Utility of 18F-fluorodeoxy glucose and 18F-sodium fluoride positron emission tomography/computed tomography in the diagnosis of medication-related osteonecrosis of the jaw: A preclinical study in a rat model.

PubMed

Kim, Yemi; Lee, Ho-Young; Yoon, Hai-Jeon; Kim, Bom Sahn

2016-04-01

The aim of this study was to determine the clinical utility of positron emission tomography/computed tomography (PET/CT) using 18F-FDG and 18F-NaF for the diagnosis of osteonecrosis of the jaw (ONJ), by observing characteristics in rat models treated with zoledronic acid (ZA) and/or dexamethasone (DX) followed by tooth extraction. A total of 48 rats were divided randomly into four groups: Group 1, rats treated with ZA and DX; Group 2, rats treated with ZA; Group 3, rats treated with DX; and Group 4, rats treated with vehicle as normal controls. They underwent examinations with both 18F-FDG and 18F-NaF PET/CT at 4 weeks prior to tooth extraction (baseline) and 4 weeks after tooth extraction. Rats were then sacrificed to evaluate the histological incidence and characteristics of ONJ. Histological and radiological characteristics of all groups were compared to assess the effects of medication and tooth extraction. Baseline PET/CT studies using 18F-FDG and 18F-NaF showed no difference in uptake among the groups. However, 18F-FDG PET/CT performed at 4 weeks after tooth extraction showed increased glucose metabolism at the extraction site in both the ZA/DX and the ZA-only groups compared with that in the vehicle-treated group, in accordance with the higher incidence of histological ONJ (p < 0.05, respectively). 18F-NaF PET/CT performed at 4 weeks after tooth extraction showed decreased bone uptake in the extraction site in the ZA/DX, ZA, and DX groups versus the vehicle group (all p < 0.05), but this was not correlated with the incidence of histological ONJ. The incidence of ONJ was highest in the ZA/DX group (66.7%), followed by the ZA group, both of which were significantly higher than in the DX and vehicle groups (both p < 0.05). 18F-FDG PET/CT as an inflammatory marker appeared to be a more appropriate imaging modality than 18F-NaF PET/CT in diagnosing ONJ in a rat model including a ZA/DX group. However, the decreased bone remodeling tendency highlighted by 18F-NaF

Incretin response to a standard test meal in a rat model of sleeve gastrectomy with diet-induced obesity.

PubMed

Al-Sabah, Suleiman; Alasfar, Fahad; Al-Khaledi, Ghanim; Dinesh, Reshma; Al-Saleh, Mervat; Abul, Habib

2014-01-01

Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects. Male Sprague-Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham). After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response. A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO.

Cognitive differences between Sprague-Dawley rats selectively bred for sensitivity or resistance to diet induced obesity.

PubMed

Gurung, Sunam; Agbaga, Martin-Paul; Myers, Dean A

2016-09-15

Epidemiological studies have shown strong correlations between high fat diets, diet-induced obesity and cognitive impairment, primarily focusing on cognitive defects after the onset of obesity. A remaining question is whether cognitive impairment precedes obesity in individuals metabolically prone to diet-induced obesity. The inbred diet-induced obesity sensitive (DIO) and resistant (DR) strains of Sprague-Dawley rats serve as models for human polygenic obesity. DIO rats become overweight on a standard rat chow and have metabolic symptoms similar to overweight humans. We hypothesized that cognitive impairment pre-exists in adult male DIO rats prior to exposure to high fat diet. Male DIO and DR rats were fed a standard rat chow diet from 4 through 20 weeks of age and subjected to the Morris water maze at 12 weeks of age. At 5 and 20 weeks of age, brains of DIO and DR males were examined for indices of inflammation, lipid peroxidation and neuroproliferation. DIO rats showed significant memory impairment on water maze and increased indices of hippocampal inflammation at 20 weeks of age compared to DR rats. At 5 weeks of age, DIO rats exhibited significantly less neural progenitor cell (NPCs) proliferation in the dentate gyrus and increased hippocampal lipid peroxidation compared to DR rats. Therefore, we conclude that DIO rats exhibit early post-weaning indices of hippocampal inflammation, lipid peroxidation and decreased NPC proliferation, as well as impaired hippocampal dependent memory by early adulthood suggesting that inherent metabolic differences predispose the DIO strain to cognitive deficit prior to exposure to high fat diet and/or obesity. Copyright © 2016. Published by Elsevier B.V.

Changes in cerebral [18F]-FDG uptake induced by acute alcohol administration in a rat model of alcoholism.

PubMed

Gispert, Juan D; Figueiras, Francisca P; Vengeliene, Valentina; Herance, José R; Rojas, Santiago; Spanagel, Rainer

2017-06-01

Several [ 18 F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [ 18 F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naïve. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [ 18 F]-FDG uptake was most apparent in alcohol-naïve rats, less intense in short-term drinkers and absent in long-term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [ 18 F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

[18F]FP-(+)-DTBZ PET study in a lactacystin-treated rat model of Parkinson disease.

PubMed

Weng, Chi-Chang; Huang, Siao-Lan; Chen, Zi-An; Lin, Kun-Ju; Hsiao, Ing-Tsung; Yen, Tzu-Chen; Kung, Mei-Ping; Wey, Shiaw-Pyng; Hsu, Ching-Han

2017-08-01

Lactacystin has been used to establish rodent models of Parkinson disease (PD), with cerebral α-synuclein inclusions. This study evaluated the uptake of [ 18 F]9-fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]FP-(+)-DTBZ), a vesicular monoamine transporter type 2 (VMAT2)-targeting radiotracer, through positron emission tomography (PET) in lactacystin-treated rat brains. Adult male Sprague-Dawley rats were randomly treated with a single intracranial dose of lactacystin (2 or 5 μg) or saline (served as the sham control) into the left medial forebrain bundle. A 30-min static [ 18 F]FP-(+)-DTBZ brain PET scan was performed following an intravenous [ 18 F]FP-(+)-DTBZ dose (approximately 22 MBq) in each animal at 2 and 3 weeks after lactacystin treatment. Upon completing the last PET scans, the animals were killed, and their brains were dissected for ex vivo autoradiography (ARG) and immunohistochemical (IHC) staining of tyrosine hydroxylase (TH) as well as VMAT2. Both the 2- and 5-μg lactacystin-treated groups exhibited significantly decreased specific [ 18 F]FP-(+)-DTBZ uptake in the ipsilateral striata (I-ST) at 2 weeks (1.51 and 1.16, respectively) and 3 weeks (1.36 and 1.00, respectively) after lactacystin treatment, compared with the uptake in the corresponding contralateral striata (C-ST) (3.48 and 3.08 for the 2- and 5-μg lactacystin-treated groups, respectively, at 2 weeks; 3.36 and 3.11 for the 2- and 5-μg lactacystin-treated groups, respectively, at 3 weeks) and the sham controls (3.34-3.53). Lactacystin-induced decline in I-ST [ 18 F]FP-(+)-DTBZ uptake was also demonstrated through ex vivo ARG, and the corresponding dopaminergic neuron damage was confirmed by the results of TH- and VMAT2-IHC studies. In this PD model, lactacystin-induced dopaminergic terminal damage in the ipsilateral striatum could be clearly visualized through in vivo [ 18 F]FP-(+)-DTBZ PET imaging. This may serve as a useful approach for evaluating the effectiveness of new

Comparative assessment of 6-[18 F]fluoro-L-m-tyrosine and 6-[18 F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model.

PubMed

Becker, Guillaume; Bahri, Mohamed Ali; Michel, Anne; Hustadt, Fabian; Garraux, Gaëtan; Luxen, André; Lemaire, Christian; Plenevaux, Alain

2017-05-01

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson's disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the preclinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [ 18 F]fluoro-3,4-dihydroxyphenyl-L-alanine ([ 18 F]FDOPA) and 6-[ 18 F]fluoro-L-m-tyrosine ([ 18 F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [ 18 F]FMT and [ 18 F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [ 18 F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [ 18 F]FMT and [ 18 F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant K c . However, only [ 18 F]FMT K c succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [ 18 F]FMT could be more sensitive, with respect of [ 18 F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L

Evaluation of [¹⁸F]PFH PET renography to predict future disease progression in a rat model of autosomal dominant polycystic kidney disease.

PubMed

Pathuri, Gopal; Hedrick, Andria F; Awasthi, Vibhudutta; Cowley, Benjamin D; Gali, Hariprasad

2016-01-01

Prognostic markers for progression of polycystic kidney disease (PKD) are limited. We evaluated the potential of early para-[(18)F]fluorohippurate ([(18)F]PFH) positron emission tomography (PET) renography to predict future progression of PKD in Han:SPRD rats with slowly progressive autosomal dominant PKD. Male and female heterozygous (Cy/+) and normal littermate (+/+) Han:SPRD rats underwent [(18)F]PFH PET renography and blood sampling to measure serum creatinine (S-Cr) and serum urea nitrogen (SUN) concentrations at 6 and 26 wk of age. T2 and T20 values, which represent the percent of the injected dose of [(18)F]PFH in kidneys at 2 and 20 min after injection, were determined from imaging data. T20/T2 ratio was assessed as a prognostic marker. Rats were euthanized after renography at 26 wk of age, and kidney weight/body weight ratios (KW/BW%) were determined as a measure of PKD progression. Male and female Cy/+ rats are known to manifest PKD of different severity, male Cy/+ rats display much more severe PKD than female rats. S-Cr and SUN concentrations did not differ between +/+ and Cy/+ rats and between female and male Cy/+ rats at 6 wk of age, but they were higher at 26 wk of age and male rats displayed higher values than female rats, which indicates inability of S-Cr and SUN to measure disease severity at an early stage. T20/T2 ratios were higher for Cy/+ than +/+ rats at 6 wk of age. Importantly, male Cy/+ rats displayed higher T20/T2 ratios than female Cy/+ rats. T20/T2 ratios obtained at 6 wk of age correlated well with S-Cr, SUN, and KW/BW% values obtained at 26 wk of age. This study indicates that T20/T2 ratio derived from [(18)F]PFH PET renography at an early age could be useful as a novel prognostic marker to predict future disease severity in a rat model of ADPKD. Copyright © 2015 Elsevier Inc. All rights reserved.

OKN-007 decreases free radical levels in a preclinical F98 rat glioma model.

PubMed

Coutinho de Souza, Patricia; Smith, Nataliya; Atolagbe, Oluwatomisin; Ziegler, Jadith; Njoku, Charity; Lerner, Megan; Ehrenshaft, Marilyn; Mason, Ronald P; Meek, Bill; Plafker, Scott M; Saunders, Debra; Mamedova, Nadezda; Towner, Rheal A

2015-10-01

Free radicals are associated with glioma tumors. Here, we report on the ability of an anticancer nitrone compound, OKN-007 [Oklahoma Nitrone 007; a disulfonyl derivative of α-phenyl-tert-butyl nitrone (PBN)] to decrease free radical levels in F98 rat gliomas using combined molecular magnetic resonance imaging (mMRI) and immunospin-trapping (IST) methodologies. Free radicals are trapped with the spin-trapping agent, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), to form DMPO macromolecule radical adducts, and then further tagged by immunospin trapping by an antibody against DMPO adducts. In this study, we combined mMRI with a biotin-Gd-DTPA-albumin-based contrast agent for signal detection with the specificity of an antibody for DMPO nitrone adducts (anti-DMPO probe), to detect in vivo free radicals in OKN-007-treated rat F98 gliomas. OKN-007 was found to significantly decrease (P < 0.05) free radical levels detected with an anti-DMPO probe in treated animals compared to untreated rats. Immunoelectron microscopy was used with gold-labeled antibiotin to detect the anti-DMPO probe within the plasma membrane of F98 tumor cells from rats administered anti-DMPO in vivo. OKN-007 was also found to decrease nuclear factor erythroid 2-related factor 2, inducible nitric oxide synthase, 3-nitrotyrosine, and malondialdehyde in ex vivo F98 glioma tissues via immunohistochemistry, as well as decrease 3-nitrotyrosine and malondialdehyde adducts in vitro in F98 cells via ELISA. The results indicate that OKN-007 effectively decreases free radicals associated with glioma tumor growth. Furthermore, this method can potentially be applied toward other types of cancers for the in vivo detection of macromolecular free radicals and the assessment of antioxidants. Copyright © 2015. Published by Elsevier Inc.

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

PubMed Central

Matthews, Jessica L.; Schultz, Irvin R.; Easterling, Michael R.; Melnick, Ronald L.

2010-01-01

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite α-halocarboxymethylglutathione (αH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical- and species-specific parameters. PMID:20045428

Polymorphisms of iodothyronine deiodinases (DIO1, DIO3) genes are not associated with recurrent depressive disorder.

PubMed

Gałecka, Elżbieta; Talarowska, Monika; Maes, Michael; Su, Kuan-Pin; Górski, Paweł; Szemraj, Janusz

2016-10-01

Depressive disorder is characterized by disturbances in the hypothalamic-pituitary-thyroid (HPT) axis and in the metabolism of thyroid hormones (TH). The evidence for changes in TH levels is observed in human sera and cerebrospinal fluid as well as in animal model studies. Iodothyronine deiodinases (DIOs) type 1, 2 and 3 (DIO1, DIO2, DIO3) are important enzymes for the synthesis and determination of TH concentration. This study aims to examine the link between recurrent depressive disorders (rDD) and two functionally known polymorphisms DIO1a-C/T (rs11206244) and DIO1b-A/G (rs12095080) within the DIO1 gene encoding DIO1 and two polymorphisms DIO3-C/T (rs17716499), DIO3-A/C (rs7150269) within the DIO3 gene encoding DIO3. Both variants were genotyped in 254 rDD patients and 197 healthy subjects using polymerase chain reaction. Basic methods and statistical analyses were used to estimate genetic variants in the risk of the disease. No significant associations were found between the polymorphisms examined here and rDD. There were no significant associations between genotypes distribution and demographic/medical variables. Odds ratios (ORdis) and corresponding 95% confidence interval (95% CI) were calculated, for example: for CC genotype of DIO1a C/T (ORdis=0.86, 95% CI: 0.59, 1.25). Functional variants within the DIO1 gene, which affect TH levels and polymorphisms in DIO3, are not confirmed to be associated with rDD. Nevertheless, considering previous data which indicate that the DIO1 gene is related to the depression, further studies on a larger sample size are recommended. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

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

Matthews, Jessica L., E-mail: Jessica_Matthews@sra.co; Schultz, Irvin R., E-mail: irv.schultz@pnl.go; Easterling, Michael R., E-mail: Michael_Easterling@sra.co

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite alpha-halocarboxymethylglutathione (alphaH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibratedmore » with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.« less

Nicotine improves obesity and hepatic steatosis and ER stress in diet-induced obese male rats.

PubMed

Seoane-Collazo, Patricia; Martínez de Morentin, Pablo B; Fernø, Johan; Diéguez, Carlos; Nogueiras, Rubén; López, Miguel

2014-05-01

Nicotine, the main addictive component of tobacco, promotes body weight reduction in humans and rodents. Recent evidence has suggested that nicotine acts in the central nervous system to modulate energy balance. Specifically, nicotine modulates hypothalamic AMP-activated protein kinase to decrease feeding and to increase brown adipose tissue thermogenesis through the sympathetic nervous system, leading to weight loss. Of note, most of this evidence has been obtained in animal models fed with normal diet or low-fat diet (LFD). However, its effectiveness in obese models remains elusive. Because obesity causes resistance towards many factors involved in energy homeostasis, the aim of this study has been to compare the effect of nicotine in a diet-induced obese (DIO) model, namely rats fed a high-fat diet, with rats fed a LFD. Our data show that chronic peripheral nicotine treatment reduced body weight by decreasing food intake and increasing brown adipose tissue thermogenesis in both LFD and DIO rats. This overall negative energy balance was associated to decreased activation of hypothalamic AMP-activated protein kinase in both models. Furthermore, nicotine improved serum lipid profile, decreased insulin serum levels, as well as reduced steatosis, inflammation, and endoplasmic reticulum stress in the liver of DIO rats but not in LFD rats. Overall, this evidence suggests that nicotine diminishes body weight and improves metabolic disorders linked to DIO and might offer a clear-cut strategy to develop new therapeutic approaches against obesity and its metabolic complications.

High and Low Activity Rats: Elevated intrinsic physical activity drives resistance to diet induced obesity in non-bred rats

PubMed Central

Perez-Leighton, Claudio E.; Boland, Kelsey; Billington, Charles; Kotz, Catherine M.

2012-01-01

Humans and rodents show large variability in their individual sensitivity to diet-induced obesity, which has been associated with differences in intrinsic spontaneous physical activity (SPA). Evidence from genetic and out-bred rat obesity models shows that higher activity of the orexin peptides results in higher intrinsic SPA and protection against diet-induced obesity. Based on this, we hypothesized that naturally occurring variation in SPA and orexin signaling activity is sufficient to drive differences in sensitivity to diet-induced obesity. We analyzed orexin activity and sensitivity to diet-induced obesity in non-manipulated male Sprague Dawley rats selected for high and low intrinsic SPA. Our results defined a new model of differential DIO sensitivity, the high-activity and low activity-rats, and suggest that naturally occurring variations in intrinsic SPA cause differences in energy expenditure that are mediated by orexin signaling and alter DIO sensitivity. PMID:23404834

[(18)F]FDG PET Neuroimaging Predicts Pentylenetetrazole (PTZ) Kindling Outcome in Rats.

PubMed

Bascuñana, Pablo; Javela, Julián; Delgado, Mercedes; Fernández de la Rosa, Rubén; Shiha, Ahmed Anis; García-García, Luis; Pozo, Miguel Ángel

2016-10-01

Epileptogenesis, i.e., development of epilepsy, involves a number of processes that alter the brain function in the way that triggers spontaneous seizures. Kindling is one of the most used animal models of temporal lobe epilepsy (TLE) and epileptogenesis, although chemical kindling suffers from high inter-assay success unpredictability. This study was aimed to analyze the eventual regional brain metabolic changes during epileptogenesis in the pentylenetetrazole (PTZ) kindling model in order to obtain a predictive kindling outcome parameter. In vivo longitudinal positron emission tomography (PET) scans with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) along the PTZ kindling protocol (35 mg/kg intraperitoneally (i.p.), 18 sessions) in adult male rats were performed in order to evaluate the regional brain metabolism. The half of the PTZ-injected rats reached the kindled state. In addition, a significant decrease of [(18)F]FDG uptake at the end of the protocol in most of the brain structures of kindled animals was found, reflecting the characteristic epilepsy-associated hypometabolism. However, PTZ-injected animals but not reaching the kindled state did not show this widespread brain hypometabolism. Retrospective analysis of the data revealed that hippocampal [(18)F]FDG uptake normalized to pons turned out to be a predictive index of the kindling outcome. Thus, a 19.06 % reduction (p = 0.008) of the above parameter was found in positively kindled rats compared to non-kindled ones just after the fifth PTZ session. Non-invasive PET neuroimaging was a useful tool for discerning epileptogenesis progression in this animal model. Particularly, the [(18)F]FDG uptake of the hippocampus proved to be an early predictive parameter to differentiate resistant and non-resistant animals to the PTZ kindling.

Whole-Genome Sequences of DA and F344 Rats with Different Susceptibilities to Arthritis, Autoimmunity, Inflammation and Cancer

PubMed Central

Guo, Xiaosen; Brenner, Max; Zhang, Xuemei; Laragione, Teresina; Tai, Shuaishuai; Li, Yanhong; Bu, Junjie; Yin, Ye; Shah, Anish A.; Kwan, Kevin; Li, Yingrui; Jun, Wang; Gulko, Pércio S.

2013-01-01

DA (D-blood group of Palm and Agouti, also known as Dark Agouti) and F344 (Fischer) are two inbred rat strains with differences in several phenotypes, including susceptibility to autoimmune disease models and inflammatory responses. While these strains have been extensively studied, little information is available about the DA and F344 genomes, as only the Brown Norway (BN) and spontaneously hypertensive rat strains have been sequenced to date. Here we report the sequencing of the DA and F344 genomes using next-generation Illumina paired-end read technology and the first de novo assembly of a rat genome. DA and F344 were sequenced with an average depth of 32-fold, covered 98.9% of the BN reference genome, and included 97.97% of known rat ESTs. New sequences could be assigned to 59 million positions with previously unknown data in the BN reference genome. Differences between DA, F344, and BN included 19 million positions in novel scaffolds, 4.09 million single nucleotide polymorphisms (SNPs) (including 1.37 million new SNPs), 458,224 short insertions and deletions, and 58,174 structural variants. Genetic differences between DA, F344, and BN, including high-impact SNPs and short insertions and deletions affecting >2500 genes, are likely to account for most of the phenotypic variation between these strains. The new DA and F344 genome sequencing data should facilitate gene discovery efforts in rat models of human disease. PMID:23695301

Whole-genome sequences of DA and F344 rats with different susceptibilities to arthritis, autoimmunity, inflammation and cancer.

PubMed

Guo, Xiaosen; Brenner, Max; Zhang, Xuemei; Laragione, Teresina; Tai, Shuaishuai; Li, Yanhong; Bu, Junjie; Yin, Ye; Shah, Anish A; Kwan, Kevin; Li, Yingrui; Jun, Wang; Gulko, Pércio S

2013-08-01

DA (D-blood group of Palm and Agouti, also known as Dark Agouti) and F344 (Fischer) are two inbred rat strains with differences in several phenotypes, including susceptibility to autoimmune disease models and inflammatory responses. While these strains have been extensively studied, little information is available about the DA and F344 genomes, as only the Brown Norway (BN) and spontaneously hypertensive rat strains have been sequenced to date. Here we report the sequencing of the DA and F344 genomes using next-generation Illumina paired-end read technology and the first de novo assembly of a rat genome. DA and F344 were sequenced with an average depth of 32-fold, covered 98.9% of the BN reference genome, and included 97.97% of known rat ESTs. New sequences could be assigned to 59 million positions with previously unknown data in the BN reference genome. Differences between DA, F344, and BN included 19 million positions in novel scaffolds, 4.09 million single nucleotide polymorphisms (SNPs) (including 1.37 million new SNPs), 458,224 short insertions and deletions, and 58,174 structural variants. Genetic differences between DA, F344, and BN, including high-impact SNPs and short insertions and deletions affecting >2500 genes, are likely to account for most of the phenotypic variation between these strains. The new DA and F344 genome sequencing data should facilitate gene discovery efforts in rat models of human disease.

Use of micro-positron emission tomography with (18)F-fallypride to measure the levels of dopamine receptor-D2 and (18)F-FDG as molecular imaging tracer in the pituitary glands and prolactinomas of Fischer-344 rats.

PubMed

Li, Ping; Gui, Songbai; Cao, Lei; Gao, Hua; Bai, Jiwei; Li, Chuzhong; Zhang, Yazhuo

2016-01-01

Dopamine receptor-D2 (DRD2) is the most important drug target in prolactinoma. The aim of this current study was to investigate the role of using micro-positron emission tomography (micro-PET) with (18)F-fallypride and (18)F-fluorodeoxyglucose ((18)F-FDG) as molecular imaging tracer in the pituitary glands and prolactinomas of Fischer-344 (F344) rats and detect the difference of the levels of DRD2 in the pituitary glands and prolactinomas of F344 rat prolactinoma models. Female F344 rat prolactinoma models were established by subcutaneous administration of 15 mg 17β-estradiol for 8 weeks. The growth of tumors was monitored by the small-animal magnetic resonance imaging and micro-PET. A series of molecular biological experiments were also performed 4 and 6 weeks after pump implantation. The micro-PET molecular imaging with (18)F-fallypride revealed a decreased expression of DRD2 in F344 rat prolactinoma models, but the micro-PET molecular imaging with (18)F-FDG presented an increased uptake in the prolactinoma compared with the pituitary gland. A decreasing trend of levels of DRD2 in F344 rat prolactinoma models was also detected by molecular biological experiments. From this, we can conclude that micro-PET with (18)F-fallypride and (18)F-FDG can be used to assess tumorigenesis of the prolactinomas in vivo and molecular imaging detection of DRD2 level in prolactinoma may be an indication of treatment effect in the animal experiment.

Changes in obestatin gene and GPR39 receptor expression in peripheral tissues of rat models of obesity, type 1 and type 2 diabetes.

