity of curcumin-diclofenac conjugate, curcumin and diclofenac in modified streptococcal cell wall-induced arthritis model in Balb/c mice to mimic rheumatoid arthritis in humans have also been studied. In all of the above studies, curcumin-diclofenac conjugate exhibited enhanced stability as compared to curcumin; its activity was twice that of diclofenac in inhibiting thermal protein denaturation taken as a measure of in vitro antiinflammatory activity; it enhanced the bioavailability of curcumin by more than five folds, and significantly (P<0.01) alleviated the symptoms of arthritis in streptococcal cell wall-induced arthritis model as compared to both diclofenac and curcumin.

Diffusion Modelling Reveals the Decision Making Processes Underlying Negative Judgement Bias in Rats.

PubMed

Hales, Claire A; Robinson, Emma S J; Houghton, Conor J

2016-01-01

Human decision making is modified by emotional state. Rodents exhibit similar biases during interpretation of ambiguous cues that can be altered by affective state manipulations. In this study, the impact of negative affective state on judgement bias in rats was measured using an ambiguous-cue interpretation task. Acute treatment with an anxiogenic drug (FG7142), and chronic restraint stress and social isolation both induced a bias towards more negative interpretation of the ambiguous cue. The diffusion model was fit to behavioural data to allow further analysis of the underlying decision making processes. To uncover the way in which parameters vary together in relation to affective state manipulations, independent component analysis was conducted on rate of information accumulation and distances to decision threshold parameters for control data. Results from this analysis were applied to parameters from negative affective state manipulations. These projected components were compared to control components to reveal the changes in decision making processes that are due to affective state manipulations. Negative affective bias in rodents induced by either FG7142 or chronic stress is due to a combination of more negative interpretation of the ambiguous cue, reduced anticipation of the high reward and increased anticipation of the low reward.

Widening and Elaboration of Consecutive Research into Therapeutic Antioxidant Enzyme Derivatives

PubMed Central

2016-01-01

Undiminishing actuality of enzyme modification for therapeutic purposes has been confirmed by application of modified enzymes in clinical practice and numerous research data on them. Intravenous injection of the superoxide dismutase-chondroitin sulfate-catalase (SOD-CHS-CAT) conjugate in preventive and medicative regimes in rats with endotoxin shock induced with a lipopolysaccharide bolus has demonstrated that antioxidant agents not only effectively prevent damage caused by oxidative stress (as believed previously) but also can be used for antioxidative stress therapy. The results obtained emphasize the importance of investigation into the pathogenesis of vascular damage and the role of oxidative stress in it. The effects of intravenous medicative injection of SOD-CHS-CAT in a rat model of endotoxin shock have demonstrated a variety in the activity of this conjugate in addition to prevention of NO conversion in peroxynitrite upon interaction with O2 ∙− superoxide radical. Together with the literature data, these findings offer a prospect for the study of NO-independent therapeutic effects of SOD-CHS-CAT, implying the importance of a better insight into the mechanisms of the conjugate activity in modeled cardiovascular damage involving vasoactive agents other than NO. PMID:27148430

Dietary supplementation with sorbitol results in selective enrichment of lactobacilli in rat intestine.

PubMed

Sarmiento-Rubiano, Luz Adriana; Zúñiga, Manuel; Pérez-Martínez, Gaspar; Yebra, María Jesús

2007-01-01

A potential prebiotic action has been ascribed to sorbitol, but in vivo evidence of this remains scarce. In the present work, the effect of sorbitol was compared to that of fructo-oligosaccharides (FOS) in a rat model. Microbiota changes, particularly in lactobacilli, were analyzed on fecal, colonic and cecal samples. Denaturing gradient gel electrophoresis (DGGE) analysis of 16S rRNA gene amplicons using universal primers showed that FOS and sorbitol diets exerted a strong influence upon gut microbiota patterns. When Lactobacillus group-specific primers were used, DGGE profiles revealed five DNA bands that belonged to Lactobacillus johnsonii, Lactobacillus sp. AD102, Lactobacillus intestinalis, Lactobacillus murinus and Lactobacillus reuteri. Although these species are present in all dietary groups, quantification by real-time PCR showed that sorbitol and FOS intake increased L. reuteri cell numbers, and sorbitol also contributed to maintaining the levels of Lactobacillus sp. AD102. Analysis of organic acid concentrations showed that sorbitol intake significantly increased colonic and cecal butyrate levels. Hence, sorbitol, which is widely used as a low-calorie sweetener, has the capacity, in our animal model, to modify gut microbiota activity in such a way as to possibly contribute to healthy colonic mucosa.

Flow cytometric detection of Pig-A mutant red blood cells using an erythroid-specific antibody: application of the method for evaluating the in vivo genotoxicity of methylphenidate in adolescent rats.

PubMed

Dobrovolsky, Vasily N; Boctor, Sherin Y; Twaddle, Nathan C; Doerge, Daniel R; Bishop, Michelle E; Manjanatha, Mugimane G; Kimoto, Takafumi; Miura, Daishiro; Heflich, Robert H; Ferguson, Sherry A

2010-03-01

A modified flow cytometry assay for Pig-A mutant rat red blood cells (RBCs) was developed using an antibody that positively identifies rat RBCs (monoclonal antibody HIS49). The assay was used in conjunction with a flow cytometric micronucleus (MN) assay to evaluate gene mutation and clastogenicity/aneugenicity in adolescent male and female rats treated with methylphenidate hydrochloride (MPH). Sprague-Dawley rats were treated orally with 3 mg/kg MPH (70/sex) or water (40/sex) 3 x /day on postnatal days (PNDs) 29-50. Eight additional rats (4/sex) were injected i.p. with N-ethyl-N-nitrosourea (ENU) on PND 28. Blood was collected on PNDs 29, 50, and 90, and used for determining serum MPH levels and/or conducting genotoxicity assays. On the first and last days of MPH treatment (PNDs 29 and 50), serum MPH levels averaged 21 pg/microl, well within the clinical treatment range. Relative to our previously published method (Miura et al. [2008]; Environ Mol Mutagen 49: 614-629), the HIS49 Pig-A mutation assay significantly reduced the background RBC mutant frequency; in the experiments with ENU-treated rats, the modification increased the overall sensitivity of the assay 2-3 fold. Even with the increased assay sensitivity, the 21 consecutive days of MPH treatment produced no evidence of Pig-A mutation induction (measured at PND 90); in addition, MPH treatment did not increase MN frequency (measured at PND 50). These results support the consensus view that the genotoxicity of MPH in pediatric patients reported earlier (El-Zein et al. [2005]: Cancer Lett 230: 284-291) cannot be reproduced in animal models, suggesting that MPH at clinically relevant levels may be nongenotoxic in humans. Published 2009 by Wiley-Liss, Inc.

Safinamide: from molecular targets to a new anti-Parkinson drug.

PubMed

Caccia, C; Maj, R; Calabresi, M; Maestroni, S; Faravelli, L; Curatolo, L; Salvati, P; Fariello, R G

2006-10-10

Ideal treatment in Parkinson's disease (PD) aims at relieving symptoms and slowing disease progression. Of all remedies, levodopa remains the most effective for symptomatic relief, but the medical need for neuroprotectant drugs is still unfulfilled. Safinamide, currently in phase III clinical trials for the treatment of PD, is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model. Safinamide potentiates levodopa-mediated increase of DA levels in DA-depleted mice and reverses the waning motor response after prolonged levodopa treatment in 6-OHDA-lesioned rats. Safinamide has excellent bioavailability, linear kinetics, and is suitable for once-a-day administration. Therefore, safinamide may be used in PD to reduce l-dopa dosage and also represents a valuable therapeutic drug to test disease-modifying potential.

Korean red ginseng protects against neuronal damage induced by transient focal ischemia in rats

PubMed Central

BAN, JU YEON; KANG, SUNG WOOK; LEE, JONG SEOK; CHUNG, JOO-HO; KO, YOUNG GWAN; CHOI, HAN SUNG

2012-01-01

In the present study, we investigated the neuroprotective effect of Korean red ginseng (KRG) following focal brain ischemia/reperfusion injury, in relation to its antioxidant activities. The middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats was employed. The KRG extract (100 mg/kg, perorally) was administered once daily for 7 days following MCAO/R. The elevated levels of lipid peroxidation in the MCAO/R group were attenuated significantly in the KRG-administered group. The significantly depleted activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase was prevented in the KRG-administered group. In the neurobehavioral evaluation expressed as the modified neurological severity score and corner-turn test, the daily intake of KRG showed consistent and significant improvement in the neurological deficits for 7 days following MCAO/R injury. These results indicate that KRG has a neuroprotective effect against ischemia/reperfusion brain injury by reducing the level of lipid peroxidation and increasing the endogenous antioxidant enzymatic activity. PMID:22969953

Reinstatement of MDMA (ecstasy) seeking by exposure to discrete drug-conditioned cues

PubMed Central

Ball, Kevin T.; Walsh, Kelly M.; Rebec, George V.

2007-01-01

The widely used recreational drug MDMA (ecstasy) supports self-administration in animals, but it is not known whether MDMA-associated cues are able to reinstate drug seeking in a relapse model of drug addiction. To assess this possibility, drug-naïve rats were trained to press a lever for MDMA infusions (0.30 mg/kg/infusion, i.v.) paired with a compound cue (light and tone) in daily 2 hr sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. Conditioned cue-induced reinstatement tests were conducted after lever pressing was extinguished in the absence of MDMA and the conditioned cues. Conditioned cues reinstated lever pressing after extinction, and the magnitude of reinstatement was positively correlated with the level of responding during MDMA self-administration. These results show for the first time that conditioned cues can trigger reinstatement of MDMA-seeking behavior in rats, and that individual differences in the pattern of MDMA self-administration can predict the magnitude of reinstatement responding. PMID:17602729

Protein ubiquitination in postsynaptic densities after hypoxia in rat neostriatum is blocked by hypothermia.

PubMed

Capani, Francisco; Saraceno, Gustavo Ezequiel; Botti, Valeria; Aon-Bertolino, Laura; de Oliveira, Diêgo Madureira; Barreto, George; Galeano, Pablo; Giraldez-Alvarez, Lisandro Diego; Coirini, Héctor

2009-10-01

Synaptic dysfunction has been associated with neuronal cell death following hypoxia. The lack of knowledge on the mechanisms underlying this dysfunction prompted us to investigate the morphological changes in the postsynaptic densities (PSDs) induced by hypoxia. The results presented here demonstrate that PSDs of the rat neostriatum are highly modified and ubiquitinated 6 months after induction of hypoxia in a model of perinatal asphyxia. Using both two dimensional (2D) and three dimensional (3D) electron microscopic analyses of synapses stained with ethanolic phosphotungstic acid (E-PTA), we observed an increment of PSD thickness dependent on the duration and severity of the hypoxic insult. The PSDs showed clear signs of damage and intense staining for ubiquitin. These morphological and molecular changes were effectively blocked by hypothermia treatment, one of the most effective strategies for hypoxia-induced brain injury available today. Our data suggest that synaptic dysfunction following hypoxia may be caused by long-term misfolding and aggregation of proteins in the PSD.

Effects of androgen-binding protein (ABP) on spermatid Tnp1 gene expression in vitro.

PubMed

Della-Maria, Julie; Gerard, Anne; Franck, Patricia; Gerard, Hubert

2002-12-30

In vitro studies were designed to determine whether Sertoli cell-delivered ABP could act on spermatogenetic events, whether such an action could occur via a paracrine or a juxtacrine pathway and whether sex steroids could be involved in this action. ABP delivery to germ cells was achieved using an in vitro model based on recombinant rat ABP-producing mouse Sertoli cells cocultivated with rat spermatids. Using semi-quantitative RT-PCR, the expression of the Tnp 1 gene encoding the Transition Protein 1, involved in the histone to protamine replacement during spermatid nuclear transformation, was analyzed. Our results provide clear evidence that Sertoli cell-derived ABP acts on spermatids by modifying the TP1 mRNA level. This outcome, strictly requiring juxtacrine conditions, is obtained in the absence of sex steroid hormones. To our knowledge this is the first evidence of an effect of ABP itself on male germ cells. Copyright 2002 Elsevier Science Ireland Ltd.

Neural pathways from thalamus associated with regulation of aggressive behavior.

PubMed

Bandler, R J; Flynn, J P

1974-01-11

Small electrolytic lesions were made through electrodes in the thalamus of cats at sites where electrical stimulation elicited attack on a rat. Staining by modified Nauta reduced silver methods revealed that significant degeneration passed caudally from the lesions and entered the midbrain dorsal central gray region. Electrical stimulation of this dorsal midbrain region elicited attack on a rat, and destruction of this region suppressed the attack elicited by thalamic stimulation.

Peroxisome proliferator-activated receptor mRNA levels are modified by dietary n-3 fatty acid restriction and energy restriction in the brain and liver of growing rats

USDA-ARS?s Scientific Manuscript database

Without dietary sources of long chain (LC) n-3 fatty acids, alpha-linolenic acid (ALA;18:3n-3) is the precursor for docosahexaenoic acid (DHA; 22:6n-3). It is not known how energy restriction (ER) impacts ALA conversion to DHA. We tested the hypothesis that ER reduces LCn-3 content in growing rats ...

A quantification strategy for missing bone mass in case of osteolytic bone lesions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fränzle, Andrea, E-mail: a.fraenzle@dkfz.de; Giske, Kristina; Bretschi, Maren

Purpose: Most of the patients who died of breast cancer have developed bone metastases. To understand the pathogenesis of bone metastases and to analyze treatment response of different bone remodeling therapies, preclinical animal models are examined. In breast cancer, bone metastases are often bone destructive. To assess treatment response of bone remodeling therapies, the volumes of these lesions have to be determined during the therapy process. The manual delineation of missing structures, especially if large parts are missing, is very time-consuming and not reproducible. Reproducibility is highly important to have comparable results during the therapy process. Therefore, a computerized approachmore » is needed. Also for the preclinical research, a reproducible measurement of the lesions is essential. Here, the authors present an automated segmentation method for the measurement of missing bone mass in a preclinical rat model with bone metastases in the hind leg bones based on 3D CT scans. Methods: The affected bone structure is compared to a healthy model. Since in this preclinical rat trial the metastasis only occurs on the right hind legs, which is assured by using vessel clips, the authors use the left body side as a healthy model. The left femur is segmented with a statistical shape model which is initialised using the automatically segmented medullary cavity. The left tibia and fibula are segmented using volume growing starting at the tibia medullary cavity and stopping at the femur boundary. Masked images of both segmentations are mirrored along the median plane and transferred manually to the position of the affected bone by rigid registration. Affected bone and healthy model are compared based on their gray values. If the gray value of a voxel indicates bone mass in the healthy model and no bone in the affected bone, this voxel is considered to be osteolytic. Results: The lesion segmentations complete the missing bone structures in a reasonable way. The mean ratiov{sub r}/v{sub m} of the reconstructed bone volume v{sub r} and the healthy model bone volume v{sub m} is 1.07, which indicates a good reconstruction of the modified bone. Conclusions: The qualitative and quantitative comparison of manual and semi-automated segmentation results have shown that comparing a modified bone structure with a healthy model can be used to identify and measure missing bone mass in a reproducible way.« less

System Performance Simulations of the RatCAP Awake Rat Brain Scanner

NASA Astrophysics Data System (ADS)

Shokouhi, S.; Vaska, P.; Schlyer, D. J.; Stoll, S. P.; Villanueva, A.; Kriplani, A.; Woody, C. L.