PubMed

Kolodziejski, Pawel Antoni; Pruszynska-Oszmalek, Ewa; Sassek, Maciej; Kaczmarek, Przemyslaw; Szczepankiewicz, Dawid; Billert, Maria; Mackowiak, Paweł; Strowski, Mathias Z; Nowak, Krzysztof W

2017-04-01

Obestatin has a role in regulating food intake and energy expenditure, but the roles of obestatin and the GPR39 receptor in obesity and type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively) are not well understood. The aim of the present study was to investigate changes in obestatin and GPR39 in pathophysiological conditions like obesity, T1DM, and T2DM. Using rat models of diet-induced obesity (DIO), T1DM and T2DM (n = 14 per group), obestatin, its precursor protein preproghrelin, and GPR39 expression was investigated in tissues involved in glucose and lipid homeostasis regulation. Furthermore, serum obestatin and ghrelin concentrations were determined. Serum obestatin concentrations were positively correlated with glucagon (r = 0.6456; P < 0.001) and visfatin (r = 0.5560; P < 0.001), and negatively correlated with insulin (r = -0.4362; P < 0.05), adiponectin (r = -0.3998; P < 0.05), and leptin (r = -0.4180; P < 0.05). There were differences in GPR39 and preproghrelin expression in the three animal models. Hepatic GPR39 and preproghrelin mRNA expression was greater in T1DM, T2DM, and obese rats than in lean controls, whereas pancreatic GPR39 mRNA and protein and preproghrelin mRNA expression was decreased in T1DM, T2DM, and DIO rats. Higher GPR39 and preproghrelin protein and mRNA levels were found in adipose tissues of T1DM compared with control. In adipose tissues of T2DM and DIO rats, GPR39 protein levels were lower than in lean or T1DM rats. Preproghrelin mRNA was higher in adipose tissues of T1DM, T2DM, and DIO than lean rats. We hypothesize that changes in obestatin, GPR39, and ghrelin may contribute to metabolic abnormalities in T1DM, T2DM, and obesity. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Age-related increases in F344 rat intestine microsomal quercetin glucuronidation

USDA-ARS?s Scientific Manuscript database

The objective of this study was to establish the extent age modifies intestinal quercetin glucuronidation capacity. Pooled microsomal fractions of three equidistant small intestine (SI) segments from 4, 12, 18, and 28 mo male F344 rats (n=8/group) were employed to model the enzyme kinetics of UDP-gl...

The translocator protein radioligand 18F-DPA-714 monitors antitumor effect of erufosine in a rat 9L intracranial glioma model.

PubMed

Awde, Ali R; Boisgard, Raphaël; Thézé, Benoit; Dubois, Albertine; Zheng, Jinzi; Dollé, Frédéric; Jacobs, Andreas H; Tavitian, Bertrand; Winkeler, Alexandra

2013-12-01

On the one hand, the translocator protein (TSPO) radioligand N,N-diethyl-2-(2-(4-(2-(18)F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ((18)F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkylphosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosis-resistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using (18)F-DPA-714 PET. In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with (18)F-DPA-714 for the time of treatment. A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in (18)F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive microglia/macrophages and glial fibrillary acidic protein-positive astrocytes. Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using (18)F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas.

The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome.

PubMed

Steiner, Michel A; Sciarretta, Carla; Pasquali, Anne; Jenck, Francois

2013-01-01

The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS). Rats were fed either standard chow (SC) or a cafeteria (CAF) diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S) diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks) and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure) were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% vs. controls) and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG) plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this model.

Generation of muscular dystrophy model rats with a CRISPR/Cas system.

PubMed

Nakamura, Katsuyuki; Fujii, Wataru; Tsuboi, Masaya; Tanihata, Jun; Teramoto, Naomi; Takeuchi, Shiho; Naito, Kunihiko; Yamanouchi, Keitaro; Nishihara, Masugi

2014-07-09

Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder caused by mutations in the Dmd gene encoding Dystrophin. DMD model animals, such as mdx mice and canine X-linked muscular dystrophy dogs, have been widely utilized in the development of a treatment for DMD. Here, we demonstrate the generation of Dmd-mutated rats using a clustered interspaced short palindromic repeats (CRISPR)/Cas system, an RNA-based genome engineering technique that is also adaptive to rats. We simultaneously targeted two exons in the rat Dmd gene, which resulted in the absence of Dystrophin expression in the F0 generation. Dmd-mutated rats exhibited a decline in muscle strength, and the emergence of degenerative/regenerative phenotypes in the skeletal muscle, heart, and diaphragm. These mutations were heritable by the next generation, and F1 male rats exhibited similar phenotypes in their skeletal muscles. These model rats should prove to be useful for developing therapeutic methods to treat DMD.

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F, MOUSE

EPA Science Inventory

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F1 MOUSE.

Bromodichloromethane (BDCM) has been shown to produce kidney and large bowel tumors in both male and female F344/N rats, kidney tumors in male B6C3F 1 mice and ...

A Neurobehavioral Study of Rats Using a Model Perfluorinated Acid, NDFDA.

DTIC Science & Technology

1982-07-13

1 AD-Alla 560 DISTICT OFVCOLUMBIAUUNIV WASHIrGTON, DEPT OF BIOLOGY F662 NEUROEHA IORAL STUDY OF RATS USING A MODEL PERFLUORINATEO AC--ETCU U JUL A2 I...S. TYPE OF REPORT & PERIOD COVERED A NEUROBEHAVIORAL STUDY OF RATS USING A MODEL Final Report PERFLUORINATED ACID, NDFDA ___nu; 6. PERFORMING O IG...OPT0 Y&’ A@E(ben Des Btntete AFOSR-TR" FINAL RPORT A NEUROBUEIAVIORAL STUDY ON RATS USING A MODEL PERFLUORINATED ACID , NDFDA Prepared by: Inez R

Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression.

PubMed

Levit, Alexander; Regis, Aaron M; Garabon, Jessica R; Oh, Seung-Hun; Desai, Sagar J; Rajakumar, Nagalingam; Hachinski, Vladimir; Agca, Yuksel; Agca, Cansu; Whitehead, Shawn N; Allman, Brian L

2017-08-30

Alzheimer disease (AD) and stroke coexist and interact; yet how they interact is not sufficiently understood. Both AD and basal ganglia stroke can impair behavioural flexibility, which can be reliably modeled in rats using an established operant based set-shifting test. Transgenic Fischer 344-APP21 rats (TgF344) overexpress pathogenic human amyloid precursor protein (hAPP) but do not spontaneously develop overt pathology, hence TgF344 rats can be used to model the effect of vascular injury in the prodromal stages of Alzheimer disease. We demonstrate that the injection of endothelin-1 (ET1) into the dorsal striatum of TgF344 rats (Tg-ET1) produced an exacerbation of behavioural inflexibility with a behavioural phenotype that was distinct from saline-injected wildtype & TgF344 rats as well as ET1-injected wildtype rats (Wt-ET1). In addition to profiling the types of errors made, interpolative modeling using logistic exposure-response regression provided an informative analysis of the timing and efficiency of behavioural flexibility. During set-shifting, Tg-ET1 committed fewer perseverative errors than Wt-ET1. However, Tg-ET1 committed significantly more regressive errors and had a less efficient strategy change than all other groups. Thus, behavioural flexibility was more vulnerable to striatal ischemic injury in TgF344 rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Carcinogenicity of acrylamide in B6C3F(1) mice and F344/N rats from a 2-year drinking water exposure.

PubMed

Beland, Frederick A; Mellick, Paul W; Olson, Greg R; Mendoza, Maria C B; Marques, M Matilde; Doerge, Daniel R

2013-01-01

Acrylamide is a component of roasted coffee and certain baked and fried carbohydrate-rich foods prepared at high temperatures. We have assessed the carcinogenicity of acrylamide in male and female B6C3F(1) mice and F344/N rats administered 0, 0.0875, 0.175, 0.35, or 0.70mM acrylamide in the drinking water ad libitum for 2 years. Acrylamide caused significant dose-related decreasing trends in the body weights of F344/N rats. Acrylamide administration resulted in significant dose-related decreasing trends in survival in both sexes of B6C3F(1) mice and in female F344/N rats. Histopathological analyses indicated significant dose-related increases in Harderian gland and lung tumors in male and female B6C3F(1) mice. Male B6C3F(1) mice also had a significantly increased incidence of forestomach tumors, while female B6C3F(1) mice had significant dose-related increases in mammary gland, ovary, and skin tumors. In male and female F344/N rats, there were significant increases in thyroid tumors. Male F344/N rats also had significant dose-related increases in testes, heart, and pancreas tumors, while female F344 rats demonstrated significant increases in clitoral gland, mammary gland, oral cavity, and skin tumors. These results, combined with previous mechanistic studies, provide strong support for the concept that acrylamide is activated to a carcinogen through metabolism to glycidamide. Published by Elsevier Ltd.

Antidiabetic and antihiperlipidemic effect of Andrographis paniculata (Burm. f.) Nees and andrographolide in high-fructose-fat-fed rats

PubMed Central

Nugroho, Agung Endro; Andrie, Mohamad; Warditiani, Ni Kadek; Siswanto, Eka; Pramono, Suwidjiyo; Lukitaningsih, Endang

2012-01-01

Objectives: Andrographis paniculata (Burm. f.) Nees originates from India and grows widely in many areas in Southeast Asian countries. Andrographis paniculata (Burm. f.) Nees has shown an antidiabetic effect in type 1 DM rats. The present study investigates the purified extract of the plant and its active compound andrographolide for antidiabetic and antihyperlipidemic effects in high-fructose-fat-fed rats, a model of type 2 DM rats. Materials and Methods: Hyperglycemia in rats was induced by high-fructose-fat diet containing 36% fructose, 15% lard, and 5% egg yolks in 0.36 g/200 gb.wt. 55 days. The rats were treated with the extract or test compound on the 50th day. Antidiabetic activity was measured by estimating mainly the pre– and postprandial blood glucose levels and other parameters such as cholesterol, LDL, triglyceride, and body weight. Results: The purified extract and andrographolide significantly (P<0.05) decreased the levels of blood glucose, triglyceride, and LDL compared to controls. However, no changes were observed in serum cholesterol and rat body weight. Metformin also showed similar effects on these parameters. Conclusions: Andrographis paniculata (Burm. f.) Nees or its active compound andrographolide showed hypoglycemic and hypolipidemic effects in high-fat-fructose-fed rat. PMID:22701250

Systemic functional expression of N-acetyltransferase polymorphism in the F344 Nat2 congenic rat

PubMed Central

Hein, David W.; Bendaly, Jean; Neale, Jason R.; Doll, Mark A.

2008-01-01

Rat lines congenic for the rat N-acetyltransferase 2 [(RAT)Nat2] gene were constructed and characterized. F344 (homozygous Nat2 rapid) males were mated to WKY (homozygous Nat2 slow) females to produce heterozygous F1. F1 females were then backcrossed to F344 males. Heterozygous acetylator female progeny from this and each successive backcross were identified by rat Nat2 genotyping and mated with F344 rapid acetylator males. Following ten generations of backcross mating, heterozygous acetylator brother/sister progeny were mated to produce the homozgygous rapid and slow acetylator Nat2 congenic rat lines. p-Aminobenzoic acid (selective for rat NAT2) and 4-aminobiphenyl N-acetyltransferase activities were expressed in all tissues examined (liver, lung, esophagus, stomach, small intestine, colon, pancreas, kidney, skin, leukocytes, and urinary bladder in male and female rats and in breast of female and prostate of male rats). NAT2 expression in rat extrahepatic tissues was much higher than in liver. In each tissue, activities were Nat2-genotype dependent, with highest levels in homozygous rapid acetylators, intermediate levels in heterozygous acetylators, and lowest in homozygous slow acetylators. Sulfamethazine (selective for rat NAT1) N-acetyltransferase activities were observed in all tissues examined in both male and female rats except for breast (females), bladder and leukocytes. In each tissue, the activity was Nat2-genotype independent, with similar levels in homozygous rapid, heterozygous, and homozygous slow acetylators. These congenic rat lines are useful to investigate the role of NAT2 genetic polymorphism in susceptibility to cancers related to arylamine carcinogen exposures. PMID:18799801

Therapeutic effects of total alkaloids of Tripterygium wilfordii Hook f. on collagen-induced arthritis in rats.

PubMed

Zhang, Yuqin; Xu, Wei; Li, Huang; Zhang, Xun; Xia, Yufa; Chu, Kedan; Chen, Lidian

2013-02-13

Tripterygium wilfordii Hook f. is one of Traditional Chinese Medicines which is commonly used to treat rheumatoid arthritis (RA). The total alkaloids were the main constituent part of Tripterygium wilfordii Hook f. It has a great significance to study the effects of the total alkaloids of Tripterygium wilfordii Hook f. (ATW) on RA. This paper aims at investigating the therapeutic effect of ATW on RA and its possible mechanism, and providing a theoretical and experimental basis for the clinical use of ATW. The model of wistar rats of type II collagen-induced arthritis (CIA) was made, and the rats were perfused a stomach with ATW for 4 weeks continuously. Then the levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-, in the serum of CIA rats were detected by enzyme linked immunosorbent assay (ELISA), and the joint pathological section of CIA rats was observed by hematoxylin and eosin (HE) staining method and the expression of IL-6, IL-8, nuclear factor kappa B (NF-κB), TNF-α were measure by immunohistochemistry staining method. Compared with model group, ATW could significantly reduce paw swelling and suppresse articular cartilage degenerated. The results also found that there was significant reduction levels of IL-6, IL-8 and TNF-α in serum of CIA rats treated with ATW and ATW inhibited the expression of IL-6, IL-8, NF-κB, TNF-α in synovial tissue. ATW not only could inhibit the symptom of CIA rats significantly but also could inhibit the production of IL-6, IL-8, TNF-α in serum and the expression of IL-6, IL-8, NF-κB and TNF-α in synovial tissue targeting the inflammatory. ATW would be a drug as a novel botanical drug for the treatment of RA. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

CARBONYL SULFIDE INHALATION PRODUCES BRAIN LESIONS IN F344 RATS.

EPA Science Inventory

Carbonyl sulfide (COS) is an intermediate in the production of pesticides and herbicides, and is a metabolite of the neurotoxicant carbon disulfide. The potential neurotoxicity of inhaled COS was investigated in F344 rats. Male rats were exposed to 0, 75, 150, 300, or 600 ppm COS...

Orchidectomy of middle-aged rats decreases liver deiodinase 1 and pituitary deiodinase 2 activity.

PubMed

Sosic-Jurjevic, Branka; Filipovic, Branko; Renko, Kostja; Ajdzanovic, Vladimir; Manojlovic-Stojanoski, Milica; Milosevic, Verica; Köhrle, Josef

2012-11-01

Endogenous androgens are involved in regulation of thyroid function and metabolism of thyroid hormones. As serum testosterone level progressively declines with age, this regulation may change. We tested how androgen deprivation, achieved by orchidectomy, affects thyroid homeostasis in middle-aged rats. Fifteen-month-old Wistar rats were orchidectomized (Orx) or sham-operated under ketamine anesthesia (15 mg/kg body weight). Five weeks after the surgery, animals were decapitated. Thyroids were used for histomorphometric and ultrastructural examinations and together with livers and pituitaries for real-time quantitative PCR and deiodinase (DIO) activity measurements. Serum testosterone, TSH, l-thyroxine (T(4)), and cholesterol (Chol) levels were determined. As expected, middle-aged control rats had lower (P<0.05) testosterone and T(4) compared with 3-month-old males. In the Orx middle-aged group, we detected diminished serum testosterone (P<0.05), no change in TSH and T(4) levels, and higher Chol level (P<0.05), in comparison with age-matched controls. Histomorphometric analysis of thyroid tissue revealed decreased relative volume densities of follicles and colloid (P<0.05). Relevant gene expressions and DIO1 enzyme activity were not changed in the thyroids of Orx rats. Liver Dio1 gene expression and DIO1 activity were decreased (P<0.05) in comparison with the control values. Pituitary levels of TSHβ, Dio1, and Dio2 mRNAs did not change, while DIO2 activity decreased (P<0.05). In conclusion, orchidectomy of middle-aged rats affected thyroid structure with no effect on serum T(4) and TSH. However, decreased liver DIO1 and pituitary DIO2 enzyme activities indicate compensatory-adaptive changes in local T(3) production.

Registering and Analyzing Rat fMRI Data in the Stereotaxic Framework by Exploiting Intrinsic Anatomical Features

PubMed Central

Lu, Hanbing; Scholl, Clara A.; Zuo, Yantao; Demny, Steven; Rea, William; Stein, Elliot A.; Yang, Yihong

2009-01-01

The value of analyzing neuroimaging data on a group level has been well established in human studies. However, there is no standard procedure for registering and analyzing fMRI data into common space in rodent functional magnetic resonance imaging (fMRI) studies. An approach for performing rat imaging data analysis in the stereotaxic framework is presented. This method is rooted in the biological observation that the skull shape and size of rat brain are essentially the same as long as their weights are within certain range. Registration is performed using rigid-body transformations without scaling or shearing, preserving the unique properties of the stable shape and size inherent in rat brain structure. Also, it does not require brain tissue masking, and is not biased towards surface coil sensitivity profile. A standard rat brain atlas is used to facilitate the identification of activated areas in common space, allowing accurate region-of-interest (ROI) analysis. This technique is evaluated from a group of rats (n = 11) undergoing routine MRI scans; the registration accuracy is estimated to be within 400 μm. The analysis of fMRI data acquired with an electrical forepaw stimulation model demonstrates the utility of this technique. The method is implemented within the AFNI framework and can be readily extended to other studies. PMID:19608368

Increased 18F-FDG Uptake Is Predictive of Rupture in a Novel Rat Abdominal Aortic Aneurysm Rupture Model

PubMed Central

English, Sean J.; Piert, Morand R.; Diaz, Jose A.; Gordon, David; Ghosh, Abhijit; D'Alecy, Louis G.; Whitesall, Steven E.; Sharma, Ashish K.; DeRoo, Elise P.; Watt, Tessa; Su, Gang; Henke, Peter K.; Eliason, Jonathan L.; Ailawadi, Gorav; Upchurch, Gilbert R.

2015-01-01

Objective To determine whether 18F-fluorodeoxyglucose (18F-FDG) micro–positron emission tomography (micro-PET) can predict abdominal aortic aneurysm (AAA) rupture. Background An infrarenal AAA model is needed to study inflammatory mechanisms that drive rupture. 18F-FDG PET can detect vascular inflammation in animal models and patients. Methods After exposing Sprague-Dawley rats to intra-aortic porcine pancreatic elastase (PPE) (12 U/mL), AAA rupture was induced by daily, subcutaneous, β-aminopropionitrile (BAPN, 300 mg/kg, N = 24) administration. Negative control AAA animals (N = 15) underwent daily saline subcutaneous injection after PPE exposure. BAPN-exposed animals that did not rupture served as positive controls [nonruptured AAA (NRAAA) 14d, N = 9]. Rupture was witnessed using radiotelemetry. Maximum standard uptakes for 18F-FDG micro-PET studies were determined. Aortic wall PAI-1, uPA, and tPA concentrations were determined by western blot analyses. Interleukin (IL)-1β, IL-6, IL-10, and MIP-2 were determined by Bio-Plex bead array. Neutrophil and macrophage populations per high-power field were quantified. Matrix metalloproteinase (MMP) activities were determined by zymography. Results When comparing ruptured AAA (RAAA) to NRAAA 14d animals, increased focal 18F-FDG uptakes were detected at subsequent sites of rupture (P = 0.03). PAI-1 expression was significantly less in RAAA tissue (P = 0.01), with comparable uPA and decreased tPA levels (P = 0.02). IL-1β (P = 0.04), IL-6 (P = 0.001), IL-10 (P = 0.04), and MIP-2 (P = 0.02)expression, neutrophil (P = 0.02) and macrophage presence (P = 0.002), and MMP9 (P < 0.0001) activity were increased in RAAA tissue. Conclusions With this AAA rupture model, increased prerupture 18F-FDG uptake on micro-PET imaging was associated with increased inflammation in the ruptured AAA wall. 18F-FDG PET imaging may be used to monitor inflammatory changes before AAA rupture. PMID:24651130

Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models.

PubMed

Kroll, Tina; Elmenhorst, David; Matusch, Andreas; Wedekind, Franziska; Weisshaupt, Angela; Beer, Simone; Bauer, Andreas

2013-08-01

While the selective 5-hydroxytryptamine type 2a receptor (5-HT2AR) radiotracer [18F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT2ARs with positron emission tomography (PET) in albino rats. Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite-corrected arterial input functions. In vivo 5-HT2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals. Overall brain uptake of [18F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals. [18F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage.

Acute toxicity of sodium formononetin-3'-sulphonate (Sul-F) in Sprague-Dawley rats and Beagle dogs.

PubMed

Li, Guisheng; Yang, Menglin; Hao, Xinmiao; Li, Chunmei; Gao, Yonglin; Tao, Jun

2015-11-01

Sodium formononetin-3'-sulphonate (Sul-F, C16H12O7SNa), a water-soluble derivate of formononetin, provided significant neuroprotective and cardioprotective effects in vitro and in vivo. The aim of this study was to evaluate acute toxicity of Sul-F after intravenous administration in rats and dogs. Animals were intravenously administered Sul-F at the maximum dosage of 2000 mg/kg and 1000 mg/kg in rats and dogs, respectively. After treatment, rats and dogs were monitored for 14 days. Body weight, clinical signs, the hematological and biochemical findings, and pathological examination were performed. The results showed that no Sul-F related clinical signs of toxicity or mortality were observed in rats. Of note, the transient vomiting was found in dogs after Sul-F administration 15-20 min. In addition, a white crystal, non-metabolic Sul-F, was found after urine volatilization in Sul-F treated animals (rats and dogs). However, neither biochemical findings nor histopathological changes due to Sul-F treatment were found in tests. In summary, the present study results provided practical guidance for selecting a safe dosage for Sul-F further studies and clinical trials in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

{sup 19}F NMR measurements of NO production in hypertensive ISIAH and OXYS rats

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

Bobko, Andrey A.; Sergeeva, Svetlana V.; Bagryanskaya, Elena G.

2005-05-06

Recently we demonstrated the principal possibility of application of {sup 19}F NMR spin-trapping technique for in vivo {sup {center_dot}}NO detection [Free Radic. Biol. Med. 36 (2004) 248]. In the present study, we employed this method to elucidate the significance of {sup {center_dot}}NO availability in animal models of hypertension. In vivo {sup {center_dot}}NO-induced conversion of the hydroxylamine of the fluorinated nitronyl nitroxide (HNN) to the hydroxylamine of the iminonitroxide (HIN) in hypertensive ISIAH and OXYS rat strains and normotensive Wistar rat strain was measured. Significantly lower HIN/HNN ratios were measured in the blood of the hypertensive rats. The NMR data weremore » found to positively correlate with the levels of nitrite/nitrate evaluated by Griess method and negatively correlate with the blood pressure. In comparison with other traditionally used methods {sup 19}F NMR spectroscopy allows in vivo evaluation of {sup {center_dot}}NO production and provides the basis for in vivo {sup {center_dot}}NO imaging.« less

Comparative disposition of (R)-(+)-pulegone in B6C3F1 mice and F344 rats.

PubMed

Chen, L-J; Lebetkin, E H; Burka, L T

2003-07-01

Pulegone is a monoterpene ketone that is usually associated with the herb pennyroyal but is also found in the essential oils from many other mint species. It is the major constituent of pennyroyal oil. Pennyroyal is used as a flavoring and fragrance and as an herbal medicine to induce menstruation and abortion. A disposition study of 14C-pulegone in B6C3F1 mice and F344 rats has been conducted at doses from 0.8 to 80 mg/kg. Mice excrete 85 to 100% of the dose in 24 h. Rats excrete only 59 to 81% of the administered radioactivity in the same time, primarily in urine and feces, with a trace in respired air. Consequently, tissue concentrations are lower in mice than in rats. Male rats tend to have higher tissue concentrations, especially in kidney, than female rats have, but this sex difference is not seen in mice. The residual radioactivity at 24 h demonstrates potential for accumulation of pulegone-derived material in several tissues following multiple doses. The metabolic profile is complex in both species, with at least three pathways involving hydroxylation, reduction, or conjugation with glutathione as first steps. Mercapturic acid pathway metabolites were detected in bile in mice and both bile and urine in rats.

ToF-SIMS cluster ion imaging of hippocampal CA1 pyramidal rat neurons

NASA Astrophysics Data System (ADS)

Francis, J. T.; Nie, H.-Y.; Taylor, A. R.; Walzak, M. J.; Chang, W. H.; MacFabe, D. F.; Lau, W. M.

2008-12-01

Recent studies have demonstrated the power of time-of-flight secondary ion mass spectrometry (ToF-SIMS) cluster ion imaging to characterize biological structures, such as that of the rat central nervous system. A large number of the studies to date have been carried out on the "structural scale" imaging several mm 2 using mounted thin sections. In this work, we present our ToF-SIMS cluster ion imaging results on hippocampal rat brain neurons, at the cellular and sub-cellular levels. As a part of an ongoing investigation to examine gut linked metabolic factors in autism spectrum disorders using a novel rat model, we have observed a possible variation in hippocampal Cornu ammonis 1 (CA1) pyramidal neuron geometry in thin, paraformaldehyde fixed brain sections. However, the fixation process alters the tissue matrix such that much biochemical information appears to be lost. In an effort to preserve as much as possible this original information, we have established a protocol using unfixed thin brain sections, along with low dose, 500 eV Cs + pre-sputtering that allows imaging down to the sub-cellular scale with minimal sample preparation.

Eicosapentenoic Acid Attenuates Allograft Rejection in an HLA-B27/EGFP Transgenic Rat Cardiac Transplantation Model.

PubMed

Liu, Zhong; Hatayama, Naoyuki; Xie, Lin; Kato, Ken; Zhu, Ping; Ochiya, Takahiro; Nagahara, Yukitoshi; Hu, Xiang; Li, Xiao-Kang

2012-01-01

The development of an animal model bearing definite antigens is important to facilitate the evaluation and modulation of specific allo-antigen responses after transplantation. In the present study, heterotopic cardiac transplantation was performed from F344/EGFPTg and F344/HLA-B27Tg rats to F344 rats. The F344 recipients accepted the F344/EGFPTg transplants, whereas they rejected the cardiac tissue from the F344/HLA-B27Tg rats by 39.4 ± 6.5 days, due to high production of anti-HLA-B27 IgM- and IgG-specific antibodies. In addition, immunization of F344 rats with skin grafts from F344/HLA-B27Tg rats resulted in robust production of anti- HLA-B27 IgM and IgG antibodies and accelerated the rejection of a secondary cardiac allograft (7.4 ± 1.9 days). Of interest, the F344 recipients rejected cardiac grafts from double transgenic F344/HLA-B27&EGFPTg rats within 9.0 ± 3.2 days, and this was associated with a significant increase in the infiltration of lymphocytes by day 7, suggesting a role for cellular immune rejection. Eicosapentenoic acid (EPA), one of the ω-3 polyunsaturated fatty acids in fish oil, could attenuate the production of anti-HLA IgG antibodies and B-cell proliferation, significantly prolonging double transgenic F344HLA-B27&EGFPTg to F344 rat cardiac allograft survival (36.1 ± 13.6 days). Moreover, the mRNA expression in the grafts was assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), revealing an increase in the expression of the HO-1, IL-10, TGF-β, IDO, and Foxp3 genes in the EPA-treated group. Hence, our data indicate that HLA-B27 and/or GFP transgenic proteins are useful for establishing a unique animal transplantation model to clarify the mechanism underlying the allogeneic cellular and humoral immune response, in which the transplant antigens are specifically presented. Furthermore, we also demonstrated that EPA was effective in the treatment of rat cardiac allograft rejection and may allow the development of

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

PubMed Central

Singleton, WG; Collins, AM; Bienemann, AS; Killick-Cole, CL; Haynes, HR; Asby, DJ; Butts, CP; Wyatt, MJ; Barua, NU; Gill, SS

2017-01-01

Background The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood–brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). Materials and methods The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. Results Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P<0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. Conclusion CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic. PMID:28260886

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model.

PubMed

Singleton, W G; Collins, A M; Bienemann, A S; Killick-Cole, C L; Haynes, H R; Asby, D J; Butts, C P; Wyatt, M J; Barua, N U; Gill, S S

2017-01-01

The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P <0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.

Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin?

PubMed

Trevaskis, James L; Turek, Victoria F; Griffin, Peter S; Wittmer, Carrie; Parkes, David G; Roth, Jonathan D

2010-05-11

Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5microg/kg) and/or CCK (5microg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300microg/kg/d) and/or CCK (100 or 300microg/kg/d) were subcutaneously infused for 7days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300microg/kg/d) to leptin (125microg/kg/d), and to the combination of amylin (50microg/kg/d) and leptin (125microg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14days. Infusion of amylin/leptin/CCK for 14days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem. Copyright 2010 Elsevier Inc. All rights reserved.

Three members of the iodothyronine deiodinase family, dio1, dio2 and dio3, are expressed in spatially and temporally specific patterns during metamorphosis of the flounder, Paralichthys olivaceus.

PubMed

Itoh, Kae; Watanabe, Kohei; Wu, Xiaoming; Suzuki, Tohru

2010-07-01

Flounder metamorphosis, marked by eye migration, lateralized pigmentation, and tissue differentiation in the stomach and skeletal muscle, is stimulated by thyroid hormone (TH). It is known that tri-iodothyronine (T3) produced by iodothyronine deiodinase type-1 (Dio1) from thyroxine (T4) enters the blood, whereas T3 produced by Dio2 penetrates into the nucleus of the Dio2-expressing cells, and then Dio3 inactivates both T4 and T3. To better understand the distinct functions of these three deiodinases in T3 regulation during flounder metamorphosis, we examined the tissue expression patterns of dio1, dio2, and dio3 in larvae of the Japanese flounder, Paralichthys olivaceus, by section in situ hybridization (SISH). We found that each deiodinase is expressed in a spatially and temporally specific pattern. dio1 is expressed in liver parenchymal cells from pro-metamorphosis to early climax, while dio2 is expressed in limited regions of the eyes, tectum, and skeletal muscles from pro-metamorphosis to post-climax. Considering these findings together with reports on other vertebrates, we predict that the liver cells expressing dio1 supply T3 to the blood, and that this systemic T3 synchronizes metamorphosis of differentiating tissues throughout the larval body, whereas the eyes, tectum, and skeletal muscles autonomously produce additional T3 for local tissue differentiation. Finally, dio3 expression is detected in skeletal muscle and gastric gland blastemas, which both undergo marked tissue differentiation at metamorphic climax. We hypothesize that dio3 expression protects these tissues from basal T3 levels early in metamorphosis, ensuring, together with the T3 surge from the liver, the synchronization of tissue differentiation at metamorphic climax.

In Vivo Imaging of Glial Activation after Unilateral Labyrinthectomy in the Rat: A [18F]GE180-PET Study.

PubMed

Zwergal, Andreas; Günther, Lisa; Brendel, Matthias; Beck, Roswitha; Lindner, Simon; Xiong, Guoming; Eilles, Eva; Unterrainer, Marcus; Albert, Nathalie Lisa; Becker-Bense, Sandra; Brandt, Thomas; Ziegler, Sibylle; la Fougère, Christian; Dieterich, Marianne; Bartenstein, Peter

2017-01-01

The functional relevance of reactive gliosis for recovery from acute unilateral vestibulopathy is unknown. In the present study, glial activation was visualized in vivo by [ 18 F]GE180-PET in a rat model of unilateral labyrinthectomy (UL) and compared to behavioral vestibular compensation (VC) overtime. 14 Sprague-Dawley rats underwent a UL by transtympanic injection of bupivacaine/arsenilate, 14 rats a SHAM UL (injection of normal saline). Glial activation was depicted with [ 18 F]GE180-PET and ex vivo autoradiography at baseline and 7, 15, 30 days after UL/SHAM UL. Postural asymmetry and nystagmus were registered at 1, 2, 3, 7, 15, 30 days after UL/SHAM UL. Signs of vestibular imbalance were found only after UL, which significantly decreased until days 15 and 30. In parallel, [ 18 F]GE180-PET and ex vivo autoradiography depicted glial activation in the ipsilesional vestibular nerve and nucleus on days 7 and 15 after UL. Correlation analysis revealed a strong negative association of [ 18 F]GE180 uptake in the ipsilesional vestibular nucleus on day 7 with the rate of postural recovery ( R  = -0.90, p  < 0.001), suggesting that glial activation accelerates VC. In conclusion, glial activation takes place in the ipsilesional vestibular nerve and nucleus within the first 30 days after UL in the rat and can be visualized in vivo by [ 18 F]GE180-PET.

In Vivo Imaging of Glial Activation after Unilateral Labyrinthectomy in the Rat: A [18F]GE180-PET Study

PubMed Central

Zwergal, Andreas; Günther, Lisa; Brendel, Matthias; Beck, Roswitha; Lindner, Simon; Xiong, Guoming; Eilles, Eva; Unterrainer, Marcus; Albert, Nathalie Lisa; Becker-Bense, Sandra; Brandt, Thomas; Ziegler, Sibylle; la Fougère, Christian; Dieterich, Marianne; Bartenstein, Peter

2017-01-01

The functional relevance of reactive gliosis for recovery from acute unilateral vestibulopathy is unknown. In the present study, glial activation was visualized in vivo by [18F]GE180-PET in a rat model of unilateral labyrinthectomy (UL) and compared to behavioral vestibular compensation (VC) overtime. 14 Sprague-Dawley rats underwent a UL by transtympanic injection of bupivacaine/arsenilate, 14 rats a SHAM UL (injection of normal saline). Glial activation was depicted with [18F]GE180-PET and ex vivo autoradiography at baseline and 7, 15, 30 days after UL/SHAM UL. Postural asymmetry and nystagmus were registered at 1, 2, 3, 7, 15, 30 days after UL/SHAM UL. Signs of vestibular imbalance were found only after UL, which significantly decreased until days 15 and 30. In parallel, [18F]GE180-PET and ex vivo autoradiography depicted glial activation in the ipsilesional vestibular nerve and nucleus on days 7 and 15 after UL. Correlation analysis revealed a strong negative association of [18F]GE180 uptake in the ipsilesional vestibular nucleus on day 7 with the rate of postural recovery (R = −0.90, p < 0.001), suggesting that glial activation accelerates VC. In conclusion, glial activation takes place in the ipsilesional vestibular nerve and nucleus within the first 30 days after UL in the rat and can be visualized in vivo by [18F]GE180-PET. PMID:29312111

Enhanced Thalamic Functional Connectivity with No fMRI Responses to Affected Forelimb Stimulation in Stroke-Recovered Rats.

PubMed

Shim, Woo H; Suh, Ji-Yeon; Kim, Jeong K; Jeong, Jaeseung; Kim, Young R

2016-01-01

Neurological recovery after stroke has been extensively investigated to provide better understanding of neurobiological mechanism, therapy, and patient management. Recent advances in neuroimaging techniques, particularly functional MRI (fMRI), have widely contributed to unravel the relationship between the altered neural function and stroke-affected brain areas. As results of previous investigations, the plastic reorganization and/or gradual restoration of the hemodynamic fMRI responses to neural stimuli have been suggested as relevant mechanisms underlying the stroke recovery process. However, divergent study results and modality-dependent outcomes have clouded the proper interpretation of variable fMRI signals. Here, we performed both evoked and resting state fMRI (rs-fMRI) to clarify the link between the fMRI phenotypes and post-stroke functional recovery. The experiments were designed to examine the altered neural activity within the contra-lesional hemisphere and other undamaged brain regions using rat models with large unilateral stroke, which despite the severe injury, exhibited nearly full recovery at ∼6 months after stroke. Surprisingly, both blood oxygenation level-dependent and blood volume-weighted (CBVw) fMRI activities elicited by electrical stimulation of the stroke-affected forelimb were completely absent, failing to reveal the neural origin of the behavioral recovery. In contrast, the functional connectivity maps showed highly robust rs-fMRI activity concentrated in the contra-lesional ventromedial nucleus of thalamus (VM). The negative finding in the stimuli-induced fMRI study using the popular rat middle cerebral artery model denotes weak association between the fMRI hemodynamic responses and neurological improvement. The results strongly caution the indiscreet interpretation of stroke-affected fMRI signals and demonstrate rs-fMRI as a complementary tool for efficiently characterizing stroke recovery.

Comparison of the Cardiac MicroPET Images Obtained Using [(18)F]FPTP and [(13)N]NH3 in Rat Myocardial Infarction Models.

PubMed

Kim, Dong-Yeon; Kim, Hyeon Sik; Jang, Hwa Youn; Kim, Ju Han; Bom, Hee-Seung; Min, Jung-Joon

2014-10-09

The short half-life of current positron emission tomography (PET) cardiac tracers limits their widespread clinical use. We previously developed a (18)F-labeled phosphonium cation, [(18)F]FPTP, that demonstrated sharply defined myocardial defects in a corresponding infarcted myocardium. The aim of this study was to compare the image properties of PET scans obtained using [(18)F]FPTP with those obtained using [(13)N]NH3 in rat myocardial infarction models. Perfusion abnormality was analyzed in 17 segments of polar map images. The myocardium-to-liver and myocardium-to-lung ratios of [(18)F]FPTP were 10.48 and 2.65 times higher, respectively, than those of [(13)N]NH3 in images acquired 30 min after tracer injection. The myocardial defect size measured by [(18)F]FPTP correlated more closely with the hypoperfused area measured by quantitative 2,3,5-triphenyltetrazolium chloride staining (r = 0.89, P < 0.01) than did [(13)N]NH3 (r = 0.84, P < 0.01). [(18)F]FPTP might be useful as a replacement for the myocardial agent [(13)N]NH3 in cardiac PET/CT applications.

Comparison of Allogeneic and Syngeneic Rat Glioma Models by Using MRI and Histopathologic Evaluation.

PubMed

Biasibetti, Elena; Valazza, Alberto; Capucchio, Maria T; Annovazzi, Laura; Battaglia, Luigi; Chirio, Daniela; Gallarate, Marina; Mellai, Marta; Muntoni, Elisabetta; Peira, Elena; Riganti, Chiara; Schiffer, Davide; Panciani, Pierpaolo; Lanotte, Michele

2017-03-01

Research in neurooncology traditionally requires appropriate in vivo animal models, on which therapeutic strategies are tested before human trials are designed and proceed. Several reproducible animal experimental models, in which human physiologic conditions can be mimicked, are available for studying glioblastoma multiforme. In an ideal rat model, the tumor is of glial origin, grows in predictable and reproducible patterns, closely resembles human gliomas histopathologically, and is weakly or nonimmunogenic. In the current study, we used MRI and histopathologic evaluation to compare the most widely used allogeneic rat glioma model, C6-Wistar, with the F98-Fischer syngeneic rat glioma model in terms of percentage tumor growth or regression and growth rate. In vivo MRI demonstrated considerable variation in tumor volume and frequency between the 2 rat models despite the same stereotactic implantation technique. Faster and more reproducible glioma growth occurred in the immunoresponsive environment of the F98-Fischer model, because the immune response is minimized toward syngeneic cells. The marked inability of the C6-Wistar allogeneic system to generate a reproducible model and the episodes of spontaneous tumor regression with this system may have been due to the increased humoral and cellular immune responses after tumor implantation.

Comparison of Allogeneic and Syngeneic Rat Glioma Models by Using MRI and Histopathologic Evaluation

PubMed Central

Biasibetti, Elena; Valazza, Alberto; Capucchio, Maria T; Annovazzi, Laura; Battaglia, Luigi; Chirio, Daniela; Gallarate, Marina; Mellai, Marta; Muntoni, Elisabetta; Peira, Elena; Riganti, Chiara; Schiffer, Davide; Panciani, Pierpaolo; Lanotte, Michele

2017-01-01

Research in neurooncology traditionally requires appropriate in vivo animal models, on which therapeutic strategies are tested before human trials are designed and proceed. Several reproducible animal experimental models, in which human physiologic conditions can be mimicked, are available for studying glioblastoma multiforme. In an ideal rat model, the tumor is of glial origin, grows in predictable and reproducible patterns, closely resembles human gliomas histopathologically, and is weakly or nonimmunogenic. In the current study, we used MRI and histopathologic evaluation to compare the most widely used allogeneic rat glioma model, C6-Wistar, with the F98-Fischer syngeneic rat glioma model in terms of percentage tumor growth or regression and growth rate. In vivo MRI demonstrated considerable variation in tumor volume and frequency between the 2 rat models despite the same stereotactic implantation technique. Faster and more reproducible glioma growth occurred in the immunoresponsive environment of the F98-Fischer model, because the immune response is minimized toward syngeneic cells. The marked inability of the C6-Wistar allogeneic system to generate a reproducible model and the episodes of spontaneous tumor regression with this system may have been due to the increased humoral and cellular immune responses after tumor implantation. PMID:28381315

Methamphetamine-sensitized rats show augmented dopamine release to methylphenidate stimulation: a positron emission tomography using [18F]fallypride.

PubMed

Ota, Miho; Ogawa, Shintaro; Kato, Koichi; Wakabayashi, Chisato; Kunugi, Hiroshi

2015-04-30

Previous studies demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents have been suggested as a useful model of schizophrenia. This study was aimed to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [18F]fallypride as a radioligand to estimate the release in a rat model of schizophrenia. Six rats were scanned by positron emission tomography (PET) twice before and after methylphenidate challenge to evaluate dopamine release. After the scans, these rats were sensitized by using repeated methamphetamine (MAP) administration. Then, they were re-scanned twice again before and after methylphenidate challenge to evaluate whether MAP-sensitized rats show greater sensitivity to methylphenidate. We revealed a main effect of MAP-pretreatment and that of metylphenidate challenge. We found that % change of distribution volume ratio after repeated administration of MAP was greater than that before sensitization. These results suggest that methylphenidate-induced striatal dopamine release increased after sensitization to MAP. PET scan using [18F]fallypride at methylphenidate-challenge may provide a biological marker for schizophrenia and be useful to diagnose schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Differences in the metabolism and disposition of inhaled (3H)benzene by F344/N rats and B6C3F1 mice

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

Sabourin, P.J.; Bechtold, W.E.; Birnbaum, L.S.

1988-06-15

Benzene is a potent hematotoxin and has been shown to cause leukemia in man. Chronic toxicity studies indicate that B6C3F1 mice are more susceptible than F334/N rats to benzene toxicity. The purpose of the studies presented in this paper was to determine if there were metabolic differences between F344/N rats and B6C3F1 mice which might be responsible for this increased susceptibility. Metabolites of benzene in blood, liver, lung, and bone marrow were measured during and following a 6-hr 50 ppm exposure to benzene vapor. Hydroquinone glucuronide, hydroquinone, and muconic acid, which reflect pathways leading to potential toxic metabolites of benzene,more » were present in much greater concentrations in the mouse than in rat tissues. Phenylsulfate, a detoxified metabolite, and an unknown water-soluble metabolite were present in approximately equal concentrations in these two species. These results indicate that the proportion of benzene metabolized via pathways leading to the formation of potentially toxic metabolites as opposed to detoxification pathways was much higher in B6C3F1 mice than in F344 rats, which may explain the higher susceptibility of mice to benzene-induced hematotoxicity and carcinogenicity.« less

Heterogeneous Stock Rat: A Unique Animal Model for Mapping Genes Influencing Bone Fragility

PubMed Central

Alam, Imranul; Koller, Daniel L.; Sun, Qiwei; Roeder, Ryan K.; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J.; Turner, Charles H.; Foroud, Tatiana

2011-01-01

Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in 4 inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high-resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from 5 of the 8 progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. PMID:21334473

Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility.

PubMed

Alam, Imranul; Koller, Daniel L; Sun, Qiwei; Roeder, Ryan K; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J; Turner, Charles H; Foroud, Tatiana

2011-05-01

Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. Copyright �

A cafeteria diet triggers intestinal inflammation and oxidative stress in obese rats.

PubMed

Gil-Cardoso, K; Ginés, I; Pinent, M; Ardévol, A; Terra, X; Blay, M

2017-01-01

The gastrointestinal alterations associated with the consumption of an obesogenic diet, such as inflammation, permeability impairment and oxidative stress, have been poorly explored in both diet-induced obesity (DIO) and genetic obesity. The aim of the present study was to examine the impact of an obesogenic diet on the gut health status of DIO rats in comparison with the Zucker (fa/fa) rat leptin receptor-deficient model of genetic obesity over time. For this purpose, female Wistar rats (n 48) were administered a standard or a cafeteria diet (CAF diet) for 12, 14·5 or 17 weeks and were compared with fa/fa Zucker rats fed a standard diet for 10 weeks. Morphometric variables, plasma biochemical parameters, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) levels in the ileum were assessed, as well as the expressions of proinflammatory genes (TNF-α and inducible nitric oxide synthase (iNOS)) and intestinal permeability genes (zonula occludens-1, claudin-1 and occludin). Both the nutritional model and the genetic obesity model showed increased body weight and metabolic alterations at the final time point. An increase in intestinal ROS production and MPO activity was observed in the gastrointestinal tracts of rats fed a CAF diet but not in the genetic obesity model. TNF-α was overexpressed in the ileum of both CAF diet and fa/fa groups, and ileal inflammation was associated with the degree of obesity and metabolic alterations. Interestingly, the 17-week CAF group and the fa/fa rats exhibited alterations in the expressions of permeability genes. Relevantly, in the hyperlipidic refined sugar diet model of obesity, the responses to chronic energy overload led to time-dependent increases in gut inflammation and oxidative stress.

NTP toxicology and carcinogenesis studies of decalin (CAS No. 91-17-8) in F344/N rats and B6C3F(1) mice and a toxicology study of decalin in male NBR rats (inhalation studies).

PubMed

2005-01-01

Decalin is used as an industrial solvent for naphthalene, fats, resins, oils, and waxes. It is also used as a substitute for turpentine in lacquers, paints, and varnishes; as a solvent and stabilizer for shoe polishes and floor waxes; and as a constituent of motor fuels and lubricants. Other applications include use as a paint thinner and remover, a patent fuel in stoves, a high-density fuel in submarine-launched cruise missile systems, and in stain removal and cleaning machinery. Decalin was nominated for study by the National Cancer Institute because of its chemical structure, its potential for consumer exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were exposed to decalin (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Groups of male NBR rats were exposed to decalin for 2 weeks. Male NBR rats do not produce alpha2u-globulin; the NBR rats were included to study the relationship of alpha2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDIES IN RATS: Groups of five male and five female F344/N rats and five male NBR rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber controls. Renal toxicity studies were performed in male F344/N and NBR rats. The numbers of labeled cells and the labeling indices in the left kidney of 200 and 400 ppm F344/N male rats were significantly greater than those in the chamber controls. The alpha2u-globulin/soluble protein ratios were significantly increased in all exposed groups of F344/N rats. Liver weights of male F344/N and NBR rats exposed to 100 ppm or greater were significantly increased, as were those of all exposed groups of females. Kidney weights of male F344/N rats

Mapping phosphorylation rate of fluoro-deoxy-glucose in rat brain by 19F chemical shift imaging

PubMed Central

Coman, Daniel; Sanganahalli, Basavaraju G.; Cheng, David; McCarthy, Timothy; Rothman, Douglas L.; Hyder, Fahmeed

2014-01-01

19F magnetic resonance spectroscopy (MRS) studies of 2-fluoro-2-deoxy-D-glucose (FDG) and 2-fluoro-2-deoxy-D-glucose-6-phosphate (FDG-6P) can be used for directly assessing total glucose metabolism in vivo. To date, 19F MRS measurements of FDG phosphorylation in the brain have either been achieved ex vivo from extracted tissue or in vivo by unusually long acquisition times. Electrophysiological and functional magnetic resonance imaging (fMRI) measurements indicate that FDG doses up to 500mg/kg can be tolerated with minimal side effects on cerebral physiology and evoked fMRI-BOLD responses to forepaw stimulation. In halothane-anesthetized rats, we report localized in vivo detection and separation of FDG and FDG-6P MRS signals with 19F 2D chemical shift imaging (CSI) at 11.7T. A metabolic model based on reversible transport between plasma and brain tissue, which included a non-saturable plasma to tissue component, was used to calculate spatial distribution of FDG and FDG-6P concentrations in rat brain. In addition, spatial distribution of rate constants and metabolic fluxes of FDG to FDG-6P conversion were estimated. Mapping the rate of FDG to FDG-6P conversion by 19F CSI provides an MR methodology that could impact other in vivo applications such as characterization of tumor pathophysiology. PMID:24581725

Transplantation of induced pluripotent stem cells improves functional recovery in Huntington's disease rat model.

PubMed

Mu, Shuhua; Wang, Jiachuan; Zhou, Guangqian; Peng, Wenda; He, Zhendan; Zhao, Zhenfu; Mo, CuiPing; Qu, Junle; Zhang, Jian

2014-01-01

The purpose of this study was to determine the functional recovery of the transplanted induced pluripotent stem cells in a rat model of Huntington's disease with use of 18F-FDG microPET/CT imaging. In a quinolinic acid-induced rat model of striatal degeneration, induced pluripotent stem cells were transplanted into the ipsilateral lateral ventricle ten days after the quinolinic acid injection. The response to the treatment was evaluated by serial 18F-FDG PET/CT scans and Morris water maze test. Histological analyses and Western blotting were performed six weeks after stem cell transplantation. After induced pluripotent stem cells transplantation, higher 18F-FDG accumulation in the injured striatum was observed during the 4 to 6-weeks period compared with the quinolinic acid-injected group, suggesting the metabolic recovery of injured striatum. The induced pluripotent stem cells transplantation improved learning and memory function (and striatal atrophy) of the rat in six week in the comparison with the quinolinic acid-treated controls. In addition, immunohistochemical analysis demonstrated that transplanted stem cells survived and migrated into the lesioned area in striatum, and most of the stem cells expressed protein markers of neurons and glial cells. Our findings show that induced pluripotent stem cells can survive, differentiate to functional neurons and improve partial striatal function and metabolism after implantation in a rat Huntington's disease model.

Sibutramine reduces feeding, body fat and improves insulin resistance in dietary-obese male Wistar rats independently of hypothalamic neuropeptide Y

PubMed Central

Brown, Michael; Bing, Chen; King, Peter; Pickavance, Lucy; Heal, David; Wilding, John

2001-01-01

We studied the effects of the novel noradrenaline and serotonin (5-HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones.Chow-fed and dietary-obese (DIO) male Wistar rats were given sibutramine (3 mg kg−1 day−1 p.o.) or deionized water for 21 days.Sibutramine decreased food intake throughout the treatment period in both dietary-obese rats (P<0.0001) and lean rats (P<0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary-obese (P<0.005) and 8% lower in lean (P<0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine-treated dietary-obese rats (P<0.05), and in treated lean rats (P<0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P<0.005), and this was corrected by sibutramine treatment (P<0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls.The hypophagic and anti-obesity effects of sibutramine in dietary-obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones. PMID:11309262

[Effect of multi-glycoside of Tripterygium wilfordii Hook. f. in intervening TGF-beta1/Smad signaling pathway of adriamycin-induced nephropathy model rat].