2005-10-01

The capability to create high quality images from data acquired by the Rat Conscious Animal PET tomograph (RatCAP) has been evaluated using modified versions of the PET Monte Carlo code Simulation System for Emission Tomography (SimSET). The proposed tomograph consists of lutetium oxyorthosilicate (LSO) crystals arranged in 12 4 /spl times/ 8 blocks. The effects of the RatCAPs small ring diameter (/spl sim/40 mm) and its block detector geometry on image quality for small animal studies have been investigated. Since the field of view will be almost as large as the ring diameter, radial elongation artifacts due to parallax error are expected to degrade the spatial resolution and thus the image quality at the edge of the field of view. In addition to Monte Carlo simulations, some preliminary results of experimentally acquired images in both two-dimensional (2-D) and 3-D modes are presented.

Adaptations of young adult rat cortical bone to 14 days of spaceflight

NASA Technical Reports Server (NTRS)

Vailas, A. C.; Vanderby, R., Jr.; Martinez, D. A.; Ashman, R. B.; Ulm, M. J.; Grindeland, R. E.; Durnova, G. N.; Kaplanskii, A.

1992-01-01

To determine whether mature humeral cortical bone would be modified significantly by an acute exposure to weightlessness, adult rats (110 days old) were subjected to 14 days of microgravity on the COSMOS 2044 biosatellite. There were no significant changes in peak force, stiffness, energy to failure, and displacement at failure in the flight rats compared with ground-based controls. Concentrations and contents of hydroxyproline, calcium, and mature stable hydroxylysylpyridinoline and lysylpyridinoline collagen cross-links remained unchanged after spaceflight. Bone lengths, cortical and endosteal areas, and regionl thicknesses showed no significant differences between flight animals and ground controls. The findings suggest that responsiveness of cortical bone to microgravity is less pronounced in adult rats than in previous spaceflight experiments in which young growing animals were used. It is hypothesized that 14 days of spaceflight may not be sufficient to impact the biochemical and biomechanical properties of cortical bone in the mature rat skeleton.

Bone growth and calcium balance during simulated weightlessness in the rat

NASA Technical Reports Server (NTRS)

Roer, Robert D.; Dillaman, Richard M.

1990-01-01

Rats, age 28 days, experiencing tail suspension in modified metabolic cages for 1, 2, and 3 wk were compared with littermate controls. Food and water consumption, urinary and fecal Ca excretion, and serum Ca were measured; hearts, fore- and hindlimb bones, skulls, and mandibles were removed for determination of wet, dry, and ash weights and Ca concentration and for histological examination. Weight gain and Ca intake and excretion were the same for both groups; both displayed net Ca gain. Suspended rats had significantly lower wet, dry, and ash weights of femora and tibiae. Dry weights of the humeri and radii/ulnae were moderately higher, and the skull and mandible dry and ash weights were significantly higher in suspended than in control rats. Cortical thickness of the femur, but not humerus, was less in suspended rats. The data are consistent with the hypothesis that bone growth is influenced by the cardiovascular changes associated with tail suspension.

Body distribution of nanoparticle-containing adriamycin injected into the hepatic artery of hepatoma-bearing rats.

PubMed

Chen, Jiang-Hao; Wang, Ling; Ling, Rui; Li, Yu; Wang, Zhe; Yao, Qing; Ma, Zhong

2004-08-01

The aim of the study was to investigate the body distribution of nanoparticle-containing adriamycin (NADR) injected into the hepatic artery of hepatoma-bearing rats. Thirty Walker-256 hepatoma-bearing rats were divided into two groups at random, with 15 rats in each. NADR and free adriamycin (FADR) were injected into the hepatic artery of animals on the seventh day after tumor implantation. At 1, 5, and 15 hr, after administration, five animals in each group were sacrificed and the ADR concentrations in the plasma, liver, heart, spleen, lungs, kidneys, and tumor were determined. The results showed that NADR substantially increased the ADR concentrations in liver, spleen, and tumor of rats compared to FADR, whereas the concentrations in plasma, heart, and lungs were significantly decreased. In conclusion, the body distribution of ADR can be modified by its encapsulation into nanoparticles and administration via the hepatic artery.

Neurotoxic behavioral effects of Lake Ontario salmon diets in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hertzler, D.R.

1990-03-01

Six experiments were conducted to examine possible neurotoxic effects of the exposure to contaminants in Lake Ontario salmon administered through the diets of rats. Rats were fed different concentrations of fish (8%, 15% or 30%) in one of three diet conditions: Lake Ontario salmon, Pacific Ocean salmon, or laboratory rat chow only. Following 20 days on the diets, rats were tested for five minutes per day in a modified open field for one or three days. Lake Ontario salmon diets consistently produced significantly lower activity, rearing, and nosepoke behaviors in comparison with ocean salmon or rat chow diet conditions. Amore » dose-response effect for concentration of lake salmon was obtained, and the attenuation effect occurred in males, females, adult or young animals, and postweaning females, with fish sampled over a five-year period. While only two of several potential contaminants were tested, both fish and brain analyses of mirex and PCBs relate to the behavioral effects.« less

The Effect of Systemic Delivery of Aminoguanidine versus Doxycycline on the Resorptive Phase of Alveolar Bone Following modified Widman Flap in Diabetic Rats: A Histopathological and Scanning Electron Microscope (SEM) study.

PubMed

Tella, E; Aldahlawi, S; Eldeeb, A; El Gazaerly, H

2014-07-01

Aminoguanidine (guanylhydrazinehydrochloride) is a drug that prevents many of the classical systemic complications of diabetes including diabetic osteopenia through its inhibitory activity on the accumulation of advanced glycation end -products (AGEs). The aim of the present study was to evaluate the effectiveness of aminoguanidine versus doxycycline in reducing alveolar bone resorption following mucoperiosteal flap in diabetic rats, using the conventional histopathology and scanning electron microscope (SEM). Twenty-seven male albino rats were used in this study. Periodontal defects were induced experimentally on lower anterior teeth. All rats were subjected to induction of diabetes, by IV injection of the pancreatic B-cells toxin alloxan monohydrate. After eight weeks following the establishment of periodontal defects in all rats, the ligation was removed and 3 rats were scarified as negative control (group 1). The remaining animals were divided into three group based on treatment applied following mucoperiosteal flap surgery. Group 2 received saline treatment only, group 3 received doxycycline periostat (1.5 mg/kg/day) for 3 weeks, and group 4 received aminoguanidine (7.3 mmol/kg) for 3 weeks. The fasting glucose level was measured weekly post operatively. After 21 days all rats were sacrificed. Three anterior parts of the mandible of each group was prepared for histopathological examination and two parts were prepared for SEM. Aminoguanidine treated group (group 4) showed statistically significant increased new bone formation, higher number of osteoblasts and decrease osteoclasts number, resorptive lacunae and existing inflammatory cell infiltration as compared to positive control group (group 2) (P<0.05). Doxycycline was also effective in reducing bone loss as documental by histopathological study. The present study showed that aminoguanidine was significantly effective in reducing alveolar bone loss and can modify the detrimental effects of diabetes in alveolar bone resorption.

The inhibitory avoidance discrimination task to investigate accuracy of memory.

PubMed

Atucha, Erika; Roozendaal, Benno

2015-01-01

The present study was aimed at developing a new inhibitory avoidance task, based on training and/or testing rats in multiple contexts, to investigate accuracy of memory. In the first experiment, male Sprague-Dawley rats were given footshock in an inhibitory avoidance apparatus and, 48 h later, retention latencies of each rat were assessed in the training apparatus (Shock box) as well as in a novel, contextually modified, apparatus. Retention latencies in the Shock box were significantly longer than those in the Novel box, indicating accurate memory of the training context. When the noradrenergic stimulant yohimbine (0.3 mg/kg, sc) was administered after the training, 48-h retention latencies in the Shock box, but not Novel box, were increased, indicating that the noradrenergic activation enhanced memory of the training experience without reducing memory accuracy. In the second experiment, rats were trained on an inhibitory avoidance discrimination task: They were first trained in an inhibitory avoidance apparatus without footshock (Non-Shock box), followed 1 min later by footshock training in a contextually modified apparatus (Shock box). Forty-eight-hour retention latencies in the Shock and Non-Shock boxes did not differ from each other but were both significantly longer than those in a Novel box, indicating that rats remembered the two training contexts but did not have episodic-like memory of the association of footshock with the correct training context. When the interval between the two training episodes was increased to 2 min, rats showed accurate memory of the association of footshock with the training context. Yohimbine administered after the training also enhanced rats' ability to remember in which training context they had received actual footshock. These findings indicate that the inhibitory avoidance discrimination task is a novel variant of the well-established inhibitory avoidance task suitable to investigate accuracy of memory.

Tributyltin chloride increases phenylephrine-induced contraction and vascular stiffness in mesenteric resistance arteries from female rats.

PubMed

Ribeiro Júnior, Rogério Faustino; Marques, Vinicius Bermond; Nunes, Dieli Oliveira; Ronconi, Karoline de Sousa; de Araújo, Julia F P; Rodrigues, Paula Lopes; Padilha, Alessandra Simão; Vassallo, Dalton Valentim; Graceli, Jones B; Stefanon, Ivanita

2016-03-15

Tributyltin chloride (TBT) is an organotin compound that reduces estrogen levels in female rats. We aimed to investigate the effects of TBT exposure on vascular tonus and vascular remodelling in the resistance arteries of female rats. Rats were treated daily with TBT (500 ng/kg) for 15 days. TBT did not change arterial blood pressure but did modify some morpho-physiological parameters of third-order mesenteric resistance arteries in the following ways: (1) decreased lumen and external diameters; (2) increased wall/lm ratio and wall thickness; (3) decreased distensibility and increased stiffness; (4) increased collagen deposition; and (5) increased pulse wave velocity. TBT exposure increased the phenylephrine-induced contractile response in mesenteric resistance arteries. However, vasodilatation responses induced by acetylcholine and sodium nitroprusside were not modified by TBT. It is suggested that TBT exposure reduces vascular nitric oxide (NO) production, because:(1) L-NAME incubation did not cause a leftward shift in the concentration-response curve for phenylephrine; (2) both eNOS protein expression; (3) in situ NO production were reduced. Incubation with L-NAME; and (4) SOD shifted the phenylephrine response curve to the left in TBT rats. Tiron, catalase, ML-171 and VAS2870 decreased vascular reactivity to phenylephrine only in TBT rats. Moreover, increased superoxide anion production was observed in the mesenteric resistance arteries of TBT rats accompanied by an increase in gp91phox, catalase, AT1 receptor and total ERK1/2 protein expression. In conclusion, these findings show that TBT induced alterations are most likely due to a reduction of NO production combined with increased O2(-) production derived from NADPH oxidase and ERK1/2 activation. These findings offer further evidence that TBT is an environmental risk factor for cardiovascular disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Exercise training protects against atherosclerotic risk factors through vascular NADPH oxidase, extracellular signal-regulated kinase 1/2 and stress-activated protein kinase/c-Jun N-terminal kinase downregulation in obese rats.

PubMed

Touati, Sabeur; Montezano, Augusto C I; Meziri, Fayçal; Riva, Catherine; Touyz, Rhian M; Laurant, Pascal

2015-02-01

Exercise training reverses atherosclerotic risk factors associated with metabolic syndrome and obesity. The aim of the present study was to determine the molecular anti-inflammatory, anti-oxidative and anti-atherogenic effects in aorta from rats with high-fat diet-induced obesity. Male Sprague-Dawley rats were placed on a high-fat (HFD) or control (CD) diet for 12 weeks. The HFD rats were then divided into four groups: (i) sedentary HFD-fed rats (HFD-S); (ii) exercise trained (motor treadmill 5 days/week, 60 min/day, 12 weeks) HFD-fed rats (HFD-Ex); (iii) modified diet (HFD to CD) sedentary rats (HF/CD-S); and (iv) an exercise-trained modified diet group (HF/CD-Ex). Tissue levels of NADPH oxidase (activity and expression), NADPH oxidase (Nox) 1, Nox2, Nox4, p47(phox) , superoxide dismutase (SOD)-1, angiotensin AT1 and AT2 receptors, phosphorylated mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)) and vascular cell adhesion molecule-1 (VCAM-1) were determined in the aorta. Plasma cytokines (tumour necrosis factor (TNF)-α and interleukin (IL)-6) levels were also measured. Obesity was accompanied by increases in NADPH oxidase activity, p47(phox) translocation, Nox4 and VCAM-1 protein expression, MAPK (ERK1/2, SAPK/JNK) phosphorylation and plasma TNF-α and IL-6 levels. Exercise training and switching from the HFD to CD reversed almost all these molecular changes. In addition, training increased aortic SOD-1 protein expression and decreased ERK1/2 phosphorylation. These findings suggest that protective effects of exercise training on atherosclerotic risk factors induced by obesity are associated with downregulation of NADPH oxidase, ERK1/2 and SAPK/JNK activity and increased SOD-1 expression. © 2014 Wiley Publishing Asia Pty Ltd.

Behavioral evaluation of visual function of rats using a visual discrimination apparatus.