PubMed

Wan, Yi-gang; Sun, Wei; Dou, Chen-hui

2011-04-01

To explore the potential molecular mechanisms of multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) for ameliorating glomerulosclerosis (GS) by observing its intervention effect on transforming growth factor (TGF)-beta1/Smad signaling pathway in adriamycin-induced nephropathy (ADRN) model rat. Fifteen female Sprague-Dawley (SD) rats were randomly divided into three groups, the sham-operation group (A), the untreated model group (B), and the GTW treated model group (C). Rats in Group B and C were made into ADRN model by right nephrectomy and intravenous injection of adriamycin (ADR, 0. 4 mL and 0. 2 mL respectively in 4 weeks). After the model was successfully established, rats in Group C were orally given GTW (50 mg/kg per day), while rats in Group B were intervened with distilled water. The intervention for two groups was 6 weeks. Rats' body weight were weighed and 24 h urinary protein excretion (Upro) detected by the end of the 2nd, 4th, 8th and 10th week. All rats were sacrificed at the end of 10th week after operation to withdraw blood and kidney tissue to examine serum biochemical parameters, glomerular morphological changes, alpha-smooth muscle actin (alpha-SMA), and collagen type I expression. Besides, the mRNA expressions of TGF-beta1, Smad3 and Smad7, as well as protein expressions of TGF-beta1, and phosphorylated Smad2/3 (p-Smad2/3) in glomeruli were detected by RT-PCR or Western blotting. As compared with Group B, in Group C, Upro and serum albumin were improved significantly, but no difference between groups was found in levels of blood urea nitrogen(BUN), serum creatinine(SCr), or hepatic cell injury. Mesangial cell proliferation, extracellular matrix (ECM) and collagen deposition were suppressed by GTW. Expressions of alpha-SMA and collagen type I decreased, and the characteristic changes of GS were attenuated. The mRNA expressions of TGF-P,31, Smad3 and protein expression of TGF-beta1, p-Smad2/3 in renal tissues were down-regulated, while the

Deficits in synaptic function occur at medial perforant path-dentate granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat Model.

PubMed

Smith, Lindsey A; McMahon, Lori L

2018-02-01

Alzheimer's disease (AD) pathology begins decades prior to onset of clinical symptoms, and the entorhinal cortex and hippocampus are among the first and most extensively impacted brain regions. The TgF344-AD rat model, which more fully recapitulates human AD pathology in an age-dependent manner, is a next generation preclinical rodent model for understanding pathophysiological processes underlying the earliest stages of AD (Cohen et al., 2013). Whether synaptic alterations occur in hippocampus prior to reported learning and memory deficit is not known. Furthermore, it is not known if specific hippocampal synapses are differentially affected by progressing AD pathology, or if synaptic deficits begin to appear at the same age in males and females in this preclinical model. Here, we investigated the time-course of synaptic changes in basal transmission, paired-pulse ratio, as an indirect measure of presynaptic release probability, long-term potentiation (LTP), and dendritic spine density at two hippocampal synapses in male and ovariectomized female TgF344-AD rats and wildtype littermates, prior to reported behavioral deficits. Decreased basal synaptic transmission begins at medial perforant path-dentate granule cell (MPP-DGC) synapses prior to Schaffer-collateral-CA1 (CA3-CA1) synapses, in the absence of a change in paired-pulse ratio (PPR) or dendritic spine density. N-methyl-d-aspartate receptor (NMDAR)-dependent LTP magnitude is unaffected at CA3-CA1 synapses at 6, 9, and 12months of age, but is significantly increased at MPP-DGC synapses in TgF344-AD rats at 6months only. Sex differences were only observed at CA3-CA1 synapses where the decrease in basal transmission occurs at a younger age in males versus females. These are the first studies to define presymptomatic alterations in hippocampal synaptic transmission in the TgF344-AD rat model. The time course of altered synaptic transmission mimics the spread of pathology through hippocampus in human AD and provides

Western diets induce blood-brain barrier leakage and alter spatial strategies in rats.

PubMed

Hargrave, Sara L; Davidson, Terry L; Zheng, Wei; Kinzig, Kimberly P

2016-02-01

Western diet (WD) intake induces obesity and metabolic dysfunction. The present study examined the effects of WD on hippocampal-dependent cognitive functioning and blood-brain barrier (BBB) permeability as a function of exposure duration, obesity phenotype, and peripheral markers of energy regulation. The use of hippocampal-dependent "place" or hippocampal-independent "response" strategies in a Y maze was assessed in male rats following 10, 40, and 90 days of WD exposure in diet-induced obese (DIO) rats, in diet resistant (DR) rats that are relatively insensitive to the obesogenic properties of WD, and in chow-fed controls. Insulin, glucose, and BBB permeability throughout several loci in the hippocampus, striatum, and cerebellum were evaluated in relation to duration of WD exposure, obesity phenotype, and type of strategy used. DIO rats had increased body weight and adiposity throughout the study, and elevated 10-day glucose and 90-day insulin levels. Throughout the study, chow-fed and DR rats reliably relied on a place strategy. DIO rats, in contrast, favored a response strategy at the 10- and 90-day time points. BBB leakage was observed in the dorsal striatum and multiple subregions of the hippocampus of DIO, but not DR or chow-fed rats. Increased ventral hippocampal BBB permeability and blood glucose levels were associated with reduced place strategy use. These data indicate that WD-induced BBB leakage is dependent on duration of diet exposure as well as obesity phenotype, and implicates BBB leakage and impaired glucoregulation in behavioral strategy and cognitive performance. (c) 2016 APA, all rights reserved).

SU-F-I-68: Longitudinal Neurochemical Changes On Rat Prefrontal Cortex of Single Prolonged Stress Model by Using Proton Magnetic Resonance Spectroscopy at 9.4T

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

Lim, S-I; Yoo, C-H; Asan Institute for Life Sciences, Asan Medical Center, Seoul, Seoul

Purpose: Single prolonged stress (SPS) is an animal model of posttraumatic stress disorder (PTSD). However, it has not been known how PTSD develops from the first exposure to traumatic events and neurochemical differences between acute/single stress and PTSD-triggering stress. Therefore, the object of this study is to determine time-dependent neurochemical changes in prefrontal cortex (PFC) of rats using in vivo proton magnetic resonance spectroscopy (1H-MRS). Methods: Male Sprague-Dawley rats (n=14; body weight=200–220g) were used. The SPS protocol was used in this study. Rats were restrained for 2h and then immediately forced to swim for 20min in water (20–24 Celsius). Aftermore » a 15-min recuperation period, rats were exposed to ether (using a desiccator) until general anesthesia occurred (<5min). In vivo proton MRS was performed 30min before the SPS (Base), approximately 10min after the SPS (D+0), 3 (D+3) and 7 (D+7) days after SPS to investigate time-dependent changes on metabolites levels in the PFC. Acquisition of in vivo MRS spectra and MRI was conducted at the four time points using 9.4 T Agilent Scanner. Concentration of metabolites was quantified by LCModel. Results: Statistical significance was analyzed using one-way ANOVA with post hoc Tukey HSD tests to assess the metabolite changes in the PFC. The SPS resulted in significant stress-induced differences for 7 days in glutamine (F(3,52)=6.750, P=0.001), choline-containing compounds (F(3,52)=16.442, P=0.000), glutamine/glutamate concentrations (F(3,52)=7.352, P=0.000). Conclusion: PTSD in human is associated with decreased neuronal activity in the PFC. In this study, SPS altered total choline, glutamine levels but not NAA levels in the PFC of the rats. Therefore, for the three stressors and quiescent period of seven days, SPS attenuated excitatory tone and membrane turnover but did not affect neural integrity in the PFC.« less

[Effect of selenium deficiency on the F344 inbred line offspring rats' neuro-behavior, ability of learning and memory].

PubMed

Hong, Liang-Li; Tian, Dong-Ping; Su, Min; Shen, Xiu-Na; Gao, Yuxia

2006-01-01

To establish the selenium (Se) deficient animal model on F344 inbred line rats and observe the effects of a long-term Se-deficiency on the offspring's neuro-behavior, abilities of learning and memory. Feeding F344 inbred line rats on Se-deficient diet to establish Se-deficient animal model. For the offspring, the body weight, physiological indexes nervous reflections for growth and development were monitored during the early postnatal period. The Se-deficient diet contained less than 0.01 mg/kg and the glutathione peroxidase (GSH-Px) activity in blood of the Se-deficient group rats is lower than the Se-normal group after feeding on Se-deficient diet for 4 weeks. For the offspring, the birth weight and the body weight of Se-deficient group were obviously lower than the Se-normal group before weaning. Se-deficient offspring rats differed from Se-normal controls in lower scores in surface righting reflex (RR) test at postnatal 4th day after delivery, cliff avoidance test at postnatal 7th day and auditory acuity trial at postnatal 10th day respectively. But these differences disappear after a few days in the same tests. In addition, no significant differences between two groups in suspending test and walking ability test at postnatal 12th and 14th day. In open field test, Se-deficient male offspring stayed less time in the middle grid and moved less. In Morris water maze test, the Se-deficient offspring spent more time to find the hidden platform at the 6th and 9th training tests in the place navigation trial. Furthermore, the Se-deficient group spent less time in target quadrant when giving the spatial probe trial. A Se-deficient animal model have been established on F344 inbred line rats successfully. A long-term Se deficiency could retard the development of the offspring in uterus and after delivery. Se deficiency also decreased the offspring's abilities of spatial learning and memory in Morris water maze test and resulted in the male offspring's nervousness to new

Streptococcal cell wall-induced arthritis and adjuvant arthritis in F344----Lewis and in Lewis----F344 bone marrow chimeras

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

van Bruggen, M.C.; van den Broek, M.F.; van den Berg, W.B.

1991-09-01

Streptococcal cell wall (SCW)-induced arthritis and adjuvant arthritis (AA) are rat models for chronic, erosive polyarthritis. Both models can be induced in susceptible Lewis rats, whereas F344 rats are resistant. In AA as well as in SCW arthritis, antigen-specific T lymphocytes have been demonstrated to be crucial for chronic disease. In this communication the authors describe their studies to probe the cellular mechanism responsible for the difference in susceptibility of Lewis and F344, using bone marrow chimeras. By transplanting bone marrow cells from F344 into lethally irradiated Lewis recipients, Lewis rats were rendered resistant to SCW arthritis induction. F344 ratsmore » reconstituted with Lewis bone marrow, i.e., Lewis----F344 chimeras, develop an arthritis upon SCW injection. For AA comparable results were obtained. These data suggest that both resistance and susceptibility to bacterium-induced chronic arthritis are mediated by hemopoietic/immune cells and that the recipiental environment does not influence the susceptibility to chronic joint inflammation.« less

Promotion of enamel caries remineralization by an amelogenin-derived peptide in a rat model.

PubMed

Han, Sili; Fan, Yingying; Zhou, Zhengli; Tu, Huanxin; Li, Danxue; Lv, Xueping; Ding, Longjiang; Zhang, Linglin

2017-01-01

An amelogenin-derived peptide has been shown to promote remineralization of demineralized enamel in an in vitro model of initial caries induced by pH cycling. The present study examines whether the peptide exerts similar effects within the complex oral environment in vivo. Specific pathogen-free Sprague-Dawley rats (n=36) were infected with Streptococcus mutans, given ad libitum access to Diet 2000 and drinking water supplemented with sucrose (10%, w/v), and then randomly divided into three groups treated with 25μM peptide solution, 1g/L NaF or deionized water. Molar teeth were swabbed twice daily with the respective solutions for 24days. Then animals were killed, their jaws were removed and caries lesions were analyzed using the quantitative light-induced fluorescence-digital (QLF-D) technique to measure changes in mineral content. To verify QLF-D results, caries were scored for lesion depth and size using the Keyes method, and analyzed using polarized light microscopy (PLM). Mineral gain was significantly higher in teeth treated with peptide or NaF than in teeth treated with water (p<0.05), based on the QLF-D results (ΔF and ΔQ). Incidence of smooth-surface and sulcal caries based on Keyes scores was similar in rats treated with peptide or NaF, and significantly lower in these groups than in rats treated with water (p<0.05). Lesions on teeth treated with peptide or NaF were shallower, based on PLM. No significant differences were observed between molar enamel caries treated with peptide or NaF. This amelogenin-derived peptide can promote remineralization in a rat caries model, indicating strong potential for clinical use. Copyright © 2016 Elsevier Ltd. All rights reserved.

Renoprotective effects of Andrographis paniculata (Burm. f.) Nees in rats

PubMed Central

Singh, Pratibha; Srivastava, Man Mohan

2009-01-01

Background Renal failure is an increasingly common condition with limited treatment options that is causing a major financial and emotional burden on the community. Andrographis paniculata is the plant used in Ayurveda for several remedies. Scientific evidence suggests its versatile biological functions that support its traditional use in the Orient. The plant is claimed to possess immunological, antibacterial, anti-inflammatory, antithrombotic, and hepatoprotective properties. But, to date, there is no study demonstrating the protective effect of A. paniculata on gentamicin-induced renal failure. The present study aims to highlight the first ever reported, antirenal failure activity of A. paniculata. Methods Male Wistar albino rats were divided into three groups: normal control, gentamicin control, and aqueous extract of A. paniculata (200 mg/kg, per oral (p.o.))-treated. The nephrotoxic model was induced by gentamicin (80 mg/kg, intraperitoeal (i.p.)). Blood samples were examined for serum creatinine, serum urea, and blood urea nitrogen after the 10 days of treatment. Results A gentamicin-induced nephrotoxic animal model was successfully prepared. Aqueous extract of A. paniculata attenuated the gentamicin-induced increase in serum creatinine, serum urea, and blood urea nitrogen levels by 176.92%, 106.27%, and 202.90%, respectively. Conclusion The present study reports that the aqueous extract (whole plant) of A. paniculata (Burm. f.) Nees exhibits a significant renoprotective effect in gentamicin-induced nephrotoxicity in male Wistar albino rats. PMID:19736602

Characterization of the 5-HT2C receptor agonist lorcaserin on efficacy and safety measures in a rat model of diet-induced obesity.

PubMed

Higgins, Guy A; Desnoyer, Jill; Van Niekerk, Annalise; Silenieks, Leo B; Lau, Winnie; Thevarkunnel, Sandy; Izhakova, Julia; DeLannoy, Ines Am; Fletcher, Paul J; DeLay, Josepha; Dobson, Howard

2015-02-01

The 5-HT2C receptor agonist lorcaserin (Belviq®) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28-day lorcaserin treatment in a diet-induced obesity (DIO) model using male, Sprague-Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1-2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle-treated controls (VEH: 10.6 ± 0.4%; LOR 1: 7.6 ± 1.2%; LOR 2: 5.4 ± 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7-day treatment period; plasma C min and C max were in the range 13-160 ng/mL (1 mg/kg b.i.d.) and 34-264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0-5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity.

Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways.

PubMed

Vickers, Alison E M; Heale, Jason; Sinclair, John R; Morris, Stephen; Rowe, Josh M; Fisher, Robyn L

2012-04-01

Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models. Inhibition of TPO occurred early as shown in rat thyroid lobes (2 h) and was sustained in both rat (24-48 h) and human (24 h) with ≥ 10 μM MMI. Thyroid from rats treated with single doses of MMI (30-1000 mg/kg) exhibited sustained TPO inhibition at 48 h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (~15-84 μM), thus demonstrating a close correlation between in vivo and ex vivo thyroid effects. A compensatory response to TPO inhibition was demonstrated in the rat thyroid lobe with significant up-regulation of genes involved in the pathway of thyroid hormone synthesis (Tpo, Dio1, Slc5a5, Tg, Tshr) and the megalin release pathway (Lrp2) by 24h with MMI (≥ 10 μM) and PTU (100 μM). Similarly, thyroid from the rat in vivo study exhibited an up-regulation of Dio1, Slc5a5, Lrp2, and Tshr. In human thyroid slices, there were few gene expression changes (Slc5a5, ~2-fold) and only at higher MMI concentrations (≥ 1500 μM, 24h). Extended exposure (48 h) resulted in up-regulation of Tpo, Dio1 and Lrp2, along with Slc5a5 and Tshr. In summary, TPO was inhibited by similar MMI concentrations in rat and human tissue, however an increased sensitivity to drug treatment in rat is indicated by the up-regulation of thyroid hormone synthesis and release gene pathways at concentrations found not to affect human tissue. Copyright © 2012 Elsevier Inc. All rights reserved.

Clear Evidence of Carcinogenic Activity by a Whole-Leaf Extract of Aloe barbadensis Miller (Aloe vera) in F344/N Rats

PubMed Central

Boudreau, Mary D.

2013-01-01

Aloe barbadensis Miller (Aloe vera) is an herbal remedy promoted to treat a variety of illnesses; however, only limited data are available on the safety of this dietary supplement. Drinking water exposure of F344/N rats and B6C3F1 mice to an Aloe vera whole-leaf extract (1, 2, and 3%) for 13 weeks resulted in goblet cell hyperplasia of the large intestine in both species. Based upon this observation, 2-year drinking water studies were conducted to assess the carcinogenic potential of an Aloe vera whole-leaf extract when administered to F344/N rats (48 per sex per group) at 0.5, 1, and 1.5%, and B6C3F1 mice (48 per sex per group) at 1, 2, and 3%. Compared with controls, survival was decreased in the 1.5% dose group of female rats. Treatment-related neoplasms and nonneoplastic lesions in both species were confined primarily to the large intestine. Incidences of adenomas and/or carcinomas of the ileo-cecal and cecal-colic junction, cecum, and ascending and transverse colon were significantly higher than controls in male and female rats in the 1 and 1.5% dose groups. There were no neoplasms of the large intestine in mice or in the 0 or 0.5% dose groups of rats. Increased incidences of mucosa hyperplasia of the large intestine were observed in F344/N rats, and increased incidences of goblet cell hyperplasia of the large intestine occurred in B6C3F1 mice. These results indicate that Aloe vera whole-leaf extract is an intestinal irritant in F344/N rats and B6C3F1 mice and a carcinogen of the large intestine in F344/N rats. PMID:22968693

Centrally administered urocortin 2 decreases gorging on high-fat diet in in both diet induced obesity-prone and -resistant rats

PubMed Central

Cottone, Pietro; Sabino, Valentina; Nagy, Tim R.; Coscina, Donald V.; Levin, Barry E.; Zorrilla, Eric P.

2013-01-01

Objective Obesity is a costly, deadly public health problem for which new treatments are needed. Individual differences in meal pattern have been proposed to play a role in obesity risk. The present study tested the hypothesis that i) the microstructure of chronic high-fat diet intake differs between genetically selected Diet-Induced Obesity (DIO) and Diet Resistant (DR) rats, and ii) central administration of urocortin 2 (Ucn 2), a corticotropin-releasing factor type 2 (CRF2) agonist, decreases high-fat diet intake not only in lean DR rats, but also in obese DIO rats. Design Male, selectively bred DIO and DR rats (n=10/genotype) were chronically fed a high-fat diet. Food and water intake as well as ingestion microstructure were then compared under baseline conditions and following third intracerebroventricular injection of Ucn 2 (0, 0.1, 0.3, 1, 3 µg). Results Irrespective of genotype, Ucn 2 reduced nocturnal food intake with a minimum effective dose of 0.3 µg, suppressing high-fat diet intake by ~40% at the 3 µg dose. Ucn 2 also made rats of both genotypes eat smaller and briefer meals, including at doses that did not reduce drinking. Obese DIO rats ate fewer but larger meals than DR rats, which they ate more quickly and consumed with 2/3rd less water. Conclusions Unlike leptin and insulin, Ucn 2 retains its full central anorectic efficacy to reduce high-fat diet intake even in obese, genetically-prone DIO rats, which otherwise show a “gorging” meal pattern. These results open new opportunities of investigation towards treating some forms of diet-induced obesity. PMID:23478425

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.

Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease.

PubMed

Rorabaugh, Jacki M; Chalermpalanupap, Termpanit; Botz-Zapp, Christian A; Fu, Vanessa M; Lembeck, Natalie A; Cohen, Robert M; Weinshenker, David

2017-11-01

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer’s disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer’s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO MALE F344/N RATS AND B6C3F1 MICE

EPA Science Inventory

A life-time exposure study was conducted to assess the carcinogenicity of bromodichloromethane (BDCM) administered in the drinking water to male F344/N rats and B6C3F1 mice. Mouse: Target concentrations of BDCM (dissolved in deionized water containing 0.25% emulphor) were 0.05, ...

Obesity-related pulmonary arterial hypertension in rats correlates with increased circulating inflammatory cytokines and lipids and with oxidant damage in the arterial wall but not with hypoxia

PubMed Central

Irwin, David C.; Garat, Chrystelle V.; Crossno, Joseph T.; MacLean, Paul S.; Sullivan, Timothy M.; Erickson, Paul F.; Jackman, Matthew R.; Harral, Julie W.; Reusch, Jane E. B.

2014-01-01

Abstract Obesity is causally linked to a number of comorbidities, including cardiovascular disease, diabetes, renal dysfunction, and cancer. Obesity has also been linked to pulmonary disorders, including pulmonary arterial hypertension (PAH). It was long believed that obesity-related PAH was the result of hypoventilation and hypoxia due to the increased mechanical load of excess body fat. However, in recent years it has been proposed that the metabolic and inflammatory disturbances of obesity may also play a role in the development of PAH. To determine whether PAH develops in obese rats in the absence of hypoxia, we assessed pulmonary hemodynamics and pulmonary artery (PA) structure in the diet-resistant/diet-induced obesity (DR/DIO) and Zucker lean/fatty rat models. We found that high-fat feeding (DR/DIO) or overfeeding (Zucker) elicited PA remodeling, neomuscularization of distal arterioles, and elevated PA pressure, accompanied by right ventricular (RV) hypertrophy. PA thickening and distal neomuscularization were also observed in DIO rats on a low-fat diet. No evidence of hypoventilation or chronic hypoxia was detected in either model, nor was there a correlation between blood glucose or insulin levels and PAH. However, circulating inflammatory cytokine levels were increased with high-fat feeding or calorie overload, and hyperlipidemia and oxidant damage in the PA wall correlated with PAH in the DR/DIO model. We conclude that hyperlipidemia and peripheral inflammation correlate with the development of PAH in obese subjects. Obesity-related inflammation may predispose to PAH even in the absence of hypoxia. PMID:25610600

Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats.

PubMed

Begg, Denovan P; Mul, Joram D; Liu, Min; Reedy, Brianne M; D'Alessio, David A; Seeley, Randy J; Woods, Stephen C

2013-03-01

Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.

Impaired postprandial releases/syntheses of ghrelin and PYY(3-36) and blunted responses to exogenous ghrelin and PYY(3-36) in a rodent model of diet-induced obesity.

PubMed

Xu, Junying; McNearney, Terry A; Chen, J D Z

2011-04-01

This study investigated the effects of peripheral administration of ghrelin and PYY(3-36) on food intake and plasma and tissue fasting and postprandial ghrelin and PYY(3-36) levels in normal-weight (NW) and diet-induced-obese (DIO) rats. In experiment one, NW and DIO rats received a single intraperitoneal injection of saline, PYY(3-36) or ghrelin; food intake was measured for 4 h. In experiment two, total plasma ghrelin and PYY(3-36), gastric fundus ghrelin, and ascending colon PYY(3-36) were measured either after a 20-h fast or 2 h after refeeding in NW and DIO rats by radioimmunoassay. Compared to the NW rats, findings in the DIO rats revealed: (i) a reduced sensitivity to both the anorectic effect of exogenous PYY(3-36) and the orexigenic effect of exogenous ghrelin; (ii) the postprandial plasma ghrelin levels were significantly higher; and (iii) refeeding decreased endogenous plasma ghrelin levels by 53% in the NW rats and 39% in DIO rats. Refeeding increased the plasma PYY(3-36) level by 58% in the NW rats versus 9% in the DIO rats (P=0.003). Compared with regular rats, DIO rats exhibit blunted responses in food intake to exogenous ghrelin and PYY(3-36). Although endogenous ghrelin and PYY(3-36) in DIO rats are not altered in the fasting state, their responses to food ingestion are blunted in comparison with regular rats. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

FORMALDEHYDE-INDUCED GENE EXPRESSION IN F344 RAT NASAL RESPIRATORY EPITHELIUM.

EPA Science Inventory

Formaldehyde-induced gene expression in F344 rat nasal respiratory epithelium

ABSTRACT

Formaldehyde, an occupational and environmental toxicant used extensively in the manufacturing of many household and personal use products, is known to induce squamous cell carci...

Initial Assessment of β3-Adrenoceptor-Activated Brown Adipose Tissue in Streptozotocin-Induced Type 1 Diabetes Rodent Model Using [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

PubMed

Baranwal, Aparna; Mirbolooki, M Reza; Mukherjee, Jogeshwar

2015-01-01

Metabolic activity of brown adipose tissue (BAT) is activated by β3-adrenoceptor agonists and norepinephrine transporter (NET) blockers and is measurable using [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography/computed tomography (PET/CT) in rats. Using the streptozotocin (STZ)-treated rat model of type 1 diabetes mellitus (T1DM), we investigated BAT activity in this rat model under fasting and nonfasting conditions using [(18)F]FDG PET/CT. Drugs that enhance BAT activity may have a potential for therapeutic development in lowering blood sugar in insulin-resistant diabetes. Rats were rendered diabetic by administration of STZ and confirmed by glucose measures. [(18)F]FDG was injected in the rats (fasted or nonfasted) pretreated with either saline or β3-adrenoceptor agonist CL316,243 or the NET blocker atomoxetine for PET/CT scans. [(18)F]FDG metabolic activity was computed as standard uptake values (SUVs) in interscapular brown adipose tissue (IBAT) and compared across the different drug treatment conditions. Blood glucose levels > 500 mg/dL were established for the STZ-treated diabetic rats. Under fasting conditions, average uptake of [(18)F]FDG in the IBAT of STZ-treated diabetic rats was approximately 70% lower compared to that of normal rats. Both CL316,243 and atomoxetine activated IBAT in normal rats had an SUV > 5, whereas activation in STZ-treated rats was significantly lower. The agonist CL316,243 activated IBAT up to threefold compared to saline in the fasted STZ-treated rat. In the nonfasted rat, the IBAT activation was up by twofold by CL316243. Atomoxetine had a greater effect on lowering blood sugar levels compared to CL316,243 in the nonfasted rats. A significant reduction in metabolic activity was observed in the STZ-treated diabetic rodent model. Increased IBAT activity in the STZ-treated diabetic rat under nonfasted conditions using the β3-adrenoceptor agonist CL316,243 suggests a potential role of BAT in modulating blood

Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [(18)F]PBR102 and [ (18)F]PBR111 in a model of excitotoxin-induced neuroinflammation.

PubMed

Callaghan, P D; Wimberley, C A; Rahardjo, G L; Berghofer, P J; Pham, T Q; Jackson, T; Zahra, D; Bourdier, T; Wyatt, N; Greguric, I; Howell, N R; Siegele, R; Pastuovic, Z; Mattner, F; Loc'h, C; Gregoire, M C; Katsifis, A

2015-01-01

The in vivo binding parameters of the novel imidazopyridine TSPO ligand [(18)F]PBR102 were assessed and compared with those of [(18)F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [(18)F]PBR102 or [(18)F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration-time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [(125)I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. The BPs of [(18)F]PBR102 [(18)F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [(11)C]PK11195. The presaturation study showed differences in the volume of distribution between the

The Establishment of Metabolic Syndrome Model by Induction of Fructose Drinking Water in Male Wistar Rats

PubMed Central

Thent, Zar Chi; Sapri, Shaiful Ridzwan; Sahruddin, Natasya Nadia; Mohd Yusof, Mohd Rafizul; Haji Suhaimi, Farihah

2014-01-01

Background. Metabolic syndrome can be caused by modification of diet by means of consumption of high carbohydrate and high fat diet such as fructose. Aims. To develop a metabolic syndrome rat model by induction of fructose drinking water (FDW) in male Wistar rats. Methods. Eighteen male Wistar rats were fed with FDW 20% and FDW 25% for a duration of eight weeks. The physiological changes with regard to food and fluid intake, as well as calorie intake, were measured. The metabolic changes such as obesity, dyslipidaemia, hypertension, and hyperglycaemia were determined. Data was presented in mean ± SEM subjected to one-way ANOVA. Results. Male Wistar rats fed with FDW 20% for eight weeks developed significant higher obesity parameters compared to those fed with FDW 25%. There was hypertrophy of adipocytes in F20 and F25. There were also systolic hypertension, hypertriglyceridemia, and hyperglycemia in both groups. Conclusion. We conclude that the metabolic syndrome rat model is best established with the induction of FDW 20% for eight weeks. This was evident in the form of higher obesity parameter which caused the development of the metabolic syndrome. PMID:25045660

Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

PubMed

2012-07-01

Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male

Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways

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

Vickers, Alison E.M., E-mail: vickers_alison@allergan.com; Heale, Jason; Sinclair, John R.

Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models. Inhibition of TPO occurred early as shown in rat thyroid lobes (2 h) and was sustained in both rat (24–48 h) and human (24 h) with ≥ 10 μM MMI. Thyroidmore » from rats treated with single doses of MMI (30–1000 mg/kg) exhibited sustained TPO inhibition at 48 h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (∼ 15–84 μM), thus demonstrating a close correlation between in vivo and ex vivo thyroid effects. A compensatory response to TPO inhibition was demonstrated in the rat thyroid lobe with significant up-regulation of genes involved in the pathway of thyroid hormone synthesis (Tpo, Dio1, Slc5a5, Tg, Tshr) and the megalin release pathway (Lrp2) by 24 h with MMI (≥ 10 μM) and PTU (100 μM). Similarly, thyroid from the rat in vivo study exhibited an up-regulation of Dio1, Slc5a5, Lrp2, and Tshr. In human thyroid slices, there were few gene expression changes (Slc5a5, ∼ 2-fold) and only at higher MMI concentrations (≥ 1500 μM, 24 h). Extended exposure (48 h) resulted in up-regulation of Tpo, Dio1 and Lrp2, along with Slc5a5 and Tshr. In summary, TPO was inhibited by similar MMI concentrations in rat and human tissue, however an increased sensitivity to drug treatment in rat is indicated by the up-regulation of thyroid hormone synthesis and release gene pathways at concentrations found not to affect human tissue. -- Highlights: ► Novel model of rat thyroid or human thyroid slices to evaluate pathways of injury. ► TPO inhibition by MMI or PTU

Evaluation of biomolecular distributions in rat brain tissues by means of ToF-SIMS using a continuous beam of Ar clusters.

PubMed

Nakano, Shusuke; Yokoyama, Yuta; Aoyagi, Satoka; Himi, Naoyuki; Fletcher, John S; Lockyer, Nicholas P; Henderson, Alex; Vickerman, John C

2016-06-08

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) provides detailed chemical structure information and high spatial resolution images. Therefore, ToF-SIMS is useful for studying biological phenomena such as ischemia. In this study, in order to evaluate cerebral microinfarction, the distribution of biomolecules generated by ischemia was measured with ToF-SIMS. ToF-SIMS data sets were analyzed by means of multivariate analysis for interpreting complex samples containing unknown information and to obtain biomolecular mapping indicated by fragment ions from the target biomolecules. Using conventional ToF-SIMS (primary ion source: Bi cluster ion), it is difficult to detect secondary ions beyond approximately 1000 u. Moreover, the intensity of secondary ions related to biomolecules is not always high enough for imaging because of low concentration even if the masses are lower than 1000 u. However, for the observation of biomolecular distributions in tissues, it is important to detect low amounts of biological molecules from a particular area of tissue. Rat brain tissue samples were measured with ToF-SIMS (J105, Ionoptika, Ltd., Chandlers Ford, UK), using a continuous beam of Ar clusters as a primary ion source. ToF-SIMS with Ar clusters efficiently detects secondary ions related to biomolecules and larger molecules. Molecules detected by ToF-SIMS were examined by analyzing ToF-SIMS data using multivariate analysis. Microspheres (45 μm diameter) were injected into the rat unilateral internal carotid artery (MS rat) to cause cerebral microinfarction. The rat brain was sliced and then measured with ToF-SIMS. The brain samples of a normal rat and the MS rat were examined to find specific secondary ions related to important biomolecules, and then the difference between them was investigated. Finally, specific secondary ions were found around vessels incorporating microspheres in the MS rat. The results suggest that important biomolecules related to cerebral

Differential effects of prenatal stress on metabolic programming in diet-induced obese and dietary-resistant rats.

PubMed

Balasubramanian, Priya; Varde, Pratibha A; Abdallah, Simon Labib; Najjar, Sonia M; MohanKumar, P S; MohanKumar, Sheba M J

2015-09-15

Stress during pregnancy is a known contributing factor for the development of obesity in the offspring. Since maternal obesity is on the rise, we wanted to identify the effects of prenatal stress in the offspring of diet-induced obese (DIO) rats and compare them with the offspring of dietary-resistant (DR) rats. We hypothesized that prenatal stress would make both DIO and DR offspring susceptible to obesity, but the effect would be more pronounced in DIO rats. Pregnant DIO and DR rats were divided into two groups: nonstressed controls (control) and prenatal stress (subjected to restraint stress, three times/day from days 14 to 21 of gestation). After recording birth weight and weaning weight, male offspring were weaned onto a chow diet for 9 wk and shifted to a high-fat (HF) diet for 1 wk. At the end of the 10th wk the animals were euthanized, and visceral adipose mass, blood glucose, serum insulin, and C-peptide levels were measured. Prenatal stress resulted in hyperinsulinemia and higher C-peptide levels without altering caloric intake, body weight gain, or fat mass in the DIO offspring after 1 wk of HF intake, but not in DR offspring. To determine the mechanism underlying the hyperinsulinemia, we measured the levels of CEACAM1 that are responsible for insulin clearance. CEACAM1 levels in the liver were reduced in prenatally stressed DIO offspring after the HF challenge, suggesting that preexisting genetic predisposition in combination with prenatal stress increases the risk for obesity in adulthood, especially when offspring are fed a HF diet. Copyright © 2015 the American Physiological Society.

Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water.

PubMed

Cullen, John M; Ward, Jerrold M; Thompson, Chad M

2016-02-01

Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response. © The Author(s) 2015.

Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water

PubMed Central

Cullen, John M.; Ward, Jerrold M.

2015-01-01

Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response. PMID:26538584

Imaging for metabotropic glutamate receptor subtype 1 in rat and monkey brains using PET with [18F]FITM.

PubMed

Yamasaki, Tomoteru; Fujinaga, Masayuki; Maeda, Jun; Kawamura, Kazunori; Yui, Joji; Hatori, Akiko; Yoshida, Yuichiro; Nagai, Yuji; Tokunaga, Masaki; Higuchi, Makoto; Suhara, Tetsuya; Fukumura, Toshimitsu; Zhang, Ming-Rong

2012-04-01

In this study, we evaluate the utility of 4-[(18)F]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]FITM) as a positron emission tomography (PET) ligand for imaging of the metabotropic glutamate receptor subtype 1 (mGluR1) in rat and monkey brains. In vivo distribution of [(18)F]FITM in brains was evaluated by PET scans with or without the mGluR1-selective antagonist (JNJ16259685). Kinetic parameters of monkey PET data were obtained using the two-tissue compartment model with arterial blood sampling. In PET studies in rat and monkey brains, the highest uptake of radioactivity was in the cerebellum, followed by moderate uptake in the thalamus, hippocampus and striatum. The lowest uptake of radioactivity was detected in the pons. These uptakes in all brain regions were dramatically decreased by pre-administration of JNJ16259685. In kinetic analysis of monkey PET, the highest volume of distribution (V(T)) was detected in the cerebellum (V(T) = 11.5). [(18)F]FITM has an excellent profile as a PET ligand for mGluR1 imaging. PET with [(18)F]FITM may prove useful for determining the regional distribution and density of mGluR1 and the mGluR1 occupancy of drugs in human brains.

Hexavalent Chromium Is Carcinogenic to F344/N Rats and B6C3F1 Mice after Chronic Oral Exposure

PubMed Central

Stout, Matthew D.; Herbert, Ronald A.; Kissling, Grace E.; Collins, Bradley J.; Travlos, Gregory S.; Witt, Kristine L.; Melnick, Ronald L.; Abdo, Kamal M.; Malarkey, David E.; Hooth, Michelle J.

2009-01-01

Background Hexavalent chromium [Cr(VI)] is a human carcinogen after inhalation exposure. Humans also ingest Cr(VI) from contaminated drinking water and soil; however, limited data exist on the oral toxicity and carcinogenicity of Cr(VI). Objective We characterized the chronic oral toxicity and carcinogenicity of Cr(VI) in rodents. Methods The National Toxicology Program (NTP) conducted 2-year drinking water studies of Cr(VI) (as sodium dichromate dihydrate) in male and female F344/N rats and B6C3F1 mice. Results Cr(VI) exposure resulted in increased incidences of rare neoplasms of the squamous epithelium that lines the oral cavity (oral mucosa and tongue) in male and female rats, and of the epithelium lining the small intestine in male and female mice. Cr(VI) exposure did not affect survival but resulted in reduced mean body weights and water consumption, due at least in part to poor palatability of the dosed water. Cr(VI) exposure resulted in transient microcytic hypochromic anemia in rats and microcytosis in mice. Nonneoplastic lesions included diffuse epithelial hyperplasia in the duodenum and jejunum of mice and histiocytic cell infiltration in the duodenum, liver, and mesenteric and pancreatic lymph nodes of rats and mice. Conclusions Cr(VI) was carcinogenic after administration in drinking water to male and female rats and mice. PMID:19479012

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol.

PubMed

Toyoda, Takeshi; Cho, Young-Man; Akagi, Jun-Ichi; Mizuta, Yasuko; Matsushita, Kohei; Nishikawa, Akiyoshi; Imaida, Katsumi; Ogawa, Kumiko

2017-01-01

3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in high-risk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 9, 28.5, 90, 285, or 900 ppm 3-MCPD in drinking water for 13 weeks. 3-MCPD treatment decreased body weight gain, increased relative kidney weights, induced anemia, and induced epithelial cell necrosis in epididymal ducts in all 3 strains. The degrees of epididymal damage were higher in F344 and lean rats than in fatty rats, while renal toxicity was most potent in F344 rats and comparable in lean and fatty rats. In contrast, the hematology data indicated that anemia was worse in fatty rats than in F344 and lean rats, and a significant decrease in hematopoietic cells in the bone marrow was observed only in fatty rats. The no-observed-adverse-effect level was estimated to be 28.5 ppm in all 3 strains for 3-MCPD. These results suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissues than their lean counterparts.

Testosterone and estradiol treatments differently affect pituitary-thyroid axis and liver deiodinase 1 activity in orchidectomized middle-aged rats.

PubMed

Šošić-Jurjević, B; Filipović, B; Renko, K; Miler, M; Trifunović, S; Ajdžanovič, V; Kӧhrle, J; Milošević, V

2015-12-01

We previously reported that orchidectomy (Orx) of middle-aged rats (15-16-month-old; MA) slightly affected pituitary-thyroid axis, but decreased liver deiodinase (Dio) type 1 and pituitary Dio2 enzyme activities. At present, we examined the effects of subsequent testosterone-propionate treatment (5mg/kg; Orx+T), and compared the effects of testosterone with the effects of estradiol-dipropionate (0.06mg/kg; Orx+E) treatment. Hormones were subcutaneously administered, daily, for three weeks, while Orx and sham-operated (SO) controls received only the vehicle. The applied dose of T did not alter serum TSH, T4 and T3 concentrations in Orx- MA, though it increased TSH when administrated to Orx young adults (2.5-month-old; Orx-YA). However, pituitaries of Orx-MA+T rats had higher relative intensity of immunofluorescence (RIF) for TSHβ; in their thyroids we found increased volume and height of follicular epithelium, decreased volume of the colloid and higher RIF for T4-bound to thyroglobulin (Tg-T4). Liver Dio1 activity was increased. E-treatment did not affect serum hormone levels, pituitary RIF for TSHβ, or liver Dio1 activity in Orx-MA rats. Thyroids had decreased relative volume and height of follicular epithelium, increased relative volume of the colloid, decreased volume of sodium-iodide symporter-immunopositive epithelium and lower RIF for Tg-T4. Detected changes were statistically significant. In conclusion, androgenization enhanced pituitary TSHβ RIF, thyroid activation and liver Dio1 enzyme activity in Orx-MA, without elevating serum TSH as in Orx-YA rats. Estrogenization induced pituitary enlargement with no effect on pituitary TSHβ RIF, serum TSH or liver Dio1 activity. E also induced alterations in thyroid histology that indicate mild suppression of its functioning, and contributed to thyroid blood vessel enlargement in Orx-MA rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Catabolism of 6-ketoprostaglandin F1alpha by the rat kidney cortex.

PubMed

Pace-Asciak, C R; Domazet, Z; Carrara, M

1977-05-25

Homogenates of the rat kidney cortex converted 5,8,9,11,12,14,15-hepta-tritiated 6-ketoprostaglandin F 1alpha into one major product identified by gas chromatography-mass spectrometry of the methoxime-methyl ester trimethylsilyl ether derivative as 6,15-diketo-9,11-dihydroxyprost-13-enoic acid. The sequence of derivatisation i.e. methoximation prior to methylation, was crucial as methylation of 15-keto catabolites of the E, F and 6-keto-F series affords degradation products. The corresponding 15-keto-13,14-dihydro catabolite was formed in much smaller quantities. Time course studies indicated that 6-keto-prostaglandin F1alpha was catabolised at a slower rate (about 2-5 fold) than prostaglandin F1alpha. The catabolic activity was blocked by NADH.

Interactive effects of oligofructose and obesity predisposition on gut hormones and microbiota in diet-induced obese rats.

PubMed

Cluny, Nina L; Eller, Lindsay K; Keenan, Catherine M; Reimer, Raylene A; Sharkey, Keith A

2015-04-01

Oligofructose (OFS) is a prebiotic that reduces energy intake and fat mass via changes in gut satiety hormones and microbiota. The effects of OFS may vary depending on predisposition to obesity. The aim of this study was to examine the effect of OFS in diet-induced obese (DIO) and diet-resistant (DR) rats. Adult, male DIO, and DR rats were randomized to: high-fat/high-sucrose (HFS) diet or HFS diet + 10% OFS for 6 weeks. Body composition, food intake, gut microbiota, plasma gut hormones, and cannabinoid CB(1) receptor expression in the nodose ganglia were measured. OFS reduced body weight, energy intake, and fat mass in both phenotypes (P < 0.05). Select gut microbiota differed in DIO versus DR rats (P < 0.05), the differences being eliminated by OFS. OFS did not modify plasma ghrelin or CB(1) expression in nodose ganglia, but plasma levels of GIP were reduced and PYY were elevated (P < 0.05) by OFS. OFS was able to reduce body weight and adiposity in both prone and resistant obese phenotypes. OFS-induced changes in gut microbiota profiles in DIO and DR rats, along with changes in gut hormone levels, likely contribute to the sustained lower body weights. © 2015 The Obesity Society.

Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.

PubMed

Joo, Illsung L; Lai, Aaron Y; Bazzigaluppi, Paolo; Koletar, Margaret M; Dorr, Adrienne; Brown, Mary E; Thomason, Lynsie A M; Sled, John G; McLaurin, JoAnne; Stefanovic, Bojana

2017-04-12

Alzheimer's disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

Rat Genome and Model Resources.

PubMed

Shimoyama, Mary; Smith, Jennifer R; Bryda, Elizabeth; Kuramoto, Takashi; Saba, Laura; Dwinell, Melinda

2017-07-01

Rats remain a major model for studying disease mechanisms and discovery, validation, and testing of new compounds to improve human health. The rat's value continues to grow as indicated by the more than 1.4 million publications (second to human) at PubMed documenting important discoveries using this model. Advanced sequencing technologies, genome modification techniques, and the development of embryonic stem cell protocols ensure the rat remains an important mammalian model for disease studies. The 2004 release of the reference genome has been followed by the production of complete genomes for more than two dozen individual strains utilizing NextGen sequencing technologies; their analyses have identified over 80 million variants. This explosion in genomic data has been accompanied by the ability to selectively edit the rat genome, leading to hundreds of new strains through multiple technologies. A number of resources have been developed to provide investigators with access to precision rat models, comprehensive datasets, and sophisticated software tools necessary for their research. Those profiled here include the Rat Genome Database, PhenoGen, Gene Editing Rat Resource Center, Rat Resource and Research Center, and the National BioResource Project for the Rat in Japan. © The Author 2017. Published by Oxford University Press.

Genotoxicity of Styrene–Acrylonitrile Trimer in Brain, Liver, and Blood Cells of Weanling F344 Rats

PubMed Central

Hobbs, Cheryl A.; Chhabra, Rajendra S.; Recio, Leslie; Streicker, Michael; Witt, Kristine L.

2012-01-01

Styrene–acrylonitrile Trimer (SAN Trimer), a by-product in production of acrylonitrile styrene plastics, was identified at a Superfund site in Dover Township, NJ, where childhood cancer incidence rates were elevated for a period of several years. SAN Trimer was therefore tested by the National Toxicology Program in a 2-year perinatal carcinogenicity study in F344/N rats and a bacterial mutagenicity assay; both studies gave negative results. To further characterize its genotoxicity, SAN Trimer was subsequently evaluated in a combined micronucleus (MN)/Comet assay in juvenile male and female F344 rats. SAN Trimer (37.5, 75, 150, or 300 mg/kg/day) was administered by gavage once daily for 4 days. Micronucleated reticulocyte (MN-RET) frequencies in blood were determined by flow cytometry, and DNA damage in blood, liver, and brain cells was assessed using the Comet assay. Highly significant dose-related increases (P < 0.0001) in MN-RET were measured in both male and female rats administered SAN Trimer. The RET population was reduced in high dose male rats, suggesting chemical-related bone marrow toxicity. Results of the Comet assay showed significant, dose-related increases in DNA damage in brain cells of male (P < 0.0074) and female (P < 0.0001) rats; increased levels of DNA damage were also measured in liver cells and leukocytes of treated rats. Chemical-related cytotoxicity was not indicated in any of the tissues examined for DNA damage. The results of this subacute MN/Comet assay indicate induction of significant genetic damage in multiple tissues of weanling F344 male and female rats after oral exposure to SAN Trimer. PMID:22351108

Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle

PubMed Central

Hitachi, Keisuke; Tsuchida, Kunihiro

2017-01-01

Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes (Dlk1, Gtl2, Rtl1/Rtl1as, and Rian) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge) locus in the skeletal muscle. PMID:27992376

Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle.

PubMed

Hitachi, Keisuke; Tsuchida, Kunihiro

2017-01-24

Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes (Dlk1, Gtl2, Rtl1/Rtl1as, and Rian) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge) locus in the skeletal muscle.

Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation.

PubMed

de La Serre, Claire Barbier; Ellis, Collin L; Lee, Jennifer; Hartman, Amber L; Rutledge, John C; Raybould, Helen E

2010-08-01

Consumption of diets high in fat and calories leads to hyperphagia and obesity, which is associated with chronic "low-grade" systemic inflammation. Ingestion of a high-fat diet alters the gut microbiota, pointing to a possible role in the development of obesity. The present study used Sprague-Dawley rats that, when fed a high-fat diet, exhibit either an obesity-prone (DIO-P) or obesity-resistant (DIO-R) phenotype, to determine whether changes in gut epithelial function and microbiota are diet or obese associated. Food intake and body weight were monitored daily in rats maintained on either low- or high-fat diets. After 8 or 12 wk, tissue was removed to determine adiposity and gut epithelial function and to analyze the gut microbiota using PCR. DIO-P but not DIO-R rats exhibit an increase in toll-like receptor (TLR4) activation associated with ileal inflammation and a decrease in intestinal alkaline phosphatase, a luminal enzyme that detoxifies lipopolysaccharide (LPS). Intestinal permeability and plasma LPS were increased together with phosphorylation of myosin light chain and localization of occludin in the cytoplasm of epithelial cells. Measurement of bacterial 16S rRNA showed a decrease in total bacterial density and an increase in the relative proportion of Bacteroidales and Clostridiales orders in high-fat-fed rats regardless of phenotype; an increase in Enterobacteriales was seen in the microbiota of DIO-P rats only. Consumption of a high-fat diet induces changes in the gut microbiota, but it is the development of inflammation that is associated with the appearance of hyperphagia and an obese phenotype.

Potential therapeutic effect of nanobased formulation of rivastigmine on rat model of Alzheimer's disease.

PubMed

Ismail, Manal Fouad; Elmeshad, Aliaa Nabil; Salem, Neveen Abdel-Hameed

2013-01-01

To sustain the effect of rivastigmine, a hydrophilic cholinesterase inhibitor, nanobased formulations were prepared. The efficacy of the prepared rivastigmine liposomes (RLs) in comparison to rivastigmine solution (RS) was assessed in an aluminium chloride (AlCl(3))-induced Alzheimer's model. Liposomes were prepared by lipid hydration (F1) and heating (F2) methods. Rats were treated with either RS or RLs (1 mg/kg/day) concomitantly with AlCl(3) (50 mg/kg/day). The study showed that the F1 method produced smaller liposomes (67.51 ± 14.2 nm) than F2 (528.7 ± 15.5 nm), but both entrapped the same amount of the drug (92.1% ± 1.4%). After 6 hours, 74.2% ± 1.5% and 60.8% ± 2.3% of rivastigmine were released from F1 and F2, respectively. Both RLs and RS improved the deterioration of spatial memory induced by AlCl(3), with RLs having a superior effect. Further biochemical measurements proved that RS and RLs were able to lower plasma C-reactive protein, homocysteine and asymmetric dimethy-larginine levels. RS significantly attenuated acetylcholinesterase (AChE) activity, whereas Na(+)/K(+)-adenosine triphosphatase (ATPase) activity was enhanced compared to the AlCl(3)-treated animals; however, RLs succeeded in normalization of AChE and Na(+)/K(+) ATPase activities. Gene-expression profile showed that cotreatment with RS to AlCl(3)-treated rats succeeded in exerting significant decreases in BACE1, AChE, and IL1B gene expression. Normalization of the expression of the aforementioned genes was achieved by coadministration of RLs to AlCl(3)-treated rats. The profound therapeutic effect of RLs over RS was evidenced by nearly preventing amyloid plaque formation, as shown in the histopathological examination of rat brain. RLs could be a potential drug-delivery system for ameliorating Alzheimer's disease.

Diminished metabolic responses to centrally-administered apelin-13 in diet-induced obese rats fed a high-fat diet.