PubMed

Thomas, Biju B; Samant, Deedar M; Seiler, Magdalene J; Aramant, Robert B; Sheikholeslami, Sharzad; Zhang, Kevin; Chen, Zhenhai; Sadda, SriniVas R

2007-05-15

A visual discrimination apparatus was developed to evaluate the visual sensitivity of normal pigmented rats (n=13) and S334ter-line-3 retinal degenerate (RD) rats (n=15). The apparatus is a modified Y maze consisting of two chambers leading to the rats' home cage. Rats were trained to find a one-way exit door leading into their home cage, based on distinguishing between two different visual alternatives (either a dark background or black and white stripes at varying luminance levels) which were randomly displayed on the back of each chamber. Within 2 weeks of training, all rats were able to distinguish between these two visual patterns. The discrimination threshold of normal pigmented rats was a luminance level of -5.37+/-0.05 log cd/m(2); whereas the threshold level of 100-day-old RD rats was -1.14+/-0.09 log cd/m(2) with considerable variability in performance. When tested at a later age (about 150 days), the threshold level of RD rats was significantly increased (-0.82+/-0.09 log cd/m(2), p<0.03, paired t-test). This apparatus could be useful to train rats at a very early age to distinguish between two different visual stimuli and may be effective for visual functional evaluations following therapeutic interventions.

Vitamin C deficiency exerts paradoxical cardiovascular effects in osteogenic disorder Shionogi (ODS) rats.

PubMed

Vergely, Catherine; Goirand, Françoise; Ecarnot-Laubriet, Aline; Renard, Céline; Moreau, Daniel; Guilland, Jean-Claude; Dumas, Monique; Rochette, Luc

2004-04-01

Vitamin C is considered to be a very efficient water-soluble antioxidant, for which several new cardiovascular properties were recently described. The aim of this study was to determine in vivo the effects of a severe depletion of vitamin C on cardiac and vascular variables and reperfusion arrhythmias. For this purpose, we used a mutant strain of Wistar rats, osteogenic disorder Shionogi (ODS). After 15 d of consuming a vitamin C-deficient diet, ODS rats had a 90% decrease in plasma and tissue levels of ascorbate compared with ODS vitamin C-supplemented rats and normal Wistar rats. However, plasma antioxidant capacity, proteins, alpha-tocopherol, urate, catecholamines, lipids, and nitrate were not influenced by the vitamin C deficiency in ODS rats. Moreover, there was no difference between ODS vitamin C-deficient and -supplemented rats in heart rate and arterial pressure. After 5 min of an in vivo regional myocardial ischemia, various severe arrhythmias were observed, but their intensities were not modified by vitamin C in vitamin C-deficient ODS rats. The vascular reactivity, measured in vitro on thoracic arteries, was not altered by ascorbate deficiency in ODS rats. These unexpected results suggest that unidentified compensatory mechanisms play a role in maintaining normal cardiac function and vascular reactivity in vitamin C-deficient rats.

Minocycline fails to exert antiepileptogenic effects in a rat status epilepticus model.

PubMed

Russmann, Vera; Goc, Joanna; Boes, Katharina; Ongerth, Tanja; Salvamoser, Josephine D; Siegl, Claudia; Potschka, Heidrun

2016-01-15

The tetracycline antibiotic minocycline can exert strong anti-inflammatory, antioxidant, and antiapoptotic effects. There is cumulating evidence that epileptogenic brain insults trigger neuroinflammation and anti-inflammatory concepts can modulate the process of epileptogenesis. Based on the mechanisms of action discussed for minocycline, the compound is of interest for intervention studies as it can prevent the polarization of microglia into a pro-inflammatory state. Here, we assessed the efficacy of sub-chronic minocycline administration initiated immediately following an electrically-induced status epilepticus in rats. The treatment did not affect the development of spontaneous seizures. However, minocycline attenuated behavioral long-term consequences of status epilepticus with a reduction in hyperactivity and hyperlocomotion. Furthermore, the compound limited the spatial learning deficits observed in the post-status epilepticus model. The typical status epilepticus-induced neuronal cell loss was evident in the hippocampus and the piriform cortex. Minocycline exposure selectively protected neurons in the piriform cortex and the hilus, but not in the hippocampal pyramidal layer. In conclusion, the data argue against an antiepileptogenic effect of minocycline in adult rats. However, the findings suggest a disease-modifying impact of the tetracycline affecting the development of behavioral co-morbidities, as well as long-term consequences on spatial learning. In addition, minocycline administration resulted in a selective neuroprotective effect. Although strong anti-inflammatory effects have been proposed for minocycline, we could not verify these effects in our experimental model. Considering the multitude of mechanisms claimed to contribute to minocycline's effects, it is of interest to further explore the exact mechanisms underlying the beneficial effects in future studies. Copyright © 2015 Elsevier B.V. All rights reserved.

Antiarthritic activity of Majoon Suranjan (a polyherbal Unani formulation) in rat

PubMed Central

Singh, Surender; Nair, Vinod; Gupta, Y.K.

2011-01-01

Background & objectives: Majoon Suranjan (MS) is a polyherbal formulation used in Unani system of medicine for the treatment of rheumatoid arthritis (RA). The present study evaluates the antiarthritic efficacy of this formulation in three different experimental models. Methods: The anti-inflammatory activity of MS (in doses of 450, 900 and 1800 mg/kg body wt) was evaluated using the turpentine oil induced paw oedema model and the antiarthritic efficacy was evaluated using the formaldehyde and complete Freund's adjuvant (CFA) induced arthritis models. Aspirin (100 mg/kg body wt) was used as the standard drug in all the models. In order to assess the safety of the test drug, oral acute and 28 day toxicity studies were also carried out. Results: MS produced a dose dependent protective effect in all the experimental models. Its antiarthritic efficacy was comparable to aspirin in formaldehyde induced arthritis and was superior to aspirin in turpentine oil induced paw oedema and CFA induced arthritis. MS also inhibited the delayed increase in joint diameter as seen in control and aspirin treated animals in CFA induced arthritis. Oral LD50 of MS was found to be >5000 mg/kg in rats. Chronic administration did not produce any significant physiological changes in the tested animals. Interpretation & conclusions: Results of the present study suggest that the antiarthritic activity of MS was due to the interplay between its anti-inflammatory and disease modifying activities, thus supporting its use in traditional medicine for the treatment of RA. PMID:21985823

Effect of histochrome on the severity of delayed effects of prenatal exposure to lead nitrate in the rat brain.

PubMed

Ryzhavsky, B Ya; Lebedko, O A; Belolubskaya, D S

2008-08-01

The effects of histochrome on the severity of delayed effects of prenatal exposure to lead nitrate were studied in the rat brain. Exposure of pregnant rats to lead nitrate during activation of free radical oxidation reduced activity of NADH- and NADPH-dehydrogenases in cortical neurons of their 40-day-old progeny, reduced the number of neurons in a visual field, increased the number of pathologically modified neurons, and stimulated rat motor activity in an elevated plus-maze. Two intraperitoneal injections of histochrome in a dose of 0.1 mg/kg before and after lead citrate challenge attenuated the manifestations of oxidative stress and prevented the changes in some morphological and histochemical parameters of the brain, developing under the effect of lead exposure.

Chronic overexpression of angiotensin-(1-7) in rats reduces cardiac reactivity to acute stress and dampens anxious behavior.

PubMed

Moura Santos, Danielle; Ribeiro Marins, Fernanda; Limborço-Filho, Marcelo; de Oliveira, Marilene Luzia; Hamamoto, Daniele; Xavier, Carlos Henrique; Moreira, Fabrício Araújo; Santos, Robson Augusto Souza; Campagnole-Santos, Maria José; Peliky Fontes, Marco Antonio

2017-03-01

Angiotensin II (Ang II) acts as a pro-stress hormone, while other evidence indicates that angiotensin-(1-7) [Ang-(1-7)] attenuates physiological responses to emotional stress. To further test this hypothesis, in groups of 5-6 rats we evaluated autonomic, cardiovascular and behavioral parameters in male Sprague-Dawley (SD) and transgenic TGR(A1-7)3292 (TG) rats chronically overexpressing Ang-(1-7). Compared to SD rats, TG rats showed reduced baseline heart rate (HR; SD 380 ± 16 versus TG 329 ± 9 beats per minute (bpm), mean ± standard error of mean, p < .05) and renal sympathetic discharge (SD 138 ± 4 versus TG 117 ± 5 spikes/second, p < .05). TG rats had an attenuated tachycardic response to acute air-puff stress (ΔHR: SD 51 ± 20 versus TG 1 ± 3 bpm; p < .05), which was reversed by intracerebroventricular injection of the Mas receptor antagonist, A-779 (ΔHR: SD 51 ± 20 versus TG 63 ± 15 bpm). TG rats showed less anxious behavior on the elevated plus maze, as revealed by more entries into open arms (SD 2 ± 2 versus TG 47 ± 5% relative to total entries; p < .05), and more time spent in the open arms (SD 5 ± 4 versus TG 53 ± 9% relative to total time, p < .05). By contrast with SD rats, diazepam (1.5 mg/kg, intraperitoneally) did not further reduce anxious behavior in TG rats, indicating a ceiling anxiolytic effect of Ang-(1-7) overexpression. Ang-(1-7) concentrations in hypothalamus and plasma, measured by mass spectrometry were two- and three-fold greater, respectively, in TG rats than in SD rats. Hence, increased endogenous Ang-(1-7) levels in TG rats diminishes renal sympathetic outflow and attenuates cardiac reactivity to emotional stress, which may be via central Mas receptors, and reduces anxious behavior. Lay summaryWe used a genetically modified rat model that produces above normal amounts of a peptide hormone called angiotensin-(1-7) to test whether this peptide can reduce some of the effects of stress. We found that angiotensin-(1-7), acting in the brain, can reduce anxiety and reduce the increase in heart rate associated with emotional stress. These findings may provide a lead for design of new drugs to reduce stress.

Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis.

PubMed

Jiang, Li; Chew, Shan-Hwu; Nakamura, Kosuke; Ohara, Yuuki; Akatsuka, Shinya; Toyokuni, Shinya

2016-07-01

Asbestos-induced mesothelial carcinogenesis is currently a profound social issue due to its extremely long incubation period and high mortality rate. Therefore, procedures to prevent malignant mesothelioma in people already exposed to asbestos are important. In previous experiments, we established an asbestos-induced rat peritoneal mesothelioma model, which revealed that local iron overload is a major cause of pathogenesis and that the induced genetic alterations are similar to human counterparts. Furthermore, we showed that oral administration of deferasirox modified the histology from sarcomatoid to the more favorable epithelioid subtype. Here, we used i.p. administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate was used to promote an iron-catalyzed Fenton reaction as a positive control. Desferal significantly decreased peritoneal fibrosis, iron deposition, and nuclear 8-hydroxy-2'-deoxyguanosine levels in mesothelial cells, whereas nitrilotriacetate significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells to counteract asbestos-induced cytotoxicity than in murine macrophages (RAW264.7). Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than rat peritoneal mesothelial cells. Because inflammogenicity of a fiber is proportionally associated with subsequent mesothelial carcinogenesis, iron elimination from the mesothelial environment can confer dual merits for preventing asbestos-induced mesothelial carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Oxidative Stress-Responsive Apoptosis Inducing Protein (ORAIP) Plays a Critical Role in High Glucose-Induced Apoptosis in Rat Cardiac Myocytes and Murine Pancreatic β-Cells.

PubMed

Yao, Takako; Fujimura, Tsutomu; Murayama, Kimie; Okumura, Ko; Seko, Yoshinori

2017-10-18

We previously identified a novel apoptosis-inducing humoral factor in the conditioned medium of hypoxic/reoxygenated-cardiac myocytes. We named this novel post-translationally-modified secreted-form of eukaryotic translation initiation factor 5A Oxidative stress-Responsive Apoptosis-Inducing Protein (ORAIP). We confirmed that myocardial ischemia/reperfusion markedly increased plasma ORAIP levels and rat myocardial ischemia/reperfusion injury was clearly suppressed by neutralizing anti-ORAIP monoclonal antibodies (mAbs) in vivo. In this study, to investigate the mechanism of cell injury of cardiac myocytes and pancreatic β-cells involved in diabetes mellitus (DM), we analyzed plasma ORAIP levels in DM model rats and the role of ORAIP in high glucose-induced apoptosis of cardiac myocytes in vitro. We also examined whether recombinant-ORAIP induces apoptosis in pancreatic β-cells. Plasma ORAIP levels in DM rats during diabetic phase were about 18 times elevated as compared with non-diabetic phase. High glucose induced massive apoptosis in cardiac myocytes (66.2 ± 2.2%), which was 78% suppressed by neutralizing anti-ORAIP mAb in vitro. Furthermore, recombinant-ORAIP clearly induced apoptosis in pancreatic β-cells in vitro. These findings strongly suggested that ORAIP plays a pivotal role in hyperglycemia-induced myocardial injury and pancreatic β-cell injury in DM. ORAIP will be a biomarker and a critical therapeutic target for cardiac injury and progression of DM itself.

Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation

PubMed Central

Yang, Liu; Shen, Zhong-Yang; Wang, Rao-Rao; Yin, Ming-Li; Zheng, Wei-Ping; Wu, Bin; Liu, Tao; Song, Hong-Li

2017-01-01

AIM To investigate the effects of heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation (RLT) in a rat model. METHODS BMMSCs were isolated and cultured in vitro using an adherent method, and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs. A rat acute rejection model following 50% RLT was established using a two-cuff technique. Recipients were divided into three groups based on the treatment received: normal saline (NS), BMMSCs and HO-1/BMMSCs. Liver function was examined at six time points. The levels of endothelin-1 (ET-1), endothelial nitric-oxide synthase (eNOS), inducible nitric-oxide synthase (iNOS), nitric oxide (NO), and hyaluronic acid (HA) were detected using an enzyme-linked immunosorbent assay. The portal vein pressure (PVP) was detected by Power Lab ML880. The expressions of ET-1, iNOS, eNOS, and von Willebrand factor (vWF) protein in the transplanted liver were detected using immunohistochemistry and Western blotting. ATPase in the transplanted liver was detected by chemical colorimetry, and the ultrastructural changes were observed under a transmission electron microscope. RESULTS HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver, and improve the liver function of rats following 50% RLT, with statistically significant differences compared with those of the NS group and BMMSCs group (P < 0.05). In term of the microcirculation of hepatic sinusoids: The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group (P < 0.01); HO-1/BMMSCs could inhibit the expressions of ET-1 and iNOS, increase the expressions of eNOS and inhibit amounts of NO production, and maintain the equilibrium of ET-1/NO (P < 0.05); and HO-1/BMMSCs increased the expression of vWF in hepatic sinusoidal endothelial cells (SECs), and promoted the degradation of HA, compared with those of the NS group and BMMSCs group (P < 0.05). In term of the energy metabolism of the transplanted liver, HO-1/BMMSCs repaired the damaged mitochondria, and improved the activity of mitochondrial aspartate aminotransferase (ASTm) and ATPase, compared with the other two groups (P <0.05). CONCLUSION HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly, and recover the energy metabolism of damaged hepatocytes in rats following RLT, thus protecting the transplanted liver. PMID:28596681

Tumor suppression effects of bilberry extracts and enzymatically modified isoquercitrin in early preneoplastic liver cell lesions induced by piperonyl butoxide promotion in a two-stage rat hepatocarcinogenesis model.

PubMed

Hara, Shintaro; Morita, Reiko; Ogawa, Takashi; Segawa, Risa; Takimoto, Norifumi; Suzuki, Kazuhiko; Hamadate, Naobumi; Hayashi, Shim-Mo; Odachi, Ayano; Ogiwara, Isao; Shibusawa, Sakae; Yoshida, Toshinori; Shibutani, Makoto

2014-08-01

To investigate the protective effect of bilberry extracts (BBE) and enzymatically modified isoquercitrin (EMIQ) on the hepatocarcinogenic process involving oxidative stress responses, we used a two-stage hepatocarcinogenesis model in N-diethylnitrosamine-initiated and piperonyl butoxide (PBO)-promoted rats. We examined the modifying effect of co-administration with BBE or EMIQ on the liver tissue environment including oxidative stress responses, cell proliferation and apoptosis, and phosphatase and tensin homolog (PTEN)/Akt and transforming growth factor (TGF)-β/Smad signalings on the induction mechanism of preneoplastic lesions during early stages of hepatocellular tumor promotion. PBO increased the numbers and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of Ki-67(+) proliferating cells within GST-P(+) foci. Co-administration of BBE or EMIQ suppressed these effects with the reductions of GST-P(+) foci (area) to 48.9-49.4% and Ki-67(+) cells to 55.5-61.4% of the PBO-promoted cases. Neither BBE nor EMIQ decreased microsomal reactive oxygen species induced by PBO. However, only EMIQ suppressed the level of thiobarbituric acid-reactive substances to 78.4% of the PBO-promoted cases. PBO increased the incidences of phospho-PTEN(-) foci, phospho-Akt substrate(+) foci, phospho-Smad3(-) foci and Smad4(-) foci in GST-P(+) foci. Both BBE and EMIQ decreased the incidences of phospho-PTEN(-) foci in GST-P(+) foci to 59.8-72.2% and Smad4(-) foci to 62.4-71.5% of the PBO-promoted cases, and BBE also suppressed the incidence of phospho-Akt substrate(+) foci in GST-P(+) foci to 75.2-75.7% of the PBO-promoted cases. These results suggest that PBO-induced tumor promotion involves facilitation of PTEN/Akt and disruptive TGF-β/Smad signalings without relation to oxidative stress responses, but this promotion was suppressed by co-treatment with BBE or EMIQ through suppression of cell proliferation activity of preneoplastic liver cells. Copyright © 2014 Elsevier GmbH. All rights reserved.

Identification of Acetaminophen Adducts of Rat Liver Microsomal Proteins using 2D-LC-MS/MS.

PubMed

Golizeh, Makan; LeBlanc, André; Sleno, Lekha

2015-11-16

Xenobiotic metabolism in the liver can give rise to reactive metabolites that covalently bind to proteins, and determining which proteins are targeted is important in drug discovery and molecular toxicology. However, there are difficulties in the analysis of these modified proteins in complex biological matrices due to their low abundance. In this study, an analytical approach was developed to systematically identify target proteins of acetaminophen (APAP) in rat liver microsomes (RLM) using two-dimensional chromatography and high-resolution tandem mass spectrometry. In vitro microsomal incubations, with and without APAP, were digested and subjected to strong cation exchange (SCX) fractionation prior to reverse-phase UHPLC-MS/MS. Four data processing strategies were combined into an efficient label-free workflow meant to eliminate potential false positives, using peptide spectral matching, statistical differential analysis, product ion screening, and a custom-built delta-mass filtering tool to pinpoint potential modified peptides. This study revealed four proteins, involved in important cellular processes, to be covalently modified by APAP. Data are available via ProteomeXchange with identifier PXD002590.

Genetic Diversity Influences the Response of the Brain to Developmental Lead Exposure

PubMed Central

Schneider, Jay S.; Talsania, Keyur; Mettil, William; Anderson, David W.

2014-01-01

Although extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the role that genetic variation may play in influencing outcomes from developmental Pb exposure. Male and female animals received either perinatal (gestation through lactation) or postnatal (birth through weaning) exposure to Pb in food (0, 250, or 750 ppm). RNA was extracted from the hippocampus at day 55 and hybridized to Affymetrix Rat Gene 1.0 ST Arrays. There were significant strain-specific effects of Pb on the hippocampal transcriptome with 978 transcripts differentially expressed in LE rats across all experimental groups, 269 transcripts differentially expressed in F344 rats, and only 179 transcripts differentially expressed in SD rats. These results were not due to strain-related differences in brain accumulation of Pb. Further, no genes were consistently differentially regulated in all experimental conditions. There was no set of “Pb toxicity” genes that are a molecular signature for Pb neurotoxicity that transcended sex, exposure condition, and strain. These results demonstrate the influence that strain and genetic background play in modifying the brain's response to developmental Pb exposure and may have relevance for better understanding the molecular underpinnings of the lack of a neurobehavioral signature in childhood Pb poisoning. PMID:24913800

Dietary zinc modifies diabetic-induced renal pathology in rats

PubMed Central

Elsaed, Wael M.; Mohamed, Hazem Abdelhamid

2017-01-01

Abstract This study was conducted to investigate how far dietary zinc (Zn) modifies the histomorphological alterations induced by diabetes in rat kidneys. The animals were divided into negative control group (10 rats). Diabetes was induced in thirty animals by streptozotocin. After confirming diabetes, the animals were divided into three groups (n = 10). Group II served as the positive control group (fed on standard diet), group III was fed on Zn deficient diet, and group IV was fed on Zn supplemented diet. Caspase-3 immune staining was used to estimate the caspase activity. Stereological procedures were used to measure the quantity of the immune stain and the surface area of the Bowman’s space. The renal cortices of group II rats revealed apparent widening of Bowman’s spaces with few apoptotic figures. The filtration barrier showed thickening of the basement membrane. The proximal convoluted tubules showed patchy loss of the apical microvilli with swollen mitochondria. The distal convoluted tubules revealed area of irregular basal enfolding. The picture was aggravated by Zn deficiency in group III besides areas of cortical interstitial fibrosis. The histopathological alterations were minimal in the cortices of group IV. A significant increase of the Bowman’s space surface area in group II and IV while decrease in group III compared with group I. The expression of Caspase-3 density was significantly increased in group II and III compared with group I while in group IV was non significant. In conclusion, dietary Zn modulated renal cortical changes caused by diabetes in rats. PMID:27882813

Disease-modifying effect of anthraquinone prodrug with boswellic acid on collagenase-induced osteoarthritis in Wistar rats.

PubMed

Dhaneshwar, Suneela; Dipmala, Patil; Abhay, Harsulkar; Prashant, Bhondave

2013-08-01

Diacerein and its active metabolite rhein are promising disease modifying agents for osteoarthritis (OA). Boswellic acid is an active ingredient of Gugglu; a herbal medicine commonly administered in osteoarthritis. Both of them possess excellent anti-inflammatory and anti-arthritic activities. It was thought interesting to conjugate rhein and boswellic acid into a mutual prodrug (DSRB) and evaluate its efficacy on collagenase-induced osteoarthritis in rats wherein the conjugate, rhein, boswellic acid and their physical mixture, were tested based on various parameters. Oral administration of 3.85 mg of rhein, 12.36 mg of boswellic acid and 15.73 mg of DSRB which would release equimolar amounts of rhein and boswellic acid, exhibited significant restoration in rat body weight as compared to the untreated arthritic control group. Increase in knee diameter (mm), due to edema was observed in group injected with collagenase, which reduced significantly with the treatment of conjugate. The hematological parameters (Hb, RBC, WBC and ESR) and biochemical parameters (CRP, SALP, SGOT and SGPT) in the osteoarthritic rats were significantly brought back to normal values on treatment with conjugate. It also showed better anti-ulcer activity than rhein. Further the histopathological studies revealed significant anti-arthritic activity of conjugate when compared with the arthritic control group. In conclusion, the conjugate at the specified dose level of 15.73 mg/kg, p. o. (BID) showed reduction in knee diameter and it could significantly normalize the hematological and biochemical abnormalities in collagenase-induced osteoarthritis in rats. Further the histopathological studies confirmed the additive anti-arthritic effect of DSRB as compared to plain rhein.

An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory.

PubMed

Liu, Jianfeng; Zhao, Liyan; Xue, Yanxue; Shi, Jie; Suo, Lin; Luo, Yixiao; Chai, Baisheng; Yang, Chang; Fang, Qin; Zhang, Yan; Bao, Yanping; Pickens, Charles L; Lu, Lin

2014-12-01

Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Nutritional recovery with rice bran did not modify energy balance and leptin and insulin levels.

PubMed

Martins, Maria Salete F; Oyama, Lila M; Latorraca, Marcia Q; Gomes-da-Silva, Maria Helena G; Nascimento, Claudia M O

2010-03-01

To investigate the effect of nutritional recovery with rice bran on energy balance, leptin and insulin levels. Weaned Wistar rats were fed on a 17% (Control - C) or 0.5% (Aproteic - A) protein diet for 12d. After this, rats were kept on a C diet (C) or recovered with control (Recovered Control - RC) or control plus recovered rice bran diet (Recovered Rice Bran - RRB). Despite the increased food intake, group A exhibited lower carcass fat associated to low serum leptin. RRB and RC groups showed lower carcass weight and energy intake and expenditure. Energy expenditure was positively associated with food intake and carcass weight. Negative correlations between HOMA-IR and energy expenditure and energy intake were observed. Nutritional recovery with rice bran did not modify energy balance, leptin and insulin levels.

In vivo monitoring of distributional transport kinetics and extravasation of quantum dots in living rat liver

NASA Astrophysics Data System (ADS)

Su, Cheng-Kuan; Sun, Yuh-Chang

2013-04-01

Although the unique optical properties of surface-modified quantum dots (QDs) have attracted wide interest in molecular biology and bioengineering, there are very few reports of their in vivo biodistribution, due to a lack of analytical techniques for characterizing the dynamic variation of QDs in living animals. In this study, we used an in vivo online monitoring system and a batch-wise elemental analytical method to investigate the biodistribution/extravasation of various surface-modified CdTeSe/ZnS (QDs) in rat liver. It is found that the surface modification dictated not only the blood retention profile but also the degree of extravasation and the clearance of extracellular QDs, making it an important variable for regulating the transfer and exchange process of QDs among three physiological compartments—bloodstream, extracellular space and Kupffer cells/hepatocytes.

In vitro and in vivo physiology of low nanomolar concentrations of Zn2+ in artificial cerebrospinal fluid.

PubMed

Tamano, Haruna; Nishio, Ryusuke; Shakushi, Yukina; Sasaki, Miku; Koike, Yuta; Osawa, Misa; Takeda, Atsushi

2017-02-17

Artificial cerebrospinal fluid (ACSF), i.e., brain extracellular medium, which includes Ca 2+ and Mg 2+ , but not other divalent cations such as Zn 2+ , has been used for in vitro and in vivo experiments. The present study deals with the physiological significance of extracellular Zn 2+ in ACSF. Spontaneous presynaptic activity is suppressed in the stratum lucidum of brain slices from young rats bathed in ACSF containing 10 nM ZnCl 2 , indicating that extracellular Zn 2+ modifies hippocampal presynaptic activity. To examine the in vivo action of 10 nM ZnCl 2 on long-term potentiation (LTP), the recording region was perfused using a recording electrode attached to a microdialysis probe. The magnitude of LTP was not modified in young rats by perfusion with ACSF containing 10 nM ZnCl 2 , compared to perfusion with ACSF without Zn 2+ , but attenuated by perfusion with ACSF containing 100 nM ZnCl 2 . Interestingly, the magnitude of LTP was not modified in aged rats even by perfusion with ACSF containing 100 nM ZnCl 2 , but enhanced by perfusion with ACSF containing 10 mM CaEDTA, an extracellular Zn 2+ chelator. The present study indicates that the basal levels of extracellular Zn 2+ , which are in the range of low nanomolar concentrations, are critical for synaptic activity and perhaps increased age-dependently.

In vitro and in vivo physiology of low nanomolar concentrations of Zn2+ in artificial cerebrospinal fluid

PubMed Central

Tamano, Haruna; Nishio, Ryusuke; Shakushi, Yukina; Sasaki, Miku; koike, Yuta; Osawa, Misa; Takeda, Atsushi

2017-01-01

Artificial cerebrospinal fluid (ACSF), i.e., brain extracellular medium, which includes Ca2+ and Mg2+, but not other divalent cations such as Zn2+, has been used for in vitro and in vivo experiments. The present study deals with the physiological significance of extracellular Zn2+ in ACSF. Spontaneous presynaptic activity is suppressed in the stratum lucidum of brain slices from young rats bathed in ACSF containing 10 nM ZnCl2, indicating that extracellular Zn2+ modifies hippocampal presynaptic activity. To examine the in vivo action of 10 nM ZnCl2 on long-term potentiation (LTP), the recording region was perfused using a recording electrode attached to a microdialysis probe. The magnitude of LTP was not modified in young rats by perfusion with ACSF containing 10 nM ZnCl2, compared to perfusion with ACSF without Zn2+, but attenuated by perfusion with ACSF containing 100 nM ZnCl2. Interestingly, the magnitude of LTP was not modified in aged rats even by perfusion with ACSF containing 100 nM ZnCl2, but enhanced by perfusion with ACSF containing 10 mM CaEDTA, an extracellular Zn2+ chelator. The present study indicates that the basal levels of extracellular Zn2+, which are in the range of low nanomolar concentrations, are critical for synaptic activity and perhaps increased age-dependently. PMID:28211543

Avocado oil supplementation modifies cardiovascular risk profile markers in a rat model of sucrose-induced metabolic changes.

PubMed

Carvajal-Zarrabal, Octavio; Nolasco-Hipolito, Cirilo; Aguilar-Uscanga, M Guadalupe; Melo-Santiesteban, Guadalupe; Hayward-Jones, Patricia M; Barradas-Dermitz, Dulce M

2014-01-01

The purpose of this study was to evaluate the effects of avocado oil administration on biochemical markers of cardiovascular risk profile in rats with metabolic changes induced by sucrose ingestion. Twenty-five rats were divided into five groups: a control group (CG; basic diet), a sick group (MC; basic diet plus 30% sucrose solution), and three other groups (MCao, MCac, and MCas; basic diet plus 30% sucrose solution plus olive oil and avocado oil extracted by centrifugation or using solvent, resp.). Glucose, total cholesterol, triglycerides, phospholipids, low- and high-density lipoproteins (LDL, HDL), very low-density lipoprotein (VLDL), lactic dehydrogenase, creatine kinase, and high sensitivity C-reactive protein concentration were analyzed. Avocado oil reduces TG, VLDL, and LDL levels, in the LDL case significantly so, without affecting HDL levels. An effect was exhibited by avocado oil similar to olive oil, with no significant difference between avocado oil extracted either by centrifugation or solvent in myocardial injury biochemical indicators. Avocado oil decreased hs-CRP levels, indicating that inflammatory processes were partially reversed. These findings suggested that avocado oil supplementation has a positive health outcome because it reduces inflammatory events and produces positive changes in the biochemical indicators studied, related to the development of metabolic syndrome.