PubMed

Clarke, K J; Whitaker, K W; Reyes, T M

2009-02-01

The central administration of apelin, a recently identified adipokine, has been shown to affect food and water intake. The present study investigated whether body weight could affect an animal's response to apelin. The effects of centrally-administered apelin-13 on food and water intake, activity and metabolic rate were investigated in adult male diet-induced obese (DIO) rats fed either a high fat (32%) or control diet. Rats were administered i.c.v. apelin-13, 15-30 min prior to lights out, and food and water intake, activity and metabolic rate were assessed. Intracerebroventricular administration of apelin-13 decreased food and water intake and respiratory exchange ratio in DIO rats on the control diet, but had no effect in DIO rats on the high-fat diet. In an effort to identify potential central mechanisms explaining the observed physiological responses, the mRNA level of the apelin receptor, APJ, was examined in the hypothalamus. A high-fat diet induced an up-regulation of the expression of the receptor. Apelin induced a down-regulation of the receptor, but only in the DIO animals on the high-fat diet. In conclusion, we have demonstrated a diminished central nervous system response to apelin that is coincident with obesity.

Characterization of the 5-HT2C receptor agonist lorcaserin on efficacy and safety measures in a rat model of diet-induced obesity

PubMed Central

Higgins, Guy A; Desnoyer, Jill; Van Niekerk, Annalise; Silenieks, Leo B; Lau, Winnie; Thevarkunnel, Sandy; Izhakova, Julia; DeLannoy, Ines AM; Fletcher, Paul J; DeLay, Josepha; Dobson, Howard

2015-01-01

The 5-HT2C receptor agonist lorcaserin (Belviq®) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28-day lorcaserin treatment in a diet-induced obesity (DIO) model using male, Sprague–Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1–2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle-treated controls (VEH: 10.6 ± 0.4%; LOR 1: 7.6 ± 1.2%; LOR 2: 5.4 ± 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7-day treatment period; plasma Cmin and Cmax were in the range 13–160 ng/mL (1 mg/kg b.i.d.) and 34–264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0–5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity. PMID:25692009

Enhanced inhibitory effects of TBT chloride on the development of F1 rats.

PubMed

Asakawa, H; Tsunoda, M; Kaido, T; Hosokawa, M; Sugaya, C; Inoue, Y; Kudo, Y; Satoh, T; Katagiri, H; Akita, H; Saji, M; Wakasa, M; Negishi, T; Tashiro, T; Aizawa, Y

2010-05-01

Neurotoxicity is one of the major effects of tributyltin (TBT). The effects on the next generation of F(1) rats exposed to TBT via the placenta and their dams' milk may be stronger than those on adults. Pregnant Wister rats were exposed to TBT at 0 and 125 ppm in their food. Half of the female F(1) rats in both groups were exposed to TBT at 125 ppm in their food from 9 to 15 weeks of age. Female F(1) rats were divided into the following groups: the control-control (CC) group, with no exposure; the TBT-control (TC) group, exposed to TBT via the placenta and their dams' milk; the control-TBT (CT) group, exposed to TBT via their food from 9 to 15 weeks of age; and the TBT-TBT (TT) group, exposed to TBT via the placenta, their dams' milk, and their food (n = 10/group). After administration, an open-field test and prepulse inhibition (PPI) test were performed at 15 weeks of age. The mean body weights of the TC and TT groups were significantly lower than that of the CC group from 9 to 15 weeks of age. The mean relative thymus weight of the TC and TT groups was significantly lower than that of the CC group. In the open-field test, a marked decrease in the total locomotion distance was observed in the TT group. The mean values in the TT and TC groups were significantly lower than that in the CC group. For the locomotion distance between 15 and 20 min, the mean values in the CT, TC, and TT groups were significantly lower than that in the CC group. The mean locomotor distance between 25 and 30 min in the TT group was significantly lower than that in the CC and TC groups. The mean values of instances of wall rearing in the TC, CT, and TT groups were significantly lower than that in the CC group. The mean value of face washing or body washing in the TT group was significantly lower than that in the CT group. There were no significant differences in indexes of the PPI test. Exposure to TBT via the placenta and their dams' milk inhibited the development of F(1) rats, which

PET imaging of cardiomyocyte apoptosis in a rat myocardial infarction model.

PubMed

Ma, Hui; Liu, Shaoyu; Xiong, Ying; Zhang, Zhanwen; Sun, Aixia; Su, Shu; Liang, Hong; Yuan, Gongjun; Tang, Ganghua

2018-06-23

Cardiomyocyte apoptosis has been observed in several cardiovascular diseases and contributes to the subsequent cardiac remodeling processes and progression to heart failure. Consequently, apoptosis imaging is helpful for noninvasively detecting the disease progression and providing treatment guidance. Here, we tested 18 F-labeled 2-(5-fluoropentyl)-2-methyl-malonic acid ( 18 F-ML-10) and 18 F-labeled 2-(3-fluoropropyl)-2-methyl-malonic acid ( 18 F-ML-8) for apoptosis imaging in rat models of myocardial infarction (MI) and compared them with 18 F-fluorodeoxyglucose ( 18 F-FDG). MI was induced in Sprague-Dawley rats by permanent left coronary artery ligation. Procedural success was confirmed by echocardiography and positron emission tomography (PET) imaging with 18 F-FDG. In vivo PET imaging with 18 F-ML-10 and 18 F-ML-8 was performed in the MI models at different time points after operation. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and immunohistochemical analyses were used to evaluate myocardial apoptosis. In vitro cell binding assays were performed to validate 18 F-ML-8 binding to apoptotic cardiomyocytes. PET imaging demonstrated high 18 F-ML-10 and 18 F-ML-8 uptake where 18 F-FDG uptake was absent. The focal accumulation of the two tracers was high on days 1 and 3 but was not notable on days 5 and 7 after surgery. The infarct-to-lung uptake ratio was 4.29 ± 0.30 for 18 F-ML-10 and 3.51 ± 0.18 for 18 F-ML-8 (n = 6, analyzed by averaging the uptake ratios on postoperative days 1 and 3, P < 0.05). The TUNEL results showed that myocardial cell apoptosis was closely related to the focal uptake of the apoptotic tracers in the infarct area. In addition, the apoptosis rates calculated from the TUNEL results were better correlated with 18 F-ML-8 uptake than with 18 F-ML-10 uptake. Ex vivo cell binding assays demonstrated that 18 F-ML-8 accumulated in apoptotic cells but not in necrotic or normal cells. PET imaging

An in vivo MRI Template Set for Morphometry, Tissue Segmentation, and fMRI Localization in Rats

PubMed Central

Valdés-Hernández, Pedro Antonio; Sumiyoshi, Akira; Nonaka, Hiroi; Haga, Risa; Aubert-Vásquez, Eduardo; Ogawa, Takeshi; Iturria-Medina, Yasser; Riera, Jorge J.; Kawashima, Ryuta

2011-01-01

Over the last decade, several papers have focused on the construction of highly detailed mouse high field magnetic resonance image (MRI) templates via non-linear registration to unbiased reference spaces, allowing for a variety of neuroimaging applications such as robust morphometric analyses. However, work in rats has only provided medium field MRI averages based on linear registration to biased spaces with the sole purpose of approximate functional MRI (fMRI) localization. This precludes any morphometric analysis in spite of the need of exploring in detail the neuroanatomical substrates of diseases in a recent advent of rat models. In this paper we present a new in vivo rat T2 MRI template set, comprising average images of both intensity and shape, obtained via non-linear registration. Also, unlike previous rat template sets, we include white and gray matter probabilistic segmentations, expanding its use to those applications demanding prior-based tissue segmentation, e.g., statistical parametric mapping (SPM) voxel-based morphometry. We also provide a preliminary digitalization of latest Paxinos and Watson atlas for anatomical and functional interpretations within the cerebral cortex. We confirmed that, like with previous templates, forepaw and hindpaw fMRI activations can be correctly localized in the expected atlas structure. To exemplify the use of our new MRI template set, were reported the volumes of brain tissues and cortical structures and probed their relationships with ontogenetic development. Other in vivo applications in the near future can be tensor-, deformation-, or voxel-based morphometry, morphological connectivity, and diffusion tensor-based anatomical connectivity. Our template set, freely available through the SPM extension website, could be an important tool for future longitudinal and/or functional extensive preclinical studies. PMID:22275894

Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease

PubMed Central

Joo, Illsung L.; Lai, Aaron Y.; Bazzigaluppi, Paolo; Koletar, Margaret M.; Dorr, Adrienne; Brown, Mary E.; Thomason, Lynsie A. M.; Sled, John G.; McLaurin, JoAnne; Stefanovic, Bojana

2017-01-01

Alzheimer’s disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans. PMID:28401931

Disposition of [14C]N,N-dimethyl-p-toluidine in F344 rats and B6C3F1 mice.

PubMed

Dix, Kelly J; Ghanbari, Katayoon; Hedtke-Weber, Briana M

2007-05-15

N,N-Dimethyl-p-toluidine (DMPT) is used as a polymerization accelerator, in industrial glues, and as an intermediate in dye and pesticide synthesis. There is potential for human exposure to DMPT. The disposition of oral and intravenous (i.v.) doses of [14C]DMPT in F344 rats and B6C3F1 mice was investigated. A single i.v. (2.5 mg/kg) or oral (2.5, 25, or 250 mg/kg) dose of [14C]DMPT (1-25 microCi) was administered in an aqueous vehicle to male rats and mice. The 25-mg/kg oral dose was administered to females to investigate possible gender differences in disposition. However, no striking gender differences were observed. Since toxicity studies conducted elsewhere used a corn oil vehicle, the 250-mg/kg oral dose also was administered in corn oil to male rats; disposition was not dependent on vehicle. Excreta (through 24 h) and tissues collected at sacrifice were analyzed for total radioactivity. Dose-dependent differences in toxicity and disposition were observed. Toxicity at the 250-mg/kg oral dose to male mice was consistent with acute renal failure. At the same dose, male rats exhibited clinical signs of toxicity through 12 h but were clinically normal by 24 h. At lower oral doses, [14C]DMPT-derived radioactivity was well absorbed and rapidly excreted, primarily in urine.

Feasibility of myocardial PET imaging using a benzylguanidine analog: meta-(3-[18F]fluoropropyl)benzylguanidine ([18F]mFPBG).

PubMed

Woo, Sang-Keun; Moon, Byung Seok; Kim, Bom Sahn; Kim, Min Hwan; Lee, Yong Jin; Jung, Jae Ho; Lee, Kyo Chul; Seo, Youngho; Kim, Wook; Lim, Sang Moo; Lee, Byung Chul; Kim, Sang Eun

2018-05-03

Global and regional sympathetic activity in the heart can be evaluated using [ 123 I]meta-iodobenzylguanidine ([ 123 I]mIBG) imaging. However, [ 123 I]mIBG is associated with low image spatial resolution and sensitivity in cardiac imaging. We investigated the capability of an F-18-labeled mIBG derivative, meta-(3-[ 18 F]fluoropropyl)benzylguanidine ([ 18 F]mFPBG), for identifying ischemic and viable myocardium in a rat model of myocardial infarction. The ex vivo biodistribution and in vivo metabolic stability of [ 18 F]mFPBG were investigated in Sprague-Dawley rats. Selective cardiac adrenergic activation was confirmed via a blocking experiment involving pretreatment with desipramine (2 mg kg -1 ), followed by the administration of [ 18 F]mFPBG. Imaging properties of [ 18 F]mFPBG were compared with those of traditional cardiac imaging radiotracers ([ 123 I]mIBG and [ 99m Tc]MIBI) in a rat model of myocardial infarction. Non-invasive image-based measurements of infarct sizes were then compared with histological findings by using Bland-Altman analysis. The differences in infarct sizes determined using histological analysis and [ 18 F]mFPBG PET were -2.55 ± 4.99% (range: -12.33 to 7.22), -2.35 ± 3.32% (range: -8.87 to 4.16), and -3.15 ± 6.16% (range: -15.24 to 8.93) at 5, 20, and 40 min, respectively. Furthermore, [ 18 F]mFPBG PET was superior to traditional imaging methods in assessing the degree of ischemia in areas of myocardial infarction, as well as the actual infarct size. Compared to [ 123 I]mIBG, [ 18 F]mFPBG showed improved spatial resolution and sensitivity in a rat model of myocardial infarction. This result suggested that [ 18 F]mFPBG is a promising cardiac PET imaging agent for potential diagnostic application in PET cardiology. Copyright © 2018 Elsevier Inc. All rights reserved.

Diet-Induced Obesity and Diet-Resistant rats: differences in the rewarding and anorectic effects of D-amphetamine

PubMed Central

Valenza, Marta; Steardo, Luca; Cottone, Pietro; Sabino, Valentina

2015-01-01

Rationale Obesity is a leading public health problem worldwide. Multiple lines of evidence associate deficits in the brain reward circuit with obesity. Objective Whether alterations in brain reward sensitivity precede or are a consequence of obesity is unknown. This study aimed to investigate both innate and obesity-induced differences in the sensitivity to the effects of an indirect dopaminergic agonist. Methods Rats genetically prone to diet-induced obesity (DIO) and their counterpart diet-resistant (DR) were fed a chow diet and their response to D-amphetamine on intracranial self-stimulation and food intake were assessed. The same variables were then evaluated after exposing the rats to a high-fat diet, after DIO rats selectively developed obesity. Finally, gene expression levels of dopamine receptor 1 and 2 as well as tyrosine hydroxylase were measured in reward-related brain regions. Results In a pre-obesity state, DIO rats showed innate decreased sensitivity to the reward-enhancing and anorectic effects of D-amphetamine, as compared to DR rats. In a diet-induced obese state, the insensitivity to the potentiating effects of D-amphetamine on ICSS threshold persisted and became more marked in DIO rats, while the anorectic effects were comparable between genotypes. Finally, innate and obesity-induced differences in the gene expression of dopamine receptors were observed. Conclusions Our results demonstrate that brain reward deficits antedate the development of obesity and worsen after obesity is fully developed, suggesting that these alterations represent vulnerability factors for its development. Moreover, our data suggests that the reward-enhancing and anorectic effects of D-amphetamine are dissociable in the context of obesity. PMID:26047964

Carcinogenicity of glycidamide in B6C3F1 mice and F344/N rats from a two-year drinking water exposure.

PubMed

Beland, Frederick A; Olson, Greg R; Mendoza, Maria C B; Marques, M Matilde; Doerge, Daniel R

2015-12-01

Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F1 mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide glycidamide. We have now examined the carcinogenic effects of glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into glycidamide. Published by Elsevier Ltd.

Worse renal disease in postmenopausal F2[Dahl S x R]-intercross rats: detection of novel QTLs affecting hypertensive kidney disease.

PubMed

Herrera, Victoria L M; Pasion, Khristine A; Moran, Ann Marie; Ruiz-Opazo, Nelson

2013-01-01

The prevalence of hypertension increases after menopause with 75% of postmenopausal women developing hypertension in the United States, along with hypertensive end organ diseases. While human and animal model studies have indicated a protective role for estrogen against cardiovascular disease and glomerulosclerosis, clinical studies of hormone replacement therapy in postmenopausal women have shown polar results with some improvement in hypertension but worsening of hypertensive kidney disease, or no effect at all. These observations suggest that the pathogenesis of postmenopausal hypertension and its target organ complications is more complex than projected, and that loss of endogenous estrogens induces epigenetic changes that alter genetic susceptibility to end-organ complications per se resulting in pathogenetic mechanisms beyond correction by hormone replacement. We studied postmenopausal-induced changes in renal disease and performed a total genome scan for quantitative trait loci (QTLs) affecting kidney disease in postmenopausal 16m-old F2[Dahl S x R]-intercross female rats. We used glomerular injury score (GIS) as quantitative trait. We compared QTLs amongst premenopausal, ovariectomized and postmenopausal F2[Dahl S x R]-intercross rats using identical phenotype characterization. Postmenopausal F2[Dahl S x R]-intercross rats exhibited increased hypertensive glomerulosclerosis (P<0.01) and equivalent levels of kidney disease when compared to premenopausal and ovariectomized F2[Dahl S x R]-intercross rats respectively. We detected three significant to highly significant GIS-QTLs (GIS-pm1 on chromosome 4, LOD 3.54; GIS-pm2 on chromosome 3, LOD 2.72; GIS-pm3 on chromosome 5, LOD 2.37) and two suggestive GIS-QTLs (GIS-pm4 on chromosome 2, LOD 1.70; GIS-pm5 on chromosome 7, LOD 1.28), all of which were unique to this postmenopausal population. Detection of increased renal disease phenotype in postmenopausal and ovariectomized subjects suggests a protective role of

Worse Renal Disease in Postmenopausal F2[Dahl S x R]-Intercross Rats: Detection of Novel QTLs Affecting Hypertensive Kidney Disease

PubMed Central

Herrera, Victoria L. M.; Pasion, Khristine A.; Moran, Ann Marie; Ruiz-Opazo, Nelson

2013-01-01

The prevalence of hypertension increases after menopause with 75% of postmenopausal women developing hypertension in the United States, along with hypertensive end organ diseases. While human and animal model studies have indicated a protective role for estrogen against cardiovascular disease and glomerulosclerosis, clinical studies of hormone replacement therapy in postmenopausal women have shown polar results with some improvement in hypertension but worsening of hypertensive kidney disease, or no effect at all. These observations suggest that the pathogenesis of postmenopausal hypertension and its target organ complications is more complex than projected, and that loss of endogenous estrogens induces epigenetic changes that alter genetic susceptibility to end-organ complications per se resulting in pathogenetic mechanisms beyond correction by hormone replacement. We studied postmenopausal-induced changes in renal disease and performed a total genome scan for quantitative trait loci (QTLs) affecting kidney disease in postmenopausal 16m-old F2[Dahl S x R]-intercross female rats. We used glomerular injury score (GIS) as quantitative trait. We compared QTLs amongst premenopausal, ovariectomized and postmenopausal F2[Dahl S x R]-intercross rats using identical phenotype characterization. Postmenopausal F2[Dahl S x R]-intercross rats exhibited increased hypertensive glomerulosclerosis (P<0.01) and equivalent levels of kidney disease when compared to premenopausal and ovariectomized F2[Dahl S x R]-intercross rats respectively. We detected three significant to highly significant GIS-QTLs (GIS-pm1 on chromosome 4, LOD 3.54; GIS-pm2 on chromosome 3, LOD 2.72; GIS-pm3 on chromosome 5, LOD 2.37) and two suggestive GIS-QTLs (GIS-pm4 on chromosome 2, LOD 1.70; GIS-pm5 on chromosome 7, LOD 1.28), all of which were unique to this postmenopausal population. Detection of increased renal disease phenotype in postmenopausal and ovariectomized subjects suggests a protective role of

NTP toxicity studies of dimethylaminopropyl chloride, hydrochloride (CAS No. 5407-04-5) administered by Gavage to F344/N rats and B6C3F1 mice.

PubMed

Abdo, Km

2007-07-01

Dimethylaminopropyl chloride, hydrochloride is used primarily as an industrial and research organic chemical intermediate acting as an alkylating reagent in Grignard and other types of reactions. It is also used as a pharmaceutical intermediate for the synthesis of many types of drugs, as an agricultural chemical intermediate, as a photographic chemical intermediate, and as a biochemical reagent for enzyme and other studies. Human occupational or other accidental exposure can occur by inhalation, ingestion, or skin absorption. Male and female F344/N rats and B6C3F1 mice received dimethylaminopropyl chloride, hydrochloride (greater than 99% pure) in water by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. In the 2-week toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg dimethylaminopropyl chloride, hydrochloride/kg body weight in deionized water by gavage, 5 days per week for 16 days. All dosed male and female rats and mice survived until the end of the 2-week study; one vehicle control female mouse died early. Mean body weights of all dosed groups of rats and mice were similar to those of the vehicle control groups. No gross or microscopic lesions were considered related to dimethylaminopropyl chloride, hydrochloride administration. In the 3-month toxicity studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg/kg in deionized water by gavage, 5 days per week for 3 months. One male rat in the 50 mg/kg group died during week 12 of the study, and one female mouse in the 100 mg/kg group died during week 9 and another during week 13. The final mean body weights of 50 mg/kg male rats and 50 mg/kg female mice were significantly less than those of the vehicle controls. Possible chemical-related clinical findings in rats

Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-βl and Smad2/3 pathways in high-fat diet-induced obesity rat model.

PubMed

Hong, Seul-Ki; Choo, Eun-Ho; Ihm, Sang-Hyun; Chang, Kiyuk; Seung, Ki-Bae

2017-11-01

Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-βl and its downstream Smad2/3 pathways may play a pivotal role in the pathogenesis of obesity-induced myocardial fibrosis, and the antidiabetic dipeptidyl peptidase 4 inhibitors (DPP4i) might affect these pathways. We investigated whether DPP4i reduces myocardial fibrosis by inhibiting the TGF-β1 and Smad2/3 pathways in the myocardium of a diet-induced obesity (DIO) rat model. Eight-week-old male spontaneously hypertensive rats (SHRs) were fed either a normal fat diet (chow) or a high-fat diet (HFD) and then the HFD-fed SHRs were randomized to either the DPP4i (MK-0626) or control (distilled water) groups for 12weeks. At 20weeks old, all the rats underwent hemodynamic and metabolic studies and Doppler echocardiography. Compared with the normal fat diet (chow)-fed SHRs, the HFD-fed SHRs developed a more intense degree of hyperglycemia and dyslipidemia and showed a constellation of left ventricular (LV) diastolic dysfunction, and exacerbated myocardial fibrosis, as well as activation of the TGF-β1 and Smad2/3 pathways. DPP4i significantly improved the metabolic and hemodynamic parameters. The echocardiogram showed that DPP4i improved the LV diastolic dysfunction (early to late ventricular filling velocity [E/A] ratio, 1.49±0.21 vs. 1.77±0.09, p<0.05). Furthermore, DPP4i significantly reduced myocardial fibrosis and collagen production by the myocardium and suppressed TGF-β1 and phosphorylation of Smad2/3 in the heart. In addition, DPP4i decreased TGF-β1-induced collagen production and TGF-β1-mediated phosphorylation and nuclear translocation of Smad2/3 in rat cardiac fibroblasts. In conclusion, DPP4 inhibition attenuated myocardial fibrosis and improved LV diastolic dysfunction in a DIO rat model by modulating the TGF-β1 and Smad2/3 pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Toxicology and carcinogenesis studies of methylphenidate hydrochloride (Cas No. 298-59-9) in F344/N rats and B6C3F1 mice (feed studies). Technical report series

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

NONE

1995-07-01

Toxicology and carcinogenicity studies were conducted by administration of methylphenidate hydrochloride in feed to groups of 70 F344/N rats of each sex at doses of 0, 100, 500, or 1,0000 ppm and to groups of 70 B6C3F1 mice of each sex at doses of 0, 50, 250, or 500 ppm. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of methylphenidate hydrochloride in male or female F344/N rats receiving 100, 500, or 1,000 ppm. There was some evidence of carcinogenic activity in male and female B6C3F1 mice, based on the occurrence of hepatocellular neoplasms.more » Treatment of female rats with methylphenidate hydrochloride was associated with a decrease in the incidence of mammary gland fibroadenomas. Administration of methylphenidate hydrochloride to male and female mice resulted in increased incidence of eosinophilic foci in the liver.« less

Propiverine-induced accumulation of nuclear and cytosolic protein in F344 rat kidneys: Isolation and identification of the accumulating protein

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

Dietrich, D.R.; Heussner, A.H.; O'Brien, E.

2008-12-15

Male and female F344 rats but not B6C3F1 mice exposed for 104 weeks to propiverine hydrochloride (1-methylpiperid-4-yl 2,2-diphenyl-2-(1-propoxy)acetate hydrochloride), used for treatment of patients with neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), presented with an accumulation of proteins in the cytosol and nuclei of renal proximal tubule epithelial cells, yet despite this, no increased renal tumor incidence was observed. In order to provide an improved interpretation of these findings and a better basis for human health risk assessment, male and female F344 rats were exposed for 16 weeks to 1000 ppm propiverine in the diet, the accumulating protein wasmore » isolated from the kidneys via cytosolic and nuclear preparations or laser-capture microdissection and analyzed using molecular weight determination and mass spectrometry. The accumulating protein was found to be D-amino acid oxidase (DAAO), an enzyme involved in amino and fatty acid metabolism. Subsequent reanalysis of kidney homogenate and nuclear samples as well as tissue sections using western blot and DAAO-immunohistochemistry, confirmed the presence and localization of DAAO in propiverine-treated male and female F344 rats. The accumulation of DAAO only in rats, and the limited similarity of rat DAAO with other species, including humans, suggests a rat-specific mechanism underlying the drug-induced renal DAAO accumulation with little relevance for patients chronically treated with propiverine.« less

[¹⁸F]Altanserin and small animal PET: impact of multidrug efflux transporters on ligand brain uptake and subsequent quantification of 5-HT₂A receptor densities in the rat brain.