Touchscreen Sustained Attention Task (SAT) for Rats.

PubMed

Bangasser, Debra A; Wicks, Brittany; Waxler, David E; Eck, Samantha R

2017-09-15

Sustained attention is the ability to monitor intermittent and unpredictable events over a prolonged period of time. This attentional process subserves other aspects of cognition and is disrupted in certain neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Thus, it is clinically important to identify mechanisms that impair and improve sustained attention. Such mechanisms are often first discovered using rodent models. Therefore, several behavior procedures for testing aspects of sustained attention have been developed for rodents. One, first described by McGaughy and Sarter (1995), called the sustained attention task (SAT), trains rats to distinguish between signal (i.e., brief light presentation) and non-signal trials. The signals are short and thus require careful attention to be perceived. Attentional demands can be increased further by introducing a distractor (e.g., flashing houselight). We have modified this task for touchscreen operant chambers, which are configured with a touchscreen on one wall that can present stimuli and record responses. Here we detail our protocol for SAT in touchscreen chambers. Additionally, we present standard measures of performance in male and female Sprague-Dawley rats. Comparable performance on this task in both sexes highlights its use for attention studies, especially as more researchers are including female rodents in their experimental design. Moreover, the easy implementation of SAT for the increasingly popular touchscreen chambers increases its utility.

The ampakine, Org 26576, bolsters early spatial reference learning and retrieval in the Morris water maze: a subchronic, dose-ranging study in rats.

PubMed

Hamlyn, Eugene; Brand, Linda; Shahid, Mohammed; Harvey, Brian H

2009-10-01

Ampakines have shown beneficial effects on cognition in selected animal models of learning. However, their ability to modify long-term spatial memory tasks has not been studied yet. This would lend credence to their possible value in treating disorders of cognition. We evaluated the actions of subchronic Org 26576 administration on spatial reference memory performance in the 5-day Morris water maze task in male Sprague-Dawley rats, at doses of 1, 3 and 10 mg/kg twice daily through intraperitoneal injection over 12 days. Org 26576 exerted a dose and time-dependent effect on spatial learning, with dosages of 3 and 10 mg/kg significantly enhancing acquisition on day 1. Globally, escape latency decreased significantly as the training days progressed in the saline and Org 26576-treated groups, indicating that significant and equal learning had taken place over the learning period. However, at the end of the learning period, all doses of Org 26576 significantly improved spatial memory storage/retrieval without confounding effects in the cued version of the task. Org 26576 offers early phase spatial memory benefits in rats, but particularly enhances search accuracy during reference memory retrieval. These results support its possible utility in treating disorders characterized by deficits in cognitive performance.

Influence of dichloromethylene bisphosphonate on the in vitro phagocytosis of hydroxyapatite particles by rat peritoneal exudate cells: an electron microscopic and chemiluminescence study.

PubMed Central

Hyvönen, P M; Kowolik, M J

1992-01-01

Transmission electron microscopy and standard chemiluminescence assays were used to investigate the in vivo effect of dichloromethylene bisphosphonate (clodronate) on the phagocytosis of pure hydroxyapatite particles by rat peritoneal macrophages and the production of chemiluminescence by the peritoneal exudate cells. Hydroxyapatite (control) and a hydroxyapatite/clodronate suspension (28 mumol clodronate per gram of hydroxyapatite, experimental) were injected into the peritoneum of rats, the clodronate dose being 10 micrograms/kg. Macrophages were harvested at 12, 24, 48, and 96 hours after injection and the particle phagocytosis was assessed by transmission electron microscopy. Hydroxyapatite alone was completely phagocytosed by 24 hours and hydroxyapatite reacted with clodronate was completely phagocytosed by 48 hours. From 48 hours onwards hydroxyapatite particle dissolution was observed in the phagosomes of cells in the two groups. At 48 hours the chemiluminescence produced by the peritoneal exudate cells was also measured. Clodronate and clodronate/hydroxyapatite enhanced cell activity on subsequent challenge with phorbol myristate acetate or zymosan. Clodronate seemed to exhibit an inhibitory effect on the phagocytic activity and an enhancement of the chemiluminescence production by the cells in this model, indicating that it was modifying the inflammatory cell response. Images PMID:1532298

Ingested d-Aspartate Facilitates the Functional Connectivity and Modifies Dendritic Spine Morphology in Rat Hippocampus.

PubMed

Kitamura, Akihiko; Hojo, Yasushi; Ikeda, Muneki; Karakawa, Sachise; Kuwahara, Tomomi; Kim, Jonghyuk; Soma, Mika; Kawato, Suguru; Tsurugizawa, Tomokazu

2018-05-30

d-Aspartate (d-Asp), the stereoisomer of l-aspartate, has a role in memory function in rodents. However, the mechanism of the effect of d-Asp has not been fully understood. In this study, we hypothesized that ingested d-Asp directly reaches the hippocampal tissues via the blood circulation and modifies the functional connectivity between hippocampus and other regions through spinogenesis in hippocampal CA1 neurons. The spinogenesis induced by the application of d-Asp was investigated using rat acute hippocampal slices. The density of CA1 spines was increased following 21 and 100 μM d-Asp application. The nongenomic spine increase pathway involved LIM kinase. In parallel to the acute slice study, brain activation was investigated in awake rats using functional MRI following the intragastric administration of 5 mM d-Asp. Furthermore, the concentration of d-Asp in the blood serum and hippocampus was significantly increased 15 min after intragastric administration of d-Asp. A functional connectivity by awake rat fMRI demonstrated increased slow-frequency synchronization in the hippocampus and other regions, including the somatosensory cortex, striatum, and the nucleus accumbens, 10-20 min after the start of d-Asp administration. These results suggest that ingested d-Asp reaches the brain through the blood circulation and modulates hippocampal neural networks through the modulation of spines.

Safety assessment of genetically modified milk containing human beta-defensin-3 on rats by a 90-day feeding study.

PubMed

Chen, Xin; Gao, Ming-Qing; Liang, Dong; Yin, Songna; Yao, Kezhen; Zhang, Yong

2017-02-01

In recent years, transgenic technology has been widely applied in many fields. There is concern about the safety of genetically modified (GM) products with the increased prevalence of GM products. In order to prevent mastitis in dairy cows, our group produced transgenic cattle expressing human beta-defensin-3 (HBD3) in their mammary glands, which confers resistance to the bacteria that cause mastitis. The milk derived from these transgenic cattle thus contained HBD3. The objective of the present study was to analyze the nutritional composition of HBD3 milk and conduct a 90-day feeding study on rats. Rats were divided into 5 groups which consumed either an AIN93G diet (growth purified diet for rodents recommended by the American Institute of Nutrition) with the addition of 10% or 30% HBD3 milk, an AIN93G diet with the addition of 10% or 30% conventional milk, or an AIN93G diet alone. The results showed that there was no difference in the nutritional composition of HBD3 and conventional milk. Furthermore, body weight, food consumption, blood biochemistry, relative organ weight, and histopathology were normal in those rats that consumed diets containing HBD3. No adverse effects were observed between groups that could be attributed to varying diets or gender. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

The specific localization of advanced glycation end-products (AGEs) in rat pancreatic islets.

PubMed

Morioka, Yuta; Teshigawara, Kiyoshi; Tomono, Yasuko; Wang, Dengli; Izushi, Yasuhisa; Wake, Hidenori; Liu, Keyue; Takahashi, Hideo Kohka; Mori, Shuji; Nishibori, Masahiro

2017-08-01

Advanced glycation end-products (AGEs) are produced by non-enzymatic glycation between protein and reducing sugar such as glucose. Although glyceraldehyde-derived AGEs (Glycer-AGEs), one of the AGEs subspecies, have been reported to be involved in the pathogenesis of various age-relating diseases such as diabetes mellitus or arteriosclerosis, little is known about the pathological and physiological mechanism of AGEs in vivo. In present study, we produced 4 kinds of polyclonal antibodies against AGEs subspecies and investigated the localization of AGEs-modified proteins in rat peripheral tissues, making use of these antibodies. We found that Glycer-AGEs and methylglyoxal-derived AGEs (MGO-AGEs) were present in pancreatic islets of healthy rats, distinguished clearly into the pancreatic α and β cells, respectively. Although streptozotocin-induced diabetic rats suffered from remarkable impairment of pancreatic islets, the localization and deposit levels of the Glycer- and MGO-AGEs were not altered in the remaining α and β cells. Remarkably, the MGO-AGEs in pancreatic β cells were localized into the insulin-secretory granules. These results suggest that the cell-specific localization of AGEs-modified proteins are presence generally in healthy peripheral tissues, involved in physiological intracellular roles, such as a post-translational modulator contributing to the secretory and/or maturational functions of insulin. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Influence of Hesperidin on the Systemic and Intestinal Rat Immune Response

PubMed Central

Camps-Bossacoma, Mariona; Franch, Àngels; Pérez-Cano, Francisco J.; Castell, Margarida

2017-01-01

Polyphenols, widely found in edible plants, influence the immune system. Nevertheless, the immunomodulatory properties of hesperidin, the predominant flavanone in oranges, have not been deeply studied. To establish the effect of hesperidin on in vivo immune response, two different conditions of immune system stimulations in Lewis rats were applied. In the first experimental design, rats were intraperitoneally immunized with ovalbumin (OVA) plus Bordetella pertussis toxin and alum as the adjuvants, and orally given 100 or 200 mg/kg hesperidin. In the second experimental design, rats were orally sensitized with OVA together with cholera toxin and fed a diet containing 0.5% hesperidin. In the first approach, hesperidin administration changed mesenteric lymph node lymphocyte (MLNL) composition, increasing the TCRαβ+ cell percentage and decreasing that of B lymphocytes. Furthermore, hesperidin enhanced the interferon (IFN)-γ production in stimulated MLNL. In the second approach, hesperidin intake modified the lymphocyte composition in the intestinal epithelium (TCRγδ+ cells) and the lamina propria (TCRγδ+, CD45RA+, natural killer, natural killer T, TCRαβ+CD4+, and TCRαβ+CD8+ cells). Nevertheless, hesperidin did not modify the level of serum anti-OVA antibodies in either study. In conclusion, hesperidin does possess immunoregulatory properties in the intestinal immune response, but this effect is not able to influence the synthesis of specific antibodies. PMID:28587283

Improvement in the neural stem cell proliferation in rats treated with modified "Shengyu" decoction may contribute to the neurorestoration.

PubMed

Chen, Miao-Miao; Zhao, Guang-Wei; He, Peng; Jiang, Zheng-Lin; Xi, Xin; Xu, Shi-Hui; Ma, Dong-Ming; Wang, Yong; Li, Yong-Cai; Wang, Guo-Hua

2015-05-13

"Shengyu" decoction, a traditional Chinese medicine, has been used to treat diseases with deficit in "qi" and "blood". The modified "Shengyu" decoction (MSD) used in the present study was designed to treat traumatic brain injury (TBI) on the basis of the "Shengyu" decoction, in which additional four herbs were added. Many ingredients in these herbs have been demonstrated to be effective for the treatment of brain injury. The present study was performed to evaluate the neurorestorative effect and the underlying mechanisms of MSD on the rat brain after a TBI. TBI was induced in the right cerebral cortex of adult rats using Feeney's weight-drop method. Intragastrical administration of MSD (1.0 ml/200 g) was begun 6h after TBI. The neurological functions and neuronal loss in the cortex and hippocampus were determined. The levels of nerve growth-related factors GDNF, NGF, NCAM, TN-C, and Nogo-A and the number of GFAP(+)/GDNF(+), BrdU(+)/nestin(+), BrdU(+)/NeuN(+) immunoreactive cells in the brain ipsilateral to TBI were also measured. Moreover, the influences of MSD on these variables were observed at the same time. We found that treatment with MSD in TBI rats ameliorated the neurological functions and alleviated neuronal loss. MSD treatment elevated the expression of GDNF, NGF, NCAM, and TN-C, and inhibited the expression of Nogo-A. Moreover, MSD treatment increased the number of GFAP(+)/GDNF(+), BrdU(+)/nestin(+), and BrdU(+)/NeuN(+) immunoreactive cells in the cortex and hippocampus. The present results suggest that MSD treatment in TBI rats could improve the proliferation of neural stem/progenitor cells and differentiation into neurons, which may facilitate neural regeneration and tissue repair and thus contribute to the recovery of neurological functions. These effects of modified "Shengyu" decoction may provide a foundation for the use of MSD as a prescription of medicinal herbs in the traditional medicine to treat brain injuries in order to improve the neurorestoration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The effect of zinc and phytoestrogen supplementation on the changes in mineral content of the femur of rats with chemically induced mammary carcinogenesis.

PubMed

Skrajnowska, Dorota; Korczak, Barbara Bobrowska-; Tokarz, Andrzej; Kazimierczuk, Agata; Klepacz, Marta; Makowska, Justyna; Gadzinski, Blazej

2015-10-01

The aim of this study was to assess skeletal effects of zinc or zinc with phytoestrogen (resveratrol or genistein) supplementation in an animal model of rats with DMBA-induced mammary carcinogenesis. The changes in bone parameters such as the length and mass were examined, as well as the changes in concentrations of selected minerals: calcium, magnesium, zinc, iron and phosphorus. Moreover, the investigations focused on finding the differences between the levels of iron and zinc in other tissues: the liver, spleen and serum of the examined rats. Fifty-six female Sprague-Dawley rats, 40 days old, were divided into four groups, regardless of the diets: standard (77mg Zn kg/food), zinc (4.6mg/mL via gavage), zinc (4.6mg/mL) plus resveratrol (0.2mg/kgbw), and zinc (4.6mg/mL) plus genistein (0.2mg/kgbw) for a period from 40 days until 20 weeks of age. The study rats were also treated with 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) to induce mammary carcinogenesis. The applied diet and the advanced mammary cancer did not affect macrometric parameters of the rats' bones, but they strongly affected their mineral content. It was found that mammary cancer, irrespectively of the applied diet, significantly modified the iron level in the femur, liver, spleen and serum of the examined rats. In addition, zinc supplementation significantly lowered the levels of calcium, magnesium and phosphorus in the femur of rats with mammary cancer as compared with respective levels in the control group. So, it was found that additional supplementation with zinc, which is generally considered to be an antioxidant, with the co-existing mammary carcinoma, increased the unfavorable changes as concerns the stability of bone tissue. The appropriate combination of zinc and phytoestrogens (resveratrol or genistein) could help prevent or slow bone loss associated with a range of skeletal disorders in breast cancer. Copyright © 2015 Elsevier GmbH. All rights reserved.

Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine.

PubMed

Deng, Xiaomin; Luyendyk, James P; Zou, Wei; Lu, Jingtao; Malle, Ernst; Ganey, Patricia E; Roth, Robert A

2007-08-01

Cotreatment of rats with nontoxic doses of ranitidine (RAN) and lipopolysaccharide (LPS) causes liver injury, and this drug-inflammation interaction might be a model for idiosyncratic adverse drug responses in humans. Both polymorphonuclear neutrophils (PMNs) and the hemostatic system have been shown to be important in the injury. We tested the hypothesis that PMNs cause liver injury by interacting with the hemostatic system and producing subsequent hypoxia. In rats cotreated with LPS/RAN, PMN depletion by anti-PMN serum reduced fibrin deposition and hypoxia in the liver. PMN depletion also reduced the plasma concentration of active plasminogen activator inhibitor-1 (PAI-1), a major down-regulator of the fibrinolytic system. This suggests that PMNs promote fibrin deposition by increasing PAI-1 concentration. PMNs were activated in the livers of LPS/RAN-cotreated rats as evidenced by increased staining for hypochlorous acid-modified proteins generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes. Antiserum against the PMN adhesion molecule CD18 protected against LPS/RAN-induced liver injury. Because CD18 is important for PMN transmigration and activation, these results suggest that PMN activation is required for the liver injury. Furthermore, anti-CD18 serum reduced biomarkers of hemostasis and hypoxia, suggesting the necessity for PMN activation in the interaction between PMNs and the hemostatic system/hypoxia. Liver injury, liver fibrin, and plasma PAI-1 concentration were also reduced by eglin C, an inhibitor of proteases released by activated PMNs. In summary, PMNs are activated in LPS/RAN-cotreated rats and participate in the liver injury in part by contributing to hemostasis and hypoxia.

In vivo microfocal computed tomography and micro-magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat.

PubMed

Jones, Michael D; Tran, Charles W; Li, Guang; Maksymowych, Walter P; Zernicke, Ronald F; Doschak, Michael R

2010-09-01

To determine whether treatment with an antiresorptive drug in combination with an antiinflammatory drug reduces periarticular bone and soft tissue adaptations associated with the progression of posttraumatic secondary osteoarthritis (OA). We used in vivo microfocal computed tomography (micro-CT) to map bony adaptations and in vivo micro-magnetic resonance imaging (micro-MRI) to examine joint inflammation in a rat model of surgically induced OA secondary to knee triad injury. We examined the arthroprotective effects of the bisphosphonates alendronate and risedronate and the nonsteroidal antiinflammatory drug (NSAID) meloxicam. Micro-CT revealed reduced levels of periarticular trabecular bone loss in animals with knee triad injury treated with the bisphosphonate drugs alendronate or risedronate, or the NSAID meloxicam, compared with untreated animals. Alendronate treatment reduced bony osteophyte development. While risedronate as a monotherapy did not positively impact osteophytogenesis, combination therapy with risedronate and meloxicam reduced osteophyte severity somewhat. Micro-MRI revealed an increased, diffuse water signal in the epiphyses of untreated rats with knee triad injury 8 weeks after surgery, suggestive of a bone marrow lesion-like stimulus. In contrast, meloxicam-treated rats showed a significant reduction in fluid signal compared with both bisphosphonate-treated groups 8 weeks after surgery. Histologic analysis qualitatively confirmed the chondroprotective effect of both bisphosphonate treatments, showing fewer degradative changes compared with untreated rats with knee triad injury. Our findings indicate that select combinations of bisphosphonate and NSAID drug therapy in the early stages of secondary OA preserve trabecular bone mass and reduce the impact of osteophytic bony adaptations and bone marrow lesion-like stimulus. Bisphosphonate and NSAID therapy may be an effective disease-modifying drug regimen if administered early after the initial injury.

Betacellulin overexpression in mesenchymal stem cells induces insulin secretion in vitro and ameliorates streptozotocin-induced hyperglycemia in rats.

PubMed

Paz, Ana H; Salton, Gabrielle Dias; Ayala-Lugo, Ana; Gomes, Cristiano; Terraciano, Paula; Scalco, Rosana; Laurino, Claudia Cilene Fernandes Correia; Passos, Eduardo Pandolfi; Schneider, Marlon R; Meurer, Luise; Cirne-Lima, Elizabeth

2011-02-01

Betacellulin (BTC), a ligand of the epidermal growth factor receptor, has been shown to promote growth and differentiation of pancreatic β-cells and to improve glucose metabolism in experimental diabetic rodent models. Mesenchymal stem cells (MSCs) have been already proved to be multipotent. Recent work has attributed to rat and human MSCs the potential to differentiate into insulin-secreting cells. Our goal was to transfect rat MSCs with a plasmid containing BTC cDNA to guide MSC differentiation into insulin-producing cells. Prior to induction of cell MSC transfection, MSCs were characterized by flow cytometry and the ability to in vitro differentiate into mesoderm cell types was evaluated. After rat MSC characterization, these cells were electroporated with a plasmid containing BTC cDNA. Transfected cells were cultivated in Dulbecco's modified Eagle medium high glucose (H-DMEM) with 10 mM nicotinamide. Then, the capability of MSC-BTC to produce insulin in vitro and in vivo was evaluated. It was possible to demonstrate by radioimmunoassay analysis that 10(4) MSC-BTC cells produced up to 0.4 ng/mL of insulin, whereas MSCs transfected with the empty vector (negative control) produced no detectable insulin levels. Moreover, MSC-BTC were positive for insulin in immunohistochemistry assay. In parallel, the expression of pancreatic marker genes was demonstrated by molecular analysis of MSC-BTC. Further, when MSC-BTC were transplanted to streptozotocin diabetic rats, BTC-transfected cells ameliorated hyperglycemia from over 500 to about 200 mg/dL at 35 days post-cell transplantation. In this way, our results clearly demonstrate that BTC overabundance enhances glucose-induced insulin secretion in MSCs in vitro as well as in vivo.

Gender hormones and the progression of experimental polycystic kidney disease.

PubMed

Stringer, Kenneth D; Komers, Radko; Osman, Shukri A; Oyama, Terry T; Lindsley, Jessie N; Anderson, Sharon

2005-10-01

Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators. Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods. Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS. Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

[The effects of lesions in the compact part of the substantia nigra on glutamate and GABA release in the pedunculopontine nucleus].

PubMed

Blanco-Lezcano, L; Rocha-Arrieta, L L; Alvarez-González, L; Martínez-Martí, L; Pavón-Fuentes, N; González-Fraguela, M E; Bauzá-Calderín, Y; Coro-Grave de Peralta, Y

The pedunculopontine nucleus (PPN), co-localized with the mesencephalic locomotor region, has been proposed as a key structure in the physiopathology of Parkinson's disease. The goal of the present study was to assess if the aminoacid neurotransmitter release in the PPN is modified by the degeneration of dopaminergic cells, from substantia nigra pars compacta in 6-hydroxidopamine (6-OHDA)-lesioned rats. In addition, it was studied the aminoacid neurotransmitter release in the PPN of rats with lesion of the subthalamic nucleus by quinolinic acid (QUIN) (100 nmol) intracerebral injection. Rats were assigned to five groups: untreated rats (I) (n = 13), 6-OHDA lesion (II) (n = 11), 6-OHDA + QUIN lesion (III) (n = 9), sham-operated (IV) (n = 10), QUIN, STN (V) lesioned (n = 9). The extracellular concentrations of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) were determined by brain microdialysis and high performance liquid chromatography (HPLC). RESULTS. GLU released in PPN from 6-OHDA lesioned rats (group II), was significantly increased in comparison with the others groups (F(4, 47) = 18.21, p < 0.001). GABA released shows significant differences between experimental groups (F(4, 45) = 12.75, p < 0.001). It was detected a higher valour (p < 0.05) in-group II. The groups III and IV exhibited intermeddle valour (p < 0.001) and groups I and IV (p < 0.001) showed the lower GABA extracellular concentrations. The infusion of artificial cerebrospinal fluid with higher potassium (100 mmol) induced an increase in the GLU and GABA released in all groups, which confirm the neuronal origin of the extracellular content. These results are in agreement with the current model of basal ganglia functioning and suggest the role of STN-PPN projection in the physiopathology of Parkinson's disease.

CHANGES IN APICAL DENDRITIC STRUCTURE CORRELATE WITH SUSTAINED ERK1/2 PHOSPHORYLATION IN MEDIAL PREFRONTAL CORTEX OF A RAT MODEL OF DOPAMINE D1 RECEPTOR AGONIST SENSITIZATION

PubMed Central

Papadeas, Sophia T.; Halloran, Christopher; McCown, Thomas J.; Breese, George R.; Blake, Bonita L.

2008-01-01

Rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch-Nyhan disease, schizophrenia and other developmental disorders of frontostriatal circuit dysfunction. In these animals, a latent sensitivity to D1 agonists is maximally exposed by repeated administration of dopamine agonists in the post-pubertal period (D1 priming). In neonate-lesioned, adult rats primed with SKF-38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher-order oblique branches was increased. Although not present in neonate-lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF-38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho-ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D1-primed rats. In support of this hypothesis, pretreatment with the MEK1/2-ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF-38393, prevented the morphological changes associated with D1 priming. Together, these findings demonstrate that repeated stimulation of D1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo. PMID:18785628

Tributyltin chloride increases phenylephrine-induced contraction and vascular stiffness in mesenteric resistance arteries from female rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ribeiro Júnior, Rogério Faustino, E-mail: rogeriofaustinoribeiro@hotmail.com; Marques, Vinicius Bermond; Nunes, Dieli Oliveira

Tributyltin chloride (TBT) is an organotin compound that reduces estrogen levels in female rats. We aimed to investigate the effects of TBT exposure on vascular tonus and vascular remodelling in the resistance arteries of female rats. Rats were treated daily with TBT (500 ng/kg) for 15 days. TBT did not change arterial blood pressure but did modify some morpho-physiological parameters of third-order mesenteric resistance arteries in the following ways: (1) decreased lumen and external diameters; (2) increased wall/lm ratio and wall thickness; (3) decreased distensibility and increased stiffness; (4) increased collagen deposition; and (5) increased pulse wave velocity. TBT exposuremore » increased the phenylephrine-induced contractile response in mesenteric resistance arteries. However, vasodilatation responses induced by acetylcholine and sodium nitroprusside were not modified by TBT. It is suggested that TBT exposure reduces vascular nitric oxide (NO) production, because:(1) L-NAME incubation did not cause a leftward shift in the concentration–response curve for phenylephrine; (2) both eNOS protein expression; (3) in situ NO production were reduced. Incubation with L-NAME; and (4) SOD shifted the phenylephrine response curve to the left in TBT rats. Tiron, catalase, ML-171 and VAS2870 decreased vascular reactivity to phenylephrine only in TBT rats. Moreover, increased superoxide anion production was observed in the mesenteric resistance arteries of TBT rats accompanied by an increase in gp91phox, catalase, AT{sub 1} receptor and total ERK1/2 protein expression. In conclusion, these findings show that TBT induced alterations are most likely due to a reduction of NO production combined with increased O{sub 2}{sup −} production derived from NADPH oxidase and ERK1/2 activation. These findings offer further evidence that TBT is an environmental risk factor for cardiovascular disease. - Highlights: • Tributyltin chloride reduces estrogen levels in female rats. • Treatment with TBT resulted in increased contractile response to phenylephrine. • Collagen deposition could be responsible for vascular stiffness after TBT exposure.« less

Renoprotective Effect of Humic Acid on Renal Ischemia-Reperfusion Injury: An Experimental Study in Rats.

PubMed

Akbas, Alpaslan; Silan, Coskun; Gulpinar, Murat Tolga; Sancak, Eyup Burak; Ozkanli, Sidika Seyma; Cakir, Dilek Ulker

2015-12-01

Humic acid is an antioxidant molecule used in agriculture and livestock breeding, as well as in medicine. Our aim was to investigate the potential renoprotective effects of humic acid in a renal ischemia reperfusion model. Twenty-one rats were randomly divided into three equal groups. Intraperitoneal serum or humic acid was injected at 1, 12, and 24 h. Non-ischemic group I was evaluated as sham. The left renal artery was clamped in serum (group II) and intraperitoneal humic acid (group III) to subject to left renal ischemic reperfusion procedure. Ischemia and reperfusion time was 60 min for each. Total antioxidant status, total oxidative status, oxidative stress index, and ischemia-modified albumin levels were analyzed biochemically from the serum samples. Kidneys were evaluated histopatologically and immunohistochemically. Biochemical results showed that total oxidative status, ischemia-modified albumin, and oxidative stress index levels were significantly decreased, but total antioxidant status was increased in the humic acid group (III) compared with the ischemia group (II) On histopathological examination, renal tubular dilatation, tubular cell damage and necrosis, dilatation of Bowman's capsule, hyaline casts, and tubular cell spillage were decreased in the humic acid group (III) compared with the ischemia group (II). Immunohistochemical results showed that apoptosis was deteriorated in group III. Renal ischemia reperfusion injury was attenuated by humic acid administration. These observations indicate that humic acid may have a potential therapeutic effect on renal ischemia reperfusion injury by preventing oxidative stress.

Genome Editing in Rats Using TALE Nucleases.

PubMed

Tesson, Laurent; Remy, Séverine; Ménoret, Séverine; Usal, Claire; Thinard, Reynald; Savignard, Chloé; De Cian, Anne; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio

2016-01-01

The rat is an important animal model to understand gene function and model human diseases. Since recent years, the development of gene-specific nucleases has become important for generating new rat models of human diseases, to analyze the role of genes and to generate human antibodies. Transcription activator-like (TALE) nucleases efficiently create gene-specific knockout rats and lead to the possibility of gene targeting by homology-directed recombination (HDR) and generating knock-in rats. We describe a detailed protocol for generating knockout and knock-in rats via microinjection of TALE nucleases into fertilized eggs. This technology is an efficient, cost- and time-effective method for creating new rat models.