PubMed

Kroll, Tina; Elmenhorst, David; Matusch, Andreas; Celik, A Avdo; Wedekind, Franziska; Weisshaupt, Angela; Beer, Simone; Bauer, Andreas

2014-01-01

The selective 5-hydroxytryptamine type 2a receptor (5-HT(2A)R) radiotracer [(18)F]altanserin is a promising ligand for in vivo brain imaging in rodents. However, [(18)F]altanserin is a substrate of P-glycoprotein (P-gp) in rats. Its applicability might therefore be constrained by both a differential expression of P-gp under pathological conditions, e.g. epilepsy, and its relatively low cerebral uptake. The aim of the present study was therefore twofold: (i) to investigate whether inhibition of multidrug transporters (MDT) is suitable to enhance the cerebral uptake of [(18)F]altanserin in vivo and (ii) to test different pharmacokinetic, particularly reference tissue-based models for exact quantification of 5-HT(2A)R densities in the rat brain. Eighteen Sprague-Dawley rats, either treated with the MDT inhibitor cyclosporine A (CsA, 50 mg/kg, n=8) or vehicle (n=10) underwent 180-min PET scans with arterial blood sampling. Kinetic analyses of tissue time-activity curves (TACs) were performed to validate invasive and non-invasive pharmacokinetic models. CsA application lead to a two- to threefold increase of [(18)F]altanserin uptake in different brain regions and showed a trend toward higher binding potentials (BP(ND)) of the radioligand. MDT inhibition led to an increased cerebral uptake of [(18)F]altanserin but did not improve the reliability of BP(ND) as a non-invasive estimate of 5-HT(2A)R. This finding is most probable caused by the heterogeneous distribution of P-gp in the rat brain and its incomplete blockade in the reference region (cerebellum). Differential MDT expressions in experimental animal models or pathological conditions are therefore likely to influence the applicability of imaging protocols and have to be carefully evaluated. © 2013.

Fatal mechanical asphyxia induces changes in energy utilization in the rat brain: An (18)F-FDG-PET study.

PubMed

Ma, Suhua; You, Shengzhong; Hao, Li; Zhang, Dongchuan; Quan, Li

2015-07-01

This study was designed to evaluate changes in brain glucose metabolism in rats following ligature strangulation. Thirteen male Wistar rats were used in the present study, divided into control (n=7) and asphyxia groups (n=6, ligature strangulation). Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) was used to evaluate brain glucose metabolism. Rats were scanned for PET-CT, and image data co-registered with a T2WI MRI template using SPM8 software. Image J was employed to draw regions of interest (ROIs) from the MRI template and acquire ROI activity information from the PET images. In the asphyxia group vs. controls, (18)F-FDG uptake (FU) was decreased in the substantia nigra (25.26%, p<0.001), rhombencephalon (pons/medulla oblongata, 13.92%, p<0.01), hypothalamus (22.06%, p<0.01), ventral tegmentum (10.12%, p<0.05) and amygdala (12.74%, p<0.05); however, FU was increased in motor (18.21%, p<0.05) and visual cortices (19.2%, p<0.05). The glucose metabolism distribution map in the asphyxiated rat brains were substantially changed versus controls. PET with (18)F-FDG can demonstrate excitement and inhibition of different brain areas even in cases of ligature strangulation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Acute Ozone (O3) Exposure Enhances Aortic Contraction in Healthy Rats while Exacerbating Pulmonary Injury in Diabetics

EPA Science Inventory

Air pollution exposure affects health adversely in individuals with type 2 diabetes (T2D) and diet induced obesity (DIO). We hypothesized that T2D and DIO would exacerbate O3 induced pulmonary responses and alter arterial reactivity. Male Wistar and Goto Kakizaki (GK) rats, a l...

Toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. I. Acute exposure and recovery studies.

PubMed Central

Bucher, J R; Gupta, B N; Adkins, B; Thompson, M; Jameson, C W; Thigpen, J E; Schwetz, B A

1987-01-01

Male and female F344/N rats and B6C3F1 mice were exposed to lethal and sublethal concentrations of methyl isocyanate by inhalation. Mortality, clinical signs, body and organ weights, and changes in clinical pathology and hematology were monitored immediately after 2-hr exposures and during the ensuing 3 months. Additional studies investigated the possible involvement of cyanide in the toxicity of methyl isocyanate. During exposures, signs of restlessness, lacrimation, and a reddish discharge from the nose and mouth were evident in rats and mice. Following exposures, rats and mice were dyspneic and weak. Deaths of rats and mice exposed to lethal concentrations (20 to 30 ppm) began within 15-18 hr, with males more prone to early death than females. A second wave of deaths occurred after 8 to 10 days, affecting primarily female rats and mice exposed to 20 to 30 ppm of methyl isocyanate, and male and female rats exposed to 10 ppm. Most deaths occurred during the first month following the exposures and were preceded by periods of severe respiratory distress. Body weights decreased in proportion to dose early, but then weight gain resumed in survivors at control rates. The only organ with a consistent, dose-related weight change was the lung, which was heavier throughout the studies in animals exposed to high concentrations of methyl isocyanate. No significant clinical pathology, or hematologic changes were observed in exposed rats. Blood and brain cholinesterase were not inhibited. Studies attempting to measure cyanide in the blood of methyl isocyanate-exposed rats, and attempting to affect lethality with a cyanide antidote (sodium nitrite and sodium thiosulfate) gave negative results.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3622444

Spontaneous motor activity during the development and maintenance of diet-induced obesity in the rat.

PubMed

Levin, B E

1991-09-01

More than 80% of most daily spontaneous activities (assessed in an Omnitech activity monitor) occurred during the last hour of light and 12 h of the dark phase in 8 chow-fed male Sprague-Dawley rats. Thirty additional rats were, therefore, monitored over this 13-h period to assess the relationship of activity to the development and maintenance of diet-induced obesity (DIO) on a diet high in energy, fat and sucrose (CM diet). Nine of 20 rats became obese after 3 months on the CM diet, with 71% greater weight gain than 10 chow-fed controls. Eleven of 20 rats were diet resistant (DR), gaining the same amount of weight as chow-fed rats. Neither initial activity levels nor initial body weights on chow (Period I) differed significantly across retrospectively identified groups. After 3 months on CM diet or chow (Period II), as well as after an additional 3 months after CM diet-fed rats returned to chow (Period III), there were significant inverse correlations (r = -.606 to -.370) between body weight at the time of testing and various measures of movement in the horizontal plane. There was no relationship to dietary content nor consistent correlations of body weight or diet group to vertical movements, an indirect measure of ingestive behavior. Patterns of time spent in the vertical position were significantly different for DIO vs. DR rats in Period III, however. Thus, differences in food intake and metabolic efficiency, rather than differences in nocturnal activity, are probably responsible for the greater weight gain in DIO-prone rats placed on CM diet.(ABSTRACT TRUNCATED AT 250 WORDS)

A physiologically based pharmacokinetic model for ethylene oxide in mouse, rat, and human.

PubMed

Fennell, T R; Brown, C D

2001-06-15

Ethylene oxide (EO) is widely used as a gaseous sterilant and industrial intermediate and is a direct-acting mutagen and carcinogen. The objective of these studies was to develop physiologically based pharmacokinetic (PB-PK) models for EO to describe the exposure-tissue dose relationship in rodents and humans. We previously reported results describing in vitro and in vivo kinetics of EO metabolism in male and female F344 rats and B6C3F1 mice. These studies were extended by determining the kinetics of EO metabolism in human liver cytosol and microsomes. The results indicate enzymatically catalyzed GSH conjugation via cytosolic glutathione S-transferase (cGST) and hydrolysis via microsomal epoxide hydrolase (mEH) occur in both rodents and humans. The in vitro kinetic constants were scaled to account for cytosolic (cGST) and microsomal (mEH) protein content and incorporated into PB-PK descriptions for mouse, rat, and human. Flow-limited models adequately predicted blood and tissue EO levels, disposition, and elimination kinetics determined experimentally in rats and mice, with the exception of testis concentrations, which were overestimated. Incorporation of a diffusion-limited description for testis improved the ability of the model to describe testis concentrations. The model accounted for nonlinear increases in blood and tissue concentrations that occur in mice on exposure to EO concentrations greater than 200 ppm. Species differences are predicted in the metabolism and exposure-dose relationship, with a nonlinear relationship observed in the mouse as a result of GSH depletion. These models represent an essential step in developing a mechanistically based EO exposure-dose-response description for estimating human risk from exposure to EO. Copyright 2001 Academic Press.

Effects of Benzo(a)pyrene on Intra-testicular Function in F-344 Rats

PubMed Central

Archibong, Anthony E.; Ramesh, Aramandla; Niaz, Mohammad S.; Brooks, Cynthia M.; Roberson, Shannon I.; Lunstra, Donald D.

2008-01-01

The objective of this study was to evaluate the reproductive risk associated with exposure of adult male Fisher-344 (F-344) rats to inhaled benzo(a)pyrene (BaP), a ubiquitous environmental toxicant present in cigarette smoke, automobile exhaust fumes and industrial emissions. Rats were assigned randomly to a treatment or control group. Treatment consisted of exposure of rats via nose-only inhalation to 75μg BaP/m3, 4 hours daily for 60 days, while control animals were unexposed (UNC). Blood samples were collected immediately on day 60 of exposures (time 0) and subsequently at 24, 48, and 72 hours, to assess the effect of exposures to BaP on plasma testosterone and luteinizing hormone (LH) concentrations. Mean testis weight, total weight of tubules and total tubular length per paired testes were reduced 33% (P< 0.025), 27% (P < 0.01) and 39%, respectively in exposed rats (P < 0.01) compared with UNC rats. The number of homogenization-resistant spermatids was significantly reduced in BaP-exposed versus UNC rats. Plasma testosterone and intra-testicular testosterone (ITT) concentrations were significantly decreased by BaP compared with those of UNC rats. The decreases in circulating plasma testosterone were accompanied by concomitant increases in plasma LH concentrations in BaP-exposed versus control rats (P < 0.05). These data suggest that 60 days exposure to inhaled BaP contribute to reduced testicular endocrine and spermatogenic functions in exposed rats. PMID:18441403

Genetic threshold hypothesis of neocortical spike-and-wave discharges in the rat: An animal model of petit mal epilepsy

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

Vadasz, C.; Fleischer, A.; Carpi, D.

1995-02-27

Neocortical high-voltage spike-and-wave discharges (HVS) in the rat are an animal model of petit mal epilepsy. Genetic analysis of total duration of HVS (s/12 hr) in reciprocal F1 and F2 hybrids of F344 and BN rats indicated that the phenotypic variability of HVS cannot be explained by simple, monogenic Mendelian model. Biometrical analysis suggested the presence of additive, dominance, and sex-linked-epistatic effects, buffering maternal influence, and heterosis. High correlation was observed between average duration (s/episode) and frequency of occurrence of spike-and-wave episodes (n/12 hr) in parental and segregating generations, indicating that common genes affect both duration and frequency of themore » spike-and-wave pattern. We propose that both genetic and developmental - environmental factors control an underlying quantitative variable, which, above a certain threshold level, precipitates HVS discharges. These findings, together with the recent availability of rat DNA markers for total genome mapping, pave the way to the identification of genes that control the susceptibility of the brain to spike-and-wave discharges. 67 refs., 3 figs., 5 tabs.« less

Embedded Weapons-Grade Tungsten Alloy Shrapnel Rapidly Induces Metastatic High-Grade Rhabdomyosarcomas in F344 Rats

PubMed Central

Kalinich, John F.; Emond, Christy A.; Dalton, Thomas K.; Mog, Steven R.; Coleman, Gary D.; Kordell, Jessica E.; Miller, Alexandra C.; McClain, David E.

2005-01-01

Continuing concern regarding the potential health and environmental effects of depleted uranium and lead has resulted in many countries adding tungsten alloy (WA)-based munitions to their battlefield arsenals as replacements for these metals. Because the alloys used in many munitions are relatively recent additions to the list of militarily relevant metals, very little is known about the health effects of these metals after internalization as embedded shrapnel. Previous work in this laboratory developed a rodent model system that mimicked shrapnel loads seen in wounded personnel from the 1991 Persian Gulf War. In the present study, we used that system and male F344 rats, implanted intramuscularly with pellets (1 mm × 2 mm cylinders) of weapons-grade WA, to simulate shrapnel wounds. Rats were implanted with 4 (low dose) or 20 pellets (high dose) of WA. Tantalum (20 pellets) and nickel (20 pellets) served as negative and positive controls, respectively. The high-dose WA-implanted rats (n = 46) developed extremely aggressive tumors surrounding the pellets within 4–5 months after implantation. The low-dose WA-implanted rats (n = 46) and nickel-implanted rats (n = 36) also developed tumors surrounding the pellets but at a slower rate. Rats implanted with tantalum (n = 46), an inert control metal, did not develop tumors. Tumor yield was 100% in both the low- and high-dose WA groups. The tumors, characterized as high-grade pleomorphic rhabdomyosarcomas by histopathology and immunohistochemical examination, rapidly metastasized to the lung and necessitated euthanasia of the animal. Significant hematologic changes, indicative of polycythemia, were also observed in the high-dose WA-implanted rats. These changes were apparent as early as 1 month postimplantation in the high-dose WA rats, well before any overt signs of tumor development. These results point out the need for further studies investigating the health effects of tungsten and tungsten-based alloys. PMID:15929896

Deiodinase activities in thyroids and tissues of iodine-deficient female rats.

PubMed

Lavado-Autric, Rosalia; Calvo, Rosa Maria; de Mena, Raquel Martinez; de Escobar, Gabriella Morreale; Obregon, Maria-Jesus

2013-01-01

Severe iodine deficiency is characterized by goiter, preferential synthesis, and secretion of T(3) in thyroids, hypothyroxinemia in plasma and tissues, normal or low plasma T(3), and slightly increased plasma TSH. We studied changes in deiodinase activities and mRNA in several tissues of rats maintained on low-iodine diets (LIDs) or LIDs supplemented with iodine (LID+I). T(4) and T(3) concentrations decreased in plasma, tissues, and thyroids of LID rats, and T(4) decreased more than T(3) (50%). The highest type 1 iodothyronine deiodinase (D1) activities were found in the thyroid, kidney, and the liver; pituitary, lung, and ovary had lower D1 activities; but the lowest levels were found in the heart and skeletal muscle. D1 activity decreased in all tissues of LID rats (10-40% of LID+I rats), except for ovary and thyroids, which D1 activity increased 2.5-fold. Maximal type 2 iodothyronine deiodinase (D2) activities were found in thyroid, brown adipose tissue, and pituitary, increasing 6.5-fold in thyroids of LID rats and about 20-fold in the whole gland. D2 always increased in response to LID, and maximal increases were found in the cerebral cortex (19-fold), thyroid, brown adipose tissue, and pituitary (6-fold). Lower D2 activities were found in the ovary, heart, and adrenal gland, which increased in LID. Type 3 iodothyronine deiodinase activity was undetectable. Thyroidal Dio1 and Dio2 mRNA increased in the LID rats, and Dio1 decreased in the lung, with no changes in mRNA expression in other tissues. Our data indicate that LID induces changes in deiodinase activities, especially in the thyroid, to counteract the low T(4) synthesis and secretion, contributing to maintain the local T(3) concentrations in the tissues with D2 activity.

F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (III) Activity in models of cognition and negative symptoms

PubMed Central

Depoortère, R; Auclair, A L; Bardin, L; Slot, L Bruins; Kleven, M S; Colpaert, F; Vacher, B; Newman-Tancredi, A

2007-01-01

Background and purpose: The D2/D3 receptor antagonist, D4 receptor partial agonist, and high efficacy 5-HT1A receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the ‘serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia. Experimental approach: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems. Key results: Through 5-HT1A activation, F15063 partially alleviated (MED: 0.04 mg kg−1) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg−1, F15063 reduced interaction by itself. F15063 (0.16 mg kg−1) selectively re-established PCP-impaired ‘cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04–0.63 mg kg−1) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D4 partial agonism, as it was blocked by the D4 antagonist L745,870. Finally, F15063 up to 40 mg kg−1 did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating. Conclusions and implications: The balance of D2/D3, D4 and 5-HT1A receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia. PMID:17375085

Tissue-engineered thyroid cell sheet rescued hypothyroidism in rat models after receiving total thyroidectomy comparing with nontransplantation models.

PubMed

Arauchi, Ayumi; Shimizu, Tatsuya; Yamato, Masayuki; Obara, Takao; Okano, Teruo

2009-12-01

For hormonal deficiency caused by endocrine organ diseases, continuous oral hormone administration is indispensable to supplement the shortage of hormones. In this study, as a more effective therapy, we have tried to reconstruct the three-dimensional thyroid tissue by the cell sheet technology, a novel tissue engineering approach. The cell suspension obtained from rat thyroid gland was cultured on temperature-responsive culture dishes, from which confluent cells detach as a cell sheet simply by reducing temperature without any enzymatic treatment. The 8-week-old Lewis rats were exposed to total thyroidectomy as hypothyroidism models and received thyroid cell sheet transplantation 1 week after total thyroidectomy. Serum levels of free triiodothyronine (fT(3)) and free thyroxine (fT(4)) significantly decreased 1 week after total thyroidectomy. On the other hand, transplantation of the thyroid cell sheets was able to restore the thyroid function 1 week after the cell sheet transplantation, and improvement was maintained for 4 weeks. Moreover, morphological analyses showed typical thyroid follicle organization, and anti-thyroid-transcription-factor-1 antibody staining demonstrated the presence of follicle epithelial cells. The presence of functional microvessels was also detected within the engineered thyroid tissues. In conclusion, our results indicate that thyroid cell sheets transplanted in a model of total thyroidectomy can reorganize histologically to resemble a typical thyroid gland and restore thyroid function in vivo. In this study, we are the first to confirm that engineered thyroid tissue can repair hypothyroidism models in rats and, therefore, cell sheet transplantation of endocrine organs may be suitable for the therapy of hormonal deficiency.

Efficacy of Intracerebral Delivery of Carboplatin in Combination With Photon Irradiation for Treatment of F98 Glioma-Bearing Rats

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

Rousseau, Julia; Universite Joseph Fourier, Grenoble; European Synchrotron Radiation Facility, Grenoble

2009-02-01

Purpose: To evaluate the efficacy of prolonged intracerebral (i.c.) administration of carboplatin by means of ALZET osmotic pumps, in combination with radiotherapy for the treatment of intracranial F98 glioma in rats. Methods and Materials: Seven days after stereotactic implantation of F98 glioma cells into the brains of Fischer rats, carboplatin was administrated i.c. by means of ALZET pumps over 6 days. Rats were treated at the European Synchrotron Radiation Facility with a single 15-Gy X-ray dose, either given alone or 24 h after administration of carboplatin. Results: Untreated rats had a mean survival time (MST) {+-} SE of 23 {+-}more » 1 days, compared with 44 {+-} 3 days for X-irradiated animals and 69 {+-} 20 days for rats that received carboplatin alone, with 3 of 13 of these surviving >195 days. Rats that received carboplatin followed by X-irradiation had a MST of >142 {+-} 21 days and a median survival time of >195 days, with 6 of 11 rats (55%) still alive at the end of the study. The corresponding percentage increases in lifespan, based on median survival times, were 25%, 85%, and 713%, respectively, for carboplatin alone, radiotherapy alone, or the combination. Conclusions: Our data demonstrate that i.c. infusion of carboplatin by means of ALZET pumps in combination with X-irradiation is highly effective for the treatment of the F98 glioma. They provide strong support for the approach of concomitantly administering chemo- and radiotherapy for the treatment of brain tumors.« less

Infusion of exogenous cholecystokinin-8, gastrin releasing peptide-29 and their combination reduce body weight in diet-induced obese male rats.

PubMed

Mhalhal, Thaer R; Washington, Martha C; Newman, Kayla; Heath, John C; Sayegh, Ayman I

2017-02-01

We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW. Published by Elsevier Ltd.

A rapid solid-phase extraction method for measurement of non-metabolised peripheral benzodiazepine receptor ligands, [(18)F]PBR102 and [(18)F]PBR111, in rat and primate plasma.

PubMed

Katsifis, Andrew; Loc'h, Christian; Henderson, David; Bourdier, Thomas; Pham, Tien; Greguric, Ivan; Lam, Peter; Callaghan, Paul; Mattner, Filomena; Eberl, Stefan; Fulham, Michael

2011-01-01

To develop a rapid and reliable method for estimating non-metabolised PBR ligands fluoroethoxy ([(18)F]PBR102)- and fluoropropoxy ([(18)F]PBR111)-substituted 2-(6-chloro-2-phenyl)imidazo[1,2-a]pyridine-3-yl)-N,N-diethylacetamides in plasma. Rats and baboons were imaged with PET up to 2 h postinjection of [(18)F]PBR102 and [(18)F]PBR111 under baseline conditions, after pre-blocking or displacement with PK11195. Arterial plasma samples were directly analysed by reverse-phase solid-phase extraction (RP-SPE) and RP-HPLC and by normal-phase TLC. SPE cartridges were successively washed with acetonitrile/water mixtures. SPE eluant radioactivity was measured in a γ-counter to determine the parent compound fraction and then analysed by HPLC and TLC for validation. In SPE, hydrophilic and lipophilic radiolabelled metabolites were eluted in water and 20% acetonitrile/water. All non-metabolised [(18)F]PBR102 and [(18)F]PBR111 were in SPE acetonitrile fraction as confirmed by HPLC and TLC analysis. Unchanged (%) [(18)F]PBR102 and [(18)F]PBR111 from SPE analysis in rat and baboon plasma agreed with those from HPLC and TLC analysis. In rats and baboons, the fraction of unchanged tracer followed a bi-exponential decrease, with half-lives of 7 to 10 min for the fast component and >80 min for the slow component for both tracers. Direct plasma SPE analysis of [(18)F]PBR102 and [(18)F]PBR111 can reliably estimate parent compound fraction. SPE was superior to HPLC for samples with low activity; it allows rapid and accurate metabolite analysis of a large number of plasma samples for improved estimation of metabolite-corrected input function during quantitative PET imaging studies. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

Potential therapeutic effect of nanobased formulation of rivastigmine on rat model of Alzheimer’s disease

PubMed Central

Ismail, Manal Fouad; ElMeshad, Aliaa Nabil; Salem, Neveen Abdel-Hameed

2013-01-01

Background To sustain the effect of rivastigmine, a hydrophilic cholinesterase inhibitor, nanobased formulations were prepared. The efficacy of the prepared rivastigmine liposomes (RLs) in comparison to rivastigmine solution (RS) was assessed in an aluminium chloride (AlCl3)-induced Alzheimer’s model. Methods Liposomes were prepared by lipid hydration (F1) and heating (F2) methods. Rats were treated with either RS or RLs (1 mg/kg/day) concomitantly with AlCl3 (50 mg/kg/day). Results The study showed that the F1 method produced smaller liposomes (67.51 ± 14.2 nm) than F2 (528.7 ± 15.5 nm), but both entrapped the same amount of the drug (92.1% ± 1.4%). After 6 hours, 74.2% ± 1.5% and 60.8% ± 2.3% of rivastigmine were released from F1 and F2, respectively. Both RLs and RS improved the deterioration of spatial memory induced by AlCl3, with RLs having a superior effect. Further biochemical measurements proved that RS and RLs were able to lower plasma C-reactive protein, homocysteine and asymmetric dimethy-larginine levels. RS significantly attenuated acetylcholinesterase (AChE) activity, whereas Na+/K+-adenosine triphosphatase (ATPase) activity was enhanced compared to the AlCl3-treated animals; however, RLs succeeded in normalization of AChE and Na+/K+ ATPase activities. Gene-expression profile showed that cotreatment with RS to AlCl3-treated rats succeeded in exerting significant decreases in BACE1, AChE, and IL1B gene expression. Normalization of the expression of the aforementioned genes was achieved by coadministration of RLs to AlCl3-treated rats. The profound therapeutic effect of RLs over RS was evidenced by nearly preventing amyloid plaque formation, as shown in the histopathological examination of rat brain. Conclusion RLs could be a potential drug-delivery system for ameliorating Alzheimer’s disease. PMID:23378761

Soy isoflavones interfere with thyroid hormone homeostasis in orchidectomized middle-aged rats

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

Šošić-Jurjević, Branka, E-mail: brankasj@ibiss.bg.ac.rs; Filipović, Branko; Wirth, Eva Katrin

We previously reported that genistein (G) and daidzein (D) administered subcutaneously (10 mg/kg) induce changes in the angio-follicular units of the thyroid gland, reduce concentration of total thyroid hormones (TH) and increase thyrotropin (TSH) in serum of orchidectomized middle-aged (16-month-old) rats. To further investigate these effects, we now examined expression levels of the thyroglobulin (Tg), thyroperoxidase (Tpo), vascular endothelial growth factor A (Vegfa) and deiodinase type 1 (Dio 1) genes in the thyroid; in the pituitary, genes involved in TH feedback control (Tsh β, Dio 1, Dio 2, Trh receptor); and in the liver and kidney, expression of T{sub 3}-activatedmore » genes Dio 1 and Spot 14, as well as transthyretin (Ttr), by quantitative real-time PCR. We also analyzed TPO-immunopositivity and immunofluorescence of T{sub 4} bound to Tg, determined thyroid T{sub 4} levels and measured deiodinase enzyme activities in examined organs. Decreased expression of Tg and Tpo genes (p < 0.05) correlated with immunohistochemical staining results, and together with decreased serum total T{sub 4} levels, indicates decreased Tg and TH synthesis following treatments with both isoflavones. However, expression of Spot 14 (p < 0.05) gene in liver and kidney was up-regulated, and liver Dio 1 expression and activity (p < 0.05) increased. At the level of pituitary, no significant change in gene expression levels, or Dio 1 and 2 enzyme activities was observed. In conclusion, both G and D impaired Tg and TH synthesis, but at the same time increased tissue availability of TH in peripheral tissues of Orx middle-aged rats. - Highlights: • We tested how genistein and daidzein interfere with thyroid hormone homeostasis. • Thyroid: decreased expression of Tg and TPO genes correlated with IHC results. • Serum: total T{sub 4} reduced and TSH increased. • Liver and kidney: expression of Spot 14 and liver Dio 1 activity increased. • Pituitary: expression of T{sub 3

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

Lack of carcinogenicity of lyophilized Agaricus blazei Murill in a F344 rat two year bioassay.