Investigations on pharmacokinetics and biodistribution of polymeric and solid lipid nanoparticulate systems of atypical antipsychotic drug: effect of material used and surface modification.

PubMed

Joseph, Emil; Saha, Ranendra N

2017-04-01

The present study focuses on the effect of material used for the preparation of nanoparticulate (NP) systems and surface modification on the pharmacokinetics and biodistribution of atypical antipsychotic, olanzapine (OLN). NP carriers of OLN were prepared from two different materials such as polymer (polycaprolactone) and solid lipid (Glyceryl monostearate). These systems were further surface modified with surfactant, Polysorbate 80 and studied for pharmacokinetics-biodistribution in Wistar rats using in-house developed bioanalytical methods. The pharmacokinetics and biodistribution studies resulted in a modified and varied distribution of NP systems with higher area under curve (AUC) values along with prolonged residence time of OLN in the rat blood circulation. The distribution of OLN to the brain was significantly enhanced with surfactant surface-modified NP systems, followed by nonsurface-modified NP formulations as compared with pure OLN solution. Biodistribution study demonstrated a low uptake of obtained NP systems by kidney and heart, thereby decreasing the nephrotoxicity and adverse cardiovascular effects. By coating the NP with surfactant, uptake of macrophage was found to be reduced. Thus, our studies confirmed that the biodistribution OLN could be modified effectively by incorporating in NP drug delivery systems prepared from different materials and surface modifications. A judicious selection of materials used for the preparation of delivery carriers and surface modifications would help to design a most efficient drug delivery system with better therapeutic efficacy.

The characterization of obese polycystic ovary syndrome rat model suitable for exercise intervention.

PubMed

Wu, Chuyan; Lin, Feng; Qiu, Shuwei; Jiang, Zhongli

2014-01-01

To develop a new polycystic ovary syndrome (PCOS) rat model suitable for exercise intervention. Thirty six rats were randomly divided into three experimental groups: PCOS rats with high-fat diet (PF, n = 24), PCOS rats with ordinary diet (PO, n = 6), and control rats with ordinary diet (CO, n = 6). Two kinds of PCOS rat model were made by adjustment diet structure and testosterone injection for 28 days. After a successful animal model, PF model rats were randomly assigned to three groups: exercise with a continuation of high-fat diet (PF-EF, n = 6), sedentary with a continuation of high-fat diet (PF-SF, n = 6), exercise with an ordinary diet (PF-EO, n = 6). Fasting blood glucose (FBG) and insulin (FINS), estrogen (E2), progesterone (P), and testosterone (T) in serum were determined by RIA, and ovarian morphology was evaluated by Image-Pro plus 6.0. Body weight, Lee index, FINS increased significantly in PF rat model. Serum levels of E2 and T were significantly higher in PF and PO than in CO. Ovary organ index and ovarian areas were significant lower in PF than in CO. After intervention for 2 weeks, the levels of 1 h postprandial blood glucose (PBG1), 2 h postprandial blood glucose (PBG2), FINS and the serum levels of T decreased significantly in PF-EF rats and PF-EO rats. The ratio of FBG/FINS was significant higher in PF-EO rats than in PF-SF rats. Ovarian morphology showed that the numbers of preantral follicles and atretic follicles decreased significantly, and the numbers of antral follicles and corpora lutea increased significantly in the rats of PF-EF and PF-EO. By combination of high-fat diet and testosterone injection, the obese PCOS rat model is conformable with the lifestyle habits of fatty foods and insufficient exercise, and has metabolic and reproductive characteristics of human PCOS. This model can be applied to study exercise intervention.

Covalent modification of proteins by cocaine

NASA Astrophysics Data System (ADS)

Deng, Shi-Xian; Bharat, Narine; Fischman, Marian C.; Landry, Donald W.

2002-03-01

Cocaine covalently modifies proteins through a reaction in which the methyl ester of cocaine acylates the -amino group of lysine residues. This reaction is highly specific in vitro, because no other amino acid reacts with cocaine, and only cocaine's methyl ester reacts with the lysine side chain. Covalently modified proteins were present in the plasma of rats and human subjects chronically exposed to cocaine. Modified endogenous proteins are immunogenic, and specific antibodies were elicited in mouse and detected in the plasma of human subjects. Covalent modification of proteins could explain cocaine's autoimmune effects and provide a new biochemical approach to cocaine's long-term actions.

[Experimental tumors of the central nervous system: standardisation of a model in rats using the 9L glioma cells].

PubMed

Michailowsky, Custódio; Niura, Flavio Key; do Valle, Angela C; Sonohara, Shigueko; Meneguin, Thales D'Alessandro; Tsanaclis, Ana Maria C

2003-06-01

A number of experimental models have been established during the last decades in order to study tumor biology and the effects of treatment or manipulation of the microenvironment of malignant glial tumors. Even though those models have been well characterised and are, to a certain extent, easily reproducible, there are limitations as to their use and to the interpretation of the results. The aim of this study is to standardize a model of a malignant glial tumor and detect possible events able to modify its development. 9L cells were inoculated intracerebrally in 48 Sprague-Dawley rats; from these, 25 animals were also implanted with a device containing electrodes for the registration of the electroencephalogramm. Animals were daily evaluated by neurologic examination. Twenty four animals developed tumor - 10 animals died either in the immediate pos-operatory period or during evolution; 14 animals did not develop tumor. Macroscopically the tumor was well demarcated from the adjacent brain; by light microscopy the tumor exhibited malignant characteristics as well as extensive infiltration of the brain parenchyma. Diagnosis was that of a malignant astrocytoma. The use of the stereotaxic frame and care to infuse a small volume of liquid containing cells during a period of 120 seconds were the most important procedures to obtain sucess in the model. Additional care should be taken in counting cells in the Neubauer camera and in maintaining cells in constant agitation before injecting the tumor-containing solution. The model here developed was efficient besides being of low cost and of relatively easy execution.

Effects of the β1 auxiliary subunit on modification of Rat Na{sub v}1.6 sodium channels expressed in HEK293 cells by the pyrethroid insecticides tefluthrin and deltamethrin

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Bingjun; Soderlund, David M., E-mail: dms6@cornell.edu

We expressed rat Na{sub v}1.6 sodium channels with or without the rat β1 subunit in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on whole-cell sodium currents. In assays with the Na{sub v}1.6 α subunit alone, both pyrethroids prolonged channel inactivation and deactivation and shifted the voltage dependence of channel activation and steady-state inactivation toward hyperpolarization. Maximal shifts in activation were ~ 18 mV for tefluthrin and ~ 24 mV for deltamethrin. These compounds also caused hyperpolarizing shifts of ~ 10–14 mV in the voltage dependence of steady-state inactivation and increased inmore » the fraction of sodium current that was resistant to inactivation. The effects of pyrethroids on the voltage-dependent gating greatly increased the size of sodium window currents compared to unmodified channels; modified channels exhibited increased probability of spontaneous opening at membrane potentials more negative than the normal threshold for channel activation and incomplete channel inactivation. Coexpression of Na{sub v}1.6 with the β1 subunit had no effect on the kinetic behavior of pyrethroid-modified channels but had divergent effects on the voltage-dependent gating of tefluthrin- or deltamethrin-modified channels, increasing the size of tefluthrin-induced window currents but decreasing the size of corresponding deltamethrin-induced currents. Unexpectedly, the β1 subunit did not confer sensitivity to use-dependent channel modification by either tefluthrin or deltamethrin. We conclude from these results that functional reconstitution of channels in vitro requires careful attention to the subunit composition of channel complexes to ensure that channels in vitro are faithful functional and pharmacological models of channels in neurons. - Highlights: • We expressed Na{sub v}1.6 sodium channels with or without β1 subunits in HEK293 cells. • Tefluthrin and deltamethrin shifted channel gating to hyperpolarized potentials. • The β1 subunit had opposite effects on the actions of tefluthrin and deltamethrin. • Auxiliary subunits are required for full reconstitution of channel function. • Channels in HEK293 cells exhibit properties similar to channels in neurons.« less

Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species

PubMed Central

Papież, Monika A; Krzyściak, Wirginia; Szade, Krzysztof; Bukowska-Straková, Karolina; Kozakowska, Magdalena; Hajduk, Karolina; Bystrowska, Beata; Dulak, Jozef; Jozkowicz, Alicja

2016-01-01

Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34+ cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34+ cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells. PMID:26893544

Potential use of gallium-doped phosphate-based glass material for periodontitis treatment.

PubMed

Sahdev, Rohan; Ansari, Tahera I; Higham, Susan M; Valappil, Sabeel P

2015-07-01

This study aimed at evaluating the potential effect of gallium-incorporated phosphate-based glasses towards periodontitis-associated bacteria, Porphyromonas gingivalis, and matrix metalloproteinase-13. Periodontitis describes a group of inflammatory diseases of the gingiva and supporting structures of the periodontium. They are initiated by the accumulation of plaque bacteria, such as the putative periodontal pathogen Porphyromonas gingivalis, but the host immune response such as elevated matrix metalloproteinases are the major contributing factor for destruction of periodontal tissues. Antibacterial assays of gallium-incorporated phosphate-based glasses were conducted on Porphyromonas gingivalis ATCC 33277 using disc diffusion assay on fastidious anaerobe agar and liquid broth assay in a modified tryptic soy broth. In vitro study investigated the effect of gallium on purified recombinant human matrix metalloproteinase-13 activity using matrix metalloproteinase assay kit. In vivo biocompatibility of gallium-incorporated phosphate-based glass was evaluated in rats as subcutaneous implants. Antibacterial assay of gallium displayed activity against Porphyromonas gingivalis (inhibition zone of 22 ± 0.5 mm compared with 0 mm for control glass, c-PBG). Gallium in the glass contributed to growth inhibitory effect on Porphyromonas gingivalis (up to 1.30 reductions in log 10 values of the viable counts compared with control) in a modified tryptic soy broth. In vitro study showed gallium-incorporated phosphate-based glasses inhibited matrix metalloproteinase activity significantly (p ≤ 0.01) compared with c-PBG. Evaluation of in vivo biocompatibility of gallium-incorporated phosphate-based glasses in rats showed a non-toxic and foreign body response after 2 weeks of implantation. The results indicate that gallium ions might act on multiple targets of biological mechanisms underlying periodontal disease. Moreover, gallium-incorporated phosphate-based glasses are biocompatible in a rat model. The findings warrant further investigation and will have important clinical implications in the future treatment and management of periodontitis. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse.

PubMed

Vengeliene, Valentina; Cannella, Nazzareno; Takahashi, Tatiane; Spanagel, Rainer

2016-09-01

The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms. In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway. An inhibitor of kynurenine-3-monooxygenase (KMO) Ro61-8048 (4 and 40 mg/kg) and its prodrug JM6 (100 and 200 mg/kg) were tested in two behavioural rat models for drug seeking and relapse-the alcohol deprivation effect (ADE) model in long-term alcohol-drinking rats and the model of cue-induced reinstatement of alcohol- and cocaine-seeking behaviour. Our results show that relapse-like alcohol drinking during the ADE was abolished by repeated intraperitoneal administration of Ro61-8048 and significantly reduced by its oral prodrug JM6. Cue-induced reinstatement of both alcohol- and cocaine-seeking behaviour was also abolished by administration of Ro61-8048. Pharmacological enhancement of endogenous kynurenic acid levels provides a novel treatment strategy to interfere with glutamatergic/NMDAR activity as well as with craving and relapse in alcohol-dependent patients and drug addicts.

Attenuation of postoperative adhesions using a modeled manual therapy.

PubMed

Bove, Geoffrey M; Chapelle, Susan L; Hanlon, Katherine E; Diamond, Michael P; Mokler, David J

2017-01-01

Postoperative adhesions are pathological attachments that develop between abdominopelvic structures following surgery. Considered unavoidable and ubiquitous, postoperative adhesions lead to bowel obstructions, infertility, pain, and reoperations. As such, they represent a substantial health care challenge. Despite over a century of research, no preventive treatment exists. We hypothesized that postoperative adhesions develop from a lack of movement of the abdominopelvic organs in the immediate postoperative period while rendered immobile by surgery and opiates, and tested whether manual therapy would prevent their development. In a modified rat cecal abrasion model, rats were allocated to receive treatment with manual therapy or not, and their resulting adhesions were quantified. We also characterized macrophage phenotype. In separate experiments we tested the safety of the treatment on a strictureplasty model, and also the efficacy of the treatment following adhesiolysis. We show that the treatment led to reduced frequency and size of cohesive adhesions, but not other types of adhesions, such as those involving intraperitoneal fatty structures. This effect was associated with a delay in the appearance of trophic macrophages. The treatment did not inhibit healing or induce undesirable complications following strictureplasty. Our results support that that maintained movements of damaged structures in the immediate postoperative period has potential to act as an effective preventive for attenuating cohesive postoperative adhesion development. Our findings lay the groundwork for further research, including mechanical and pharmacologic approaches to maintain movements during healing.

Rates of in vivo (arterial) and in vitro biocorrosion for pure magnesium.

PubMed

Bowen, Patrick K; Drelich, Adam; Drelich, Jaroslaw; Goldman, Jeremy

2015-01-01

The development of magnesium-based materials for bioabsorbable stents relies heavily on corrosion testing by immersion in pseudophysiological solutions, where magnesium degrades faster than it does in vivo. The quantitative difference in corrosion kinetics in vitro and in vivo is largely unknown, but, if determined, would help reduce dependence on animal models. In order to create a quantitative in vitro-in vivo correlation based on an accepted measure of corrosion (penetration rate), commercially pure magnesium wires were corroded in vivo in the abdominal aortas of rats for 5-32 days, and in vitro for up to 14 days using Dulbecco's modified eagle medium. Cross-sectioning, scanning electron microscopy, image analysis, a modified penetration rate tailored to degraded wires, and empirical modeling were used to analyze the corroded specimens. In vitro penetration rates were consistently higher than comparable in vivo rates by a factor of 1.2-1.9× (±0.2×). For a sample <20% corroded, an approximate in vitro-in vivo multiplier of 1.3 ± 0.2× was applied, whereas a multiplier of 1.8 ± 0.2× became appropriate when the magnesium specimen was 25-35% degraded. © 2014 Wiley Periodicals, Inc.

Ex-vivo transduced autologous skin fibroblasts expressing human Lim Mineralization Protein-3 efficiently form new bone in animal models

PubMed Central

Lattanzi, Wanda; Parrilla, Claudio; Fetoni, Annarita; Logroscino, Giandomenico; Straface, Giuseppe; Pecorini, Giovanni; Stigliano, Egidio; Tampieri, Anna; Bedini, Rossella; Pecci, Raffaella; Michetti, Fabrizio; Gambotto, Andrea; Robbins, Paul D.; Pola, Enrico

2012-01-01

Local gene transfer of the human LIM Mineralization Protein (LMP), a novel intracellular positive regulator of the osteoblast differentiation program, can induce efficient bone formation in rodents. In order to develop a clinically relevant gene therapy approach to facilitate bone healing, we have used primary dermal fibroblasts transduced ex vivo with Ad.LMP3 and seeded on an hydroxyapatite/collagen matrix prior to autologous implantation. Here we demonstrate that genetically modified autologous dermal fibroblasts expressing Ad.LMP-3 are able to induce ectopic bone formation following implantation of the matrix into the mouse triceps and paravertebral muscles. Moreover, implantation of the Ad.LMP-3-modified dermal fibroblasts into a rat mandibular bone critical size defect model results in efficient healing as determined by X-ray, histology and three dimensional micro computed tomography (3DμCT). These results demonstrate the effectiveness of the non-secreted intracellular osteogenic factor LMP-3, in inducing bone formation in vivo. Moreover, the utilization of autologous dermal fibroblasts implanted on a biomaterial represents a promising approach for possible future clinical applications aimed at inducing new bone formation. PMID:18633445

Hormonal and metabolic responses of hypophysectomized rats with head-down suspension

NASA Technical Reports Server (NTRS)

Tipton, C. M.; Grindeland, R. E.; Woodman, C. R.; Gosselink, K.; Linderman, J. K.; Mukku, V. R.; Gooselink, K.

1994-01-01

The primary purpose of this investigation was to secure select anatomical and physiological measurements from hypophysectomized rats and their sham-operated control to determine how various endocrine influences could be modified by conditions of simulated microgravity. The focal point of the study was the exercise responses after head-down suspension; however, we were also interested in obtaining insights on nonexercise-related mechanisms. Since more details and information concerning this study will be published elsewhere, we will highlight those findings which warrant further research.

Inkjet Gene Printing: A Novel Approach to Achieve Gene Modified Cells for Tissue Engineering

DTIC Science & Technology

2008-12-01

and pIRES-VEGF-GFP (BD Biosciences, Bedford, MA) encoding the cDNAs of jellyfish Aequorea victoria green fluorescent protein, driven by the...prepared from rat-tail Type I collagen gels using a previously reported protocol(Xu et al. 2005). Briefly, rat- tail Type I collagen (BD Biosciences...aliquots of the mixture were dispersed onto coverslips and cured in an incubator for 3–5 h. Once the gel set, the collagen bio-paper was ready for

Effects of harmane on growth and in vivo metabolism of aflatoxin B1 in male and female rats.

PubMed

Billaud, C

1991-01-01

The role of harmane, a beta-carboline formed during pyrolysis of tryptophan, on the metabolism of AFB1, growth and some parameters of the nutritional status was investigated in the rat. Male and female Wistar rats were fed a semi-synthetic diet containing AFB1 (2 ppm), harmane (250 ppm) or both compounds, for 33 days after weaning. Qualitative and quantitative differences in the urinary and faecal excretion of parental compound and metabolites were assessed by HPLC analysis. Harmane did not modify appreciably the growth and the other nutritional parameters studied. Similar excretion patterns of AFB1 metabolites were observed in males and females. Harmane caused a limited increase in the excretion of AFM1 in faeces but not in urine, without altering the growth process in rats of either sex.

A 90-day subchronic study of rats fed lean pork from genetically modified pigs with muscle-specific expression of recombinant follistatin.

PubMed

Zou, Shiying; Tang, Min; He, Xiaoyun; Cao, Yuan; Zhao, Jie; Xu, Wentao; Liang, Zhihong; Huang, Kunlun

2015-11-01

Because cardiovascular disease incidence has rapidly increased in recent years, people are choosing relatively healthier diets with low animal fat. A transgenic pig with low fat and a high percentage of lean meat was created in 2011; this pig overexpresses the follistatin (FST) gene. To evaluate the safety of lean pork derived from genetically modified (GM) pigs, a subchronic oral toxicity study was conducted using Sprague-Dawley rats. GM pork and non-GM pork were incorporated into the diet at levels of 3.75%, 7.5%, and 15% (w/w), and the main nutrients of the various diets were subsequently balanced. The safety of GM pork was assessed by comparison of the toxicology response variables in Sprague-Dawley rats consuming diets containing GM pork with those consuming non-GM pork. No treatment-related adverse or toxic effects were observed based on an examination of the daily clinical signs, body weight, food consumption, hematology, serum biochemistry, and organ weight or based on gross and histopathological examination. The results demonstrate that GM pork is as safe for consumption as conventional pork. Copyright © 2015 Elsevier Inc. All rights reserved.

Conditional expression of the type 2 angiotensin II receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury.

PubMed

Feng, Jian; Liu, Jian-Ping; Miao, Li; He, Guo-Xiang; Li, De; Wang, Hai-Dong; Jing, Tao

2014-10-01

Percutaneous coronary interventions (PCIs) are an effective treatment for obstructive coronary artery diseases. However, the procedure's success is limited by remodeling and formation of neointima. In the present study, we engineered rat mesenchymal stem cells (MSCs) to express type 2 angiotensin II receptor (AT2R) using a tetracycline-regulated system that can strictly regulate AT2R expression. We tested the ability of the modified MSCs to reduce neointima formation following arterial injury. We subjected rats to balloon injury, and reverse transcriptase polymerase chain reaction (RT-PCR) indicated no significant AT2R expression in normal rat arteries. Low expression of AT2R was observed at 28 days after balloon-induced injury. Interestingly, MSCs alone were unable to reduce neointimal hyperplasia after balloon-induced injury; after transplantation of modified MSCs, doxycycline treatment significantly upregulated neointimal AT2R expression and inhibited osteopontin mRNA expression, as well as neointimal formation. Taken together, these results suggest that transplantation of MSCs conditionally expressing AT2R could effectively suppress neointimal hyperplasia following balloon-induced injury. Therefore, MSCs with a doxycycline-controlled gene induction system may be useful for the management of arterial injury after PCI.

A novel biodegradable PCL film for tendon reconstruction: Achilles tendon defect model in rats.

PubMed

Kazimoğlu, C; Bölükbaşi, S; Kanatli, U; Senköylü, A; Altun, N S; Babaç, C; Yavuz, H; Pişkin, E

2003-09-01

This study aims to investigate applicability of poly(epsilon-caprolactone) (PCL) biodegradable films for repair of gaps in Achilles tendons in a rat model, also comparing surgical repair versus no repair approaches. PCL was synthesized with tailor-made properties, then, PCL films were prepared by solvent casting. Seventy-five outbred Sprague-Dawley rats were randomly allocated into five groups: (i) sham operated (skin incision only); (ii) no repair (complete division of the Achilles tendon and plantaris tendon without repair); (iii) Achilles repair (with a modified Kessler type suture); and (iv) plasty of Achilles tendon defects with the biodegradable PCL films, and (v) animals subjected to 1 cm mid-substance defect with no repair. Functional performance was determined from the measurements of hindpaw prints utilizing the Achilles functional index. The animals were killed 8 weeks after surgery and histological and biomechanical evaluations were made. All groups subjected to Achilles tendon division had a significant functional impairment that gradually improved so that by day 28 there were no functional impairments in any group whereas animals with a defect remained impaired. The magnitude of the biomechanical and morphological changes at postoperative 8 weeks were similar for no repair group (conservative), Achilles repair group and tendonplasty group (biodegradable PCL film group). The initial rate of functional recovery was significantly different for primary suture, Achilles repair group and PCL film group (p>0.01). But, at the 28th day, functional recovery was quite similar to the other groups. In summary, our results suggest that the PCL film can be an alternative biomaterial for tendon replacement.

Full field optical coherence tomography can identify spermatogenesis in a rodent sertoli-cell only model.

PubMed

Ramasamy, Ranjith; Sterling, Joshua; Manzoor, Maryem; Salamoon, Bekheit; Jain, Manu; Fisher, Erik; Li, Phillip S; Schlegel, Peter N; Mukherjee, Sushmita

2012-01-01

Microdissection testicular sperm extraction (micro-TESE) has replaced conventional testis biopsies as a method of choice for obtaining sperm for in vitro fertilization for men with nonobstructive azoospermia. A technical challenge of micro-TESE is that the low magnification inspection of the tubules with a surgical microscope is insufficient to definitively identify sperm-containing tubules, necessitating tissue removal and cytologic assessment. Full field optical coherence tomography (FFOCT) uses white light interference microscopy to generate quick high-resolution tomographic images of fresh (unprocessed and unstained) tissue. Furthermore, by using a nonlaser safe light source (150 W halogen lamp) for tissue illumination, it ensures that the sperm extracted for in vitro fertilization are not photo-damaged or mutagenized. A focal Sertoli-cell only rodent model was created with busulfan injection in adult rats. Ex vivo testicular tissues from both normal and busulfan-treated rats were imaged with a commercial modified FFOCT system, Light-CT™, and the images were correlated with gold standard hematoxylin and eosin staining. Light-CT™ identified spermatogenesis within the seminiferous tubules in freshly excised testicular tissue, without the use of exogenous contrast or fixation. Normal adult rats exhibited tubules with uniform size and shape (diameter 328 ±11 μm). The busulfan-treated animals showed marked heterogeneity in tubular size and shape (diameter 178 ± 35 μm) and only 10% contained sperm within the lumen. FFOCT has the potential to facilitate real-time visualization of spermatogenesis in humans, and aid in micro-TESE for men with infertility.

Visualizing the engram: learning stabilizes odor representations in the olfactory network.

PubMed

Shakhawat, Amin M D; Gheidi, Ali; Hou, Qinlong; Dhillon, Sandeep K; Marrone, Diano F; Harley, Carolyn W; Yuan, Qi

2014-11-12

The nature of memory is a central issue in neuroscience. How does our representation of the world change with learning and experience? Here we use the transcription of Arc mRNA, which permits probing the neural representations of temporally separated events, to address this in a well characterized odor learning model. Rat pups readily associate odor with maternal care. In pups, the lateralized olfactory networks are independent, permitting separate training and within-subject control. We use multiday training to create an enduring memory of peppermint odor. Training stabilized rewarded, but not nonrewarded, odor representations in both mitral cells and associated granule cells of the olfactory bulb and in the pyramidal cells of the anterior piriform cortex. An enlarged core of stable, likely highly active neurons represent rewarded odor at both stages of the olfactory network. Odor representations in anterior piriform cortex were sparser than typical in adult rat and did not enlarge with learning. This sparser representation of odor is congruent with the maturation of lateral olfactory tract input in rat pups. Cortical representations elsewhere have been shown to be highly variable in electrophysiological experiments, suggesting brains operate normally using dynamic and network-modulated representations. The olfactory cortical representations here are consistent with the generalized associative model of sparse variable cortical representation, as normal responses to repeated odors were highly variable (∼70% of the cells change as indexed by Arc). Learning and memory modified rewarded odor ensembles to increase stability in a core representational component. Copyright © 2014 the authors 0270-6474/14/3415394-08$15.00/0.

Resonance energy transfer between sites in rat liver glutathione S-transferase, 1-1, selectively modified at cysteine-17 and cysteine-111.

PubMed

Hu, L; Colman, R F

1997-02-18

Monobromobimane (mBBr) can label both Cys111 and Cys17 of rat liver glutathione S-transferase, 1-1 (GST 1-1). However, selective modification of Cys111 was achieved by the maleimide-based sulfhydryl reagents N-ethylmaleimide (NEM) and fluorescein 5-maleimide (NFM). Incubation of GST 1-1 with 5 mM NEM for 30 min at pH 7.5 and 25 degrees C leads to the formation of modified enzyme with 92% residual activity toward 1-chloro-2,4-dinitrobenzene and completely blocks Cys111 from subsequent reaction with either NFM or mBBr. Reaction of GST 1-1 with 0.2 mM NFM under the same conditions affords a modified enzyme with only 14% residual activity even though NFM and NEM target the same Cys111. The results indicate that when the bulky fluorescein is covalently bound to Cys111, the ligand projects into both the xenobiotic binding site and the glutathione site. After NEM or NFM modification of GST 1-1, the enzyme was further modified by monobromobimane at Cys17 with loss of activity. Together with the only tryptophan (Trp20), fluorescein linked to Cys111 and bimane to Cys17 provide three fluorescent probes to study the solution structure of GST 1-1. Fluorescence spectral analysis suggests that Trp20 and bimane linked to Cys17 are located in a relatively hydrophobic environment, while fluorescein linked to Cys111 is located in a charged environment. These fluorescent probes constitute three sets of donor-acceptor pairs for the measurement of fluorescence energy transfer, and distances calculated from such measurements are 20 A between Trp20 and bimane at Cys17, 19 A between Trp20 and fluorescein at Cys111, and < 22 A between bimane at Cys17 and fluorescein at Cys111. Molecular modeling studies indicate that fluorescein lies between the two subunits, is surrounded by charged residues, and is extended into the xenobiotic binding site. They also suggest that mBBr must approach from the dimer interface in order to reach the reaction site at Cys17.

[Rosuvastatin improves insulin sensitivity in overweight rats induced by high fat diet. Role of SIRT1 in adipose tissue].

PubMed

Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; Cachofeiro, Victoria; Lahera, Vicente; de Las Heras, Natalia

2014-01-01

To study the effects of rosuvastatin on insulin resistance in overweight rats induced by high fat diet, as well as potential mediators. We used male Wistar rats fed with a standard diet (CT) or high fat diet (33.5% fat) (HFD); half of the animals HFD were treated with rosuvastatin (15mg/kg/day) (HFD+Rosu) for 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Treatment with Rosu did not modify body weight or the weight of the adipose packages in HFD rat. Plasma glucose and insulin levels and HOMA index were higher in HFD rats, and rosuvastatin treatment reduced them. Leptin/adiponectin ratio in plasma and lumbar adipose tissue were higher in HDF rats, and were reduced by rosuvastatin. SIRT-1, PPAR-γ and GLUT-4 protein expression in lumbar adipose tissue were lower in HFD rats and Rosu normalized expression of the three mediators. Rosuvastatin ameliorates insulin sensitivity induced by HFD in rats. This effect is mediated by several mechanisms including reduction of leptin and enhancement of SIRT-1, PPAR-γ and GLUT-4 expression in white adipose tissue. SIRT1 could be considered a major mediator of the beneficial effects of rosuvastatin on insulin sensitivity in overweight rats induced by diet. Copyright © 2013 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.