PubMed

Lee, I P; Kang, B H; Roh, J K; Kim, J R

2008-01-01

The Brazilian mushroom Agaricus blazei Murill has antimutagenic, antioxidant, immunostimulatory and antitumorigenic activities, and is increasingly consumed as a health food worldwide. We undertook the present study to evaluate the chronic toxicity and oncogenicity of A. blazei Murill in F344 rats. To establish a no-observed-adverse-effect level (NOAEL), four treatment groups of 100 rats each (50 males and 50 females) were fed a powder diet containing lyophilized A. blazei aqueous extract at 0, 6250, 12,500, and 25,000 ppm for up to 2 years. During this period, there was no remarkable change in mean body weight, body weight gain, hematologic or serum chemistry parameters, or absolute or relative organ weights in control or treatment groups. Mortality in male treatment groups (26%, 16%, and 30%), however, was significantly lower than in controls (48%). Histopathological studies showed no increased incidence of tumors in any treatment group, and total tumor incidence across all groups was comparable to historical data. In conclusion, an A. blazei Murill lyophilized powder diet even at 25,000 ppm (1176 mg/kgb x w x /day for male rats and 1518 mg/kgb.w./day for female rats) resulted in no remarkable carcinogenic effects in F344 rats over a 2-year period. Therefore, the dietary NOAEL is 25,000 ppm.

Prostaglandin F2α receptor silencing attenuates vascular remodeling in rats with type 2 diabetes.

PubMed

Li, Ya; Han, Lu; Ding, Wen-Yuan; Ti, Yun; Li, Yi-Hui; Tang, Meng-Xiong; Wang, Zhi-Hao; Zhang, Yun; Zhang, Wei; Zhong, Ming

2015-12-01

Vascular remodeling is an important feature of diabetic macrovascular complications. The prostaglandin F2α receptor (FP), the expression of which is upregulated by insulin resistance and diabetes, is reportedly involved in myocardial remodeling. In this study, we aimed to investigate whether the FP receptor is implicated in diabetes-induced vascular remodeling. A type 2 diabetic rat model was induced through a high-fat diet and low-dose streptozotocin (STZ). Thirty-two rats were randomized into four groups: control, diabetes, diabetes treated with empty virus and diabetes treated with FP receptor-shRNA. Then, we evaluated the metabolic index, FP receptor expression and vascular remodeling. We used FP receptor gene silencing in vivo to investigate the role that the FP receptor plays in the pathophysiologic features of vascular remodeling. Diabetic rats displayed increased levels of blood glucose, cholesterol, and triglycerides, as well as severe insulin resistance and FP receptor overexpression. In addition, increased medial thickness, excessive collagen deposition and diminished elastic fibers were observed in the diabetic rats, resulting in vascular remodeling. In the FP receptor-shRNA group, the medial thickness, collagen content, elastin/collagen ratio, and collagen I/collagen III content ratio were markedly decreased. Additionally, with FP receptor gene silencing, the JNK phosphorylation level was markedly decreased. Silencing of the FP receptor exerts a protective effect on diabetes-induced vascular remodeling, thereby suggesting a new therapeutic target for vascular remodeling in diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f

PubMed Central

Morimoto, Megumi; Amano, Yuichiro; Oka, Masahiro; Harada, Ayako; Fujita, Hisashi; Hikichi, Yukiko; Tozawa, Ryuichi; Yamaoka, Masuo

2017-01-01

Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical

Visualizing Nerve Injury in a Neuropathic Pain Model with [18F]FTC-146 PET/MRI.

PubMed

Shen, Bin; Behera, Deepak; James, Michelle L; Reyes, Samantha T; Andrews, Lauren; Cipriano, Peter W; Klukinov, Michael; Lutz, Amanda Brosius; Mavlyutov, Timur; Rosenberg, Jarrett; Ruoho, Arnold E; McCurdy, Christopher R; Gambhir, Sanjiv S; Yeomans, David C; Biswal, Sandip; Chin, Frederick T

2017-01-01

The ability to locate nerve injury and ensuing neuroinflammation would have tremendous clinical value for improving both the diagnosis and subsequent management of patients suffering from pain, weakness, and other neurologic phenomena associated with peripheral nerve injury. Although several non-invasive techniques exist for assessing the clinical manifestations and morphological aspects of nerve injury, they often fail to provide accurate diagnoses due to limited specificity and/or sensitivity. Herein, we describe a new imaging strategy for visualizing a molecular biomarker of nerve injury/neuroinflammation, i.e. , the sigma-1 receptor (S1R), in a rat model of nerve injury and neuropathic pain. The two-fold higher increase of S1Rs was shown in the injured compared to the uninjured nerve by Western blotting analyses. With our novel S1R-selective radioligand, [ 18 F]FTC-146 (6-(3-[ 18 F]fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[ d ]thiazol-2(3H)-one), and positron emission tomography-magnetic resonance imaging (PET/MRI), we could accurately locate the site of nerve injury created in the rat model. We verified the accuracy of this technique by ex vivo autoradiography and immunostaining, which demonstrated a strong correlation between accumulation of [ 18 F]FTC-146 and S1R staining. Finally, pain relief could also be achieved by blocking S1Rs in the neuroma with local administration of non-radioactive [ 19 F]FTC-146. In summary, [ 18 F]FTC-146 S1R PET/MR imaging has the potential to impact how we diagnose, manage and treat patients with nerve injury, and thus warrants further investigation.

Structural and functional differences in the dio1 gene in mice with inherited type 1 deiodinase deficiency.

PubMed

Maia, A L; Berry, M J; Sabbag, R; Harney, J W; Larsen, P R

1995-08-01

The type 1 deiodinase (D1) provides the major portion of the circulating T3 in vertebrates. In C3H and certain other inbred mice, liver and kidney D1 activity is 5- to 10-fold lower than in the common phenotype, C57. The lower D1 levels are paralleled by a decreased normal-sized dio1 mRNA and hyperthyroxinemia. Low activity cosegregates with a restriction fragment length variant (RFLV) in both inbred and recombinant strains, indicating it is due to differences in the dio1 gene. The exonic structure and the deduced amino acid sequences are identical for both strains and highly homologous to that of the rat. The RFLV is due to an approximately 150-base pair expansion of repetitive sequences in the second intron of the C3H gene, but this segment does not differentially affect the transient expression of a human GH gene. The promoter and 5'-flanking regions of the C3H and C57 dio1 genes are very similar and are GC rich without TATA or CCAAT boxes. However, functional assays of 1.5-kilobase 5'-flanking dio1-CAT constructs showed 2- to 3-fold higher activity of the C57-CAT constructs. Deletion mutants showed that sequences between -705 and -162 were the cause of this. In this region, the only major difference between the two genes is a 21-base pair insert containing five CTG repeats in the C3H promoter. This difference also cosegregates with low D1 activity and the intron RFLV in four other mouse strains. The correlation of the CTG repeat insert with both in vitro and in vivo expression and the absence of other significant sequence differences in the 5'-flanking region argue that this is the major explanation for the impaired expression of the dio1 gene and the resulting hyperthyroxinemia of the C3H mouse.

Development of Ultra Long Duration Local Anesthetic Agents in a Rat Model

DTIC Science & Technology

1994-02-24

this formulation is not toxic to the spinal cord. Initial trials with lecithin-coated bupivacaine microcrystals indic,-.. that this preparation also has...an ultra long duration local anesthetic effect, producing a 43 hour block in the rat tail. Clinical trials of this preparation in a human model are...l f _ _ _ Memorandum for LTC Dean E. Calcagni, M.D. Director, Combat Casualty Research Program USAMRDC Subject: Annual Report for Clinical

Studies on the pathogenicity of anaerobes, especially Prevotella bivia, in a rat pyometra model.

PubMed Central

Mikamo, H; Kawazoe, K; Izumi, K; Watanabe, K; Ueno, K; Tamaya, T

1998-01-01

OBJECTIVE: Prevotella bivia is one of the anaerobic bacteria that resides in the flora of the female genital tract. We studied the pathogenicity of P. bivia in a rat pyometra model. METHODS: The experimental animal (rat) model of pyometra was developed to investigate the pathogenicity of P. bivia in a rat pyometra model. RESULTS: In the groups inoculated with aerobes alone, the infection rate was 10% (1/10) in the Staphylococcus aureus- or Staphylococcus agalactiae-inoculated group and 20% (2/10) in the Escherichia coli-inoculated group. Infection was not established in the groups inoculated with anaerobes alone. High infection rates were observed in all the mixed-infection groups. In the S. agalactiae- and Bacteroides fragilis-, S. agalactiae- and P. bivia-, F. coli- and B. fragilis-, and E. coli- and P. bivia-inoculated groups, an infection rate of 100% (10/10) was demonstrated. The efficacy of antibiotics such as flomoxef (FMOX) could be determined using a rat pyometra model. In relation to the alteration of vaginal microbial flora during the menstrual cycle, estrogen increased the growth of P. bivia. CONCLUSION: Mixture of aerobic bacteria and P. bivia increased the pathogenicity of P. bivia. Estrogen would be useful for raising up the inflammatory change of the uterus in experimental models of genital tract infection due to P. bivia. PMID:9702587

Fructose Consumption Does Not Worsen Bone Deficits Resulting From High-Fat Feeding in Young Male Rats

PubMed Central

Yarrow, Joshua F.; Toklu, Hale Z.; Balaez, Alex; Phillips, Ean G.; Otzel, Dana M.; Chen, Cong; Wronski, Thomas J.; Aguirre, J. Ignacio; Sakarya, Yasemin; Tümer, Nihal; Scarpace, Philip J.

2016-01-01

Dietary-induced obesity (DIO) resulting from high-fat (HF) or high-sugar diets produces a host of deleterious metabolic consequences including adverse bone development. We compared the effects of feeding standard rodent chow (Control), a 30% moderately HF (starch-based/sugar-free) diet, or a combined 30%/40% HF/high-fructose (HF/F) diet for 12 weeks on cancellous/cortical bone development in male Sprague-Dawley rats aged 8 weeks. Both HF feeding regimens reduced the lean/fat mass ratio, elevated circulating leptin, and reduced serum total antioxidant capacity (tAOC) when compared with Controls. Distal femur cancellous bone mineral density (BMD) was 23–34% lower in both HF groups (p<0.001) and was characterized by lower cancellous bone volume (BV/TV, p<0.01), lower trabecular number (Tb.N, p<0.001), and increased trabecular separation versus Controls (p<0.001). Cancellous BMD, BV/TV, and Tb.N were negatively associated with leptin and positively associated with tAOC at the distal femur. Similar cancellous bone deficits were observed at the proximal tibia, along with increased bone marrow adipocyte density (p<0.05), which was negatively associated with BV/TV and Tb.N. HF/F animals also exhibited lower osteoblast surface and reduced circulating osteocalcin (p<0.05). Cortical thickness (p<0.01) and tissue mineral density (p<0.05) were higher in both HF-fed groups versus Controls, while whole bone biomechanical characteristics were not different among groups. These results demonstrate that “westernized” HF diets worsen cancellous, but not cortical, bone parameters in skeletally-immature male rats and that fructose incorporation into HF diets does not exacerbate bone loss. In addition, they suggest that leptin and/or oxidative stress may influence DIO-induced alterations in adolescent bone development. PMID:26855373

Fructose consumption does not worsen bone deficits resulting from high-fat feeding in young male rats.

PubMed

Yarrow, Joshua F; Toklu, Hale Z; Balaez, Alex; Phillips, Ean G; Otzel, Dana M; Chen, Cong; Wronski, Thomas J; Aguirre, J Ignacio; Sakarya, Yasemin; Tümer, Nihal; Scarpace, Philip J

2016-04-01

Dietary-induced obesity (DIO) resulting from high-fat (HF) or high-sugar diets produces a host of deleterious metabolic consequences including adverse bone development. We compared the effects of feeding standard rodent chow (Control), a 30% moderately HF (starch-based/sugar-free) diet, or a combined 30%/40% HF/high-fructose (HF/F) diet for 12weeks on cancellous/cortical bone development in male Sprague-Dawley rats aged 8weeks. Both HF feeding regimens reduced the lean/fat mass ratio, elevated circulating leptin, and reduced serum total antioxidant capacity (tAOC) when compared with Controls. Distal femur cancellous bone mineral density (BMD) was 23-34% lower in both HF groups (p<0.001) and was characterized by lower cancellous bone volume (BV/TV, p<0.01), lower trabecular number (Tb.N, p<0.001), and increased trabecular separation versus Controls (p<0.001). Cancellous BMD, BV/TV, and Tb.N were negatively associated with leptin and positively associated with tAOC at the distal femur. Similar cancellous bone deficits were observed at the proximal tibia, along with increased bone marrow adipocyte density (p<0.05), which was negatively associated with BV/TV and Tb.N. HF/F animals also exhibited lower osteoblast surface and reduced circulating osteocalcin (p<0.05). Cortical thickness (p<0.01) and tissue mineral density (p<0.05) were higher in both HF-fed groups versus Controls, while whole bone biomechanical characteristics were not different among groups. These results demonstrate that "westernized" HF diets worsen cancellous, but not cortical, bone parameters in skeletally-immature male rats and that fructose incorporation into HF diets does not exacerbate bone loss. In addition, they suggest that leptin and/or oxidative stress may influence DIO-induced alterations in adolescent bone development. Published by Elsevier Inc.

Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer.

PubMed

Santoro, Ana B; Vargens, Daniela D; Barros Filho, Mateus de Camargo; Bulzico, Daniel A; Kowalski, Luiz Paulo; Meirelles, Ricardo M R; Paula, Daniela P; Neves, Ronaldo R S; Pessoa, Cencita N; Struchine, Claudio J; Suarez-Kurtz, Guilherme

2014-11-01

To evaluate the impact of genetic polymorphisms in uridine 5'-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T4 ; 3,5,3',5'-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC). Patients (n = 268) submitted to total thyroidectomy and ablation by (131) I, under T4 therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T4 dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables. A regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T4 dosage. The association of T4 dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T4 glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T4 dosage. UGT1A haplotypes associate with T4 dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted. © 2014 The British Pharmacological Society.

Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer

PubMed Central

Santoro, Ana B; Vargens, Daniela D; Barros Filho, Mateus de Camargo; Bulzico, Daniel A; Kowalski, Luiz Paulo; Meirelles, Ricardo M R; Paula, Daniela P; Neves, Ronaldo R S; Pessoa, Cencita N; Struchine, Claudio J; Suarez-Kurtz, Guilherme

2014-01-01

Aim To evaluate the impact of genetic polymorphisms in uridine 5′-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T4; 3,5,3′,5′-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC). Methods Patients (n = 268) submitted to total thyroidectomy and ablation by 131I, under T4 therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T4 dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables. Results A regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T4 dosage. The association of T4 dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T4 glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T4 dosage. Conclusion UGT1A haplotypes associate with T4 dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted. PMID:24910925

Ntp report on the toxicity studies of ethylbenzene in f344/n rats and b6c3f1 mice (inhalation studies). Report for 29 March-30 June 1988

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

Chan, P.

1992-03-01

Inhalation toxicology studies of ethylbenzene (99% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to ethylbenzene vapor at chamber concentrations of 0 to 1000 ppm, 6 hours per day, 5 days per week for 13 weeks. No rats or mice died during the 13-week exposure. Body weight gains were slightly lower in the high dose groups of male and female rats, but the differences were not statistically significant. Absolute and relative kidney, liver, and lung weights were increased in the exposed rats, while weight increases occurred only in the livers of exposed mice.more » No changes were observed in the evaluation of sperm or vaginal cytology in rats or mice. Ethylbenzene was not mutagenic in Salmonella and did not induce chromosomal aberrations or sister chromatid exchanges in Chinese hamster ovary (CHO) cells in vitro, though it did induce trifluorothymidine resistance in mouse lymphoma cells at the highest concentration tested. Micronuclei assays in peripheral blood of mice were negative.« less

Dipentyl Phthalate F1 Male rat necropsy data, requested by a ...

EPA Pesticide Factsheets

This is a dataset, and it has no abstract. See the manuscript for additional information. Gray LE Jr, Furr J, Tatum-Gibbs KR, Lambright C, Sampson H, Hannas BR, Wilson VS, Hotchkiss A, Foster PM. Establishing the "Biological Relevance" of DipentylPhthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels. Toxicol Sci. 2016 Jan;149(1):178-91. doi: 10.1093/toxsci/kfv224. Epub 2015 Oct 9. PubMed PMID: 26454885; PubMed CentralPMCID: PMC4715258. Dipentyl Phthalate F1 Male rat necropsy data from our 2016 publication. These data were requested by a mathematical statistician in NCEA that is using the data for nested BMD calculations for their ongoing assessment of this phthalate. We continue to provide NCEA and other regulatory groups data on the phthalates for their assessments.

Disposition and pharmacokinetics of phenethyl isothiocyanate and 6-phenylhexyl isothiocyanate in F344 rats.

PubMed

Conaway, C C; Jiao, D; Kohri, T; Liebes, L; Chung, F L

1999-01-01

Naturally occurring phenethyl isothiocyanate (PEITC) and its synthetic homolog 6-phenylhexyl isothiocyanate (PHITC) are both effective inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor development in A/J mice and F344 rats. To help explain why PHITC is considerably more efficacious than PEITC in chemopreventive potency, comparative disposition and pharmacokinetics data for male F344 rats were obtained after a single gavage dose of 50 micromol/kg (3.71 microCi/micromol) [14C]PEITC or 50 micromol/kg (6.59 microCi/micromol) [14C]PHITC in corn oil. After [14C]PEITC dosing, whole blood 14C peaked at 2.9 h, with an elimination half-life (T1/2e) of 21.7 h; blood 14C from [14C]PHITC-treated rats peaked at 8.9 h, with an T1/2e of 20.5 h. In lungs, the target organ, the T1/2e for [14C]PHITC and its labeled metabolites were more than twice that for [14C]PEITC and its labeled metabolites. The effective dose (area under the concentration-time curve) for 14C from PHITC was greater than 2.5 times the area under the concentration-time curve of 14C from PEITC in liver, lungs, and several other tissues. During 48 h, approximately 16.5% of the administered dose of [14C]PHITC was expired as [14C]CO2, more than 100 times the [14C]CO2 expired by rats treated with [14C]PEITC. In rats given [14C]PEITC, 88.7 +/- 2.2% and 9.9 +/- 1.9% of the dose appeared in the urine and feces, respectively, during 48 h; however, rats given [14C]PHITC excreted 7.2 +/- 0.8% of the dose of 14C in urine and 47.4 +/- 14.0% in the feces. Higher effective doses of PHITC in the lungs and other organs may be the basis, in part, for its greater potency as a chemopreventive agent.

Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities.

PubMed

Parent, Maxime J; Zimmer, Eduardo R; Shin, Monica; Kang, Min Su; Fonov, Vladimir S; Mathieu, Axel; Aliaga, Antonio; Kostikov, Alexey; Do Carmo, Sonia; Dea, Doris; Poirier, Judes; Soucy, Jean-Paul; Gauthier, Serge; Cuello, A Claudio; Rosa-Neto, Pedro

2017-12-13

Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9-11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [ 18 F]FDG) or detectable fibrillary amyloidosis (measured with PET [ 18 F]NAV4694). At more advanced ages (16-19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ 1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages. SIGNIFICANCE STATEMENT The present study proposes a "back translation" of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses. Copyright © 2017 Parent et al.

Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities

PubMed Central

Parent, Maxime J.; Kang, Min Su; Mathieu, Axel; Aliaga, Antonio; Do Carmo, Sonia; Dea, Doris; Gauthier, Serge; Cuello, A. Claudio

2017-01-01

Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9–11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16–19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages. SIGNIFICANCE STATEMENT The present study proposes a “back translation” of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses. PMID:29097597

The chemo-mechanical coupled model for F(1)F(0)-motor.

PubMed

Xu, Lizhong; Liu, Fang

2012-04-01

F(1)F(0)-motor (ATP synthase) is the universal enzyme in biological energy conversion that is present in the membranes of mitochondria, chloroplasts and bacteria. It uses the energy of the proton gradient across the membrane to synthesize ATP. Previous theory and model about rotation of the ATP synthase is reviewed, then a novel chemo-mechanical coupled model for rotation of the F(1)F(0)-motor is proposed. In the model, more events are considered simultaneously that includes the movement of F(1), the movement of F(0), reactions at F(1) and reactions at F(0). Using the model, the possible substep modes of the rotation for F(1)F(0) are predicted, the dependence of the motor efficiency and its rotation rate on the rigidity of the γ shaft is investigated. We conclude that the γ shaft has a large rotation rate for a limited driving potential because two ends of the γ shaft can rotate alternately for its flexibility. The flexibility also makes the efficiency of F(1)F(0) drop because elastic twisting deformation power is needed during alternate rotation of the γ shaft at two ends. Copyright © 2012 Elsevier Ltd. All rights reserved.

Specific binding of [(18)F]fluoroethyl-harmol to monoamine oxidase A in rat brain cryostat sections, and compartmental analysis of binding in living brain.

PubMed

Maschauer, Simone; Haller, Adelina; Riss, Patrick J; Kuwert, Torsten; Prante, Olaf; Cumming, Paul

2015-12-01

We investigated [(18)F]fluoroethyl-harmol ([(18)F]FEH) as a reversible and selective ligand for positron emission tomography (PET) studies of monoamine oxidase A (MAO-A). Binding of [(18)F]FEH in rat brain cryostat sections indicated high affinity (KD = 3 nM), and density (Bmax; 600 pmol/g). The plasma free fraction was 45%, and untransformed parent constituted only 13% of plasma radioactivity at 10 min after injection. Compartmental analysis of PET recordings in pargyline-treated rats showed high permeability to brain (K1; 0.32 mL/g/min) and slow washout (k2; 0.024/min), resulting in a uniformly high equilibrium distribution volume (VD; 20 mL/g). Using this VD to estimate unbound ligand in brain of untreated rats, the binding potential ranged from 4.2 in cerebellum to 7.2 in thalamus. We also calculated maps of rats receiving [(18)F]FEH at a range of specific activities, and then estimated saturation binding parameters in the living brain. In thalamus, striatum and frontal cortex KD was globally close to 300 nM and Bmax was close to 1600 pmol/g; the 100-fold discrepancy in affinity suggests a very low free fraction for [(18)F]FEH in the living brain. Based on a synthesis of findings, we calculate the endogenous dopamine concentration to be 0.4 μM in the striatal compartment containing MAO-A, thus unlikely to exert competition against [(18)F]FEH binding in vivo. In summary, [(18)F]FEH has good properties for the detection of MAO-A in the rat brain by PET, and may present logistic advantages for clinical research at centers lacking a medical cyclotron. We made a compartmental analysis of [(18)F]fluoroethylharmol ([(18)F]FEH) binding to monoamine oxidase A (MAO-A) in living rat brain and estimated the saturation binding parameters from the binding potential (BPND). The Bmax was of comparable magnitude to that in vitro, but with apparent affinity (300 nM), it was 100-fold lower in vivo. PET imaging with [(18) F]FEH is well suited for quantitation of MAO-A in living

Hypothalamic neural projections are permanently disrupted in diet-induced obese rats.

PubMed

Bouret, Sebastien G; Gorski, Judith N; Patterson, Christa M; Chen, Stephen; Levin, Barry E; Simerly, Richard B

2008-02-01

The arcuate nucleus of the hypothalamus (ARH) is a key component of hypothalamic pathways regulating energy balance, and leptin is required for normal development of ARH projections. Diet-induced obesity (DIO) has a polygenic mode of inheritance, and DIO individuals develop the metabolic syndrome when a moderate amount of fat is added to the diet. Here we demonstrate that rats selectively bred to develop DIO, which are known to be leptin resistant before they become obese, have defective ARH projections that persist into adulthood. Furthermore, the ability of leptin to activate intracellular signaling in ARH neurons in vivo and to promote ARH neurite outgrowth in vitro is significantly reduced in DIO neonates. Thus, animals that are genetically predisposed toward obesity display an abnormal organization of hypothalamic pathways involved in energy homeostasis that may be the result of diminished responsiveness of ARH neurons to the trophic actions of leptin during postnatal development.

Increased serum and testicular androgen levels in F1 rats with lifetime exposure to soy isoflavones.

PubMed

McVey, Mark J; Cooke, Gerard M; Curran, Ivan H A

2004-07-01

The consequences of dietary soy isoflavones on serum and testicular androgen levels were examined in F1 male rats from a multigeneration study investigating the effects of diets varying in isoflavone content. Rats were fed either a soy-free casein based diet (AIN93G) or a diet in which alcohol-washed soy protein replaced casein as the protein source and to which increasing amounts of Novasoy, a commercially available isoflavone supplement were added. Analysis of these diets showed that the isoflavone content in each diet was 0 (diet 1; casein based control), 31.7 (diet 2; alcohol-washed soy-based diet control), 36.1 (diet 3), 74.5 (diet 4), 235.6 (diet 5) and 1046.6 (diet 6) mg total isoflavones/kg pelleted diet. The levels of isoflavones in diet 1 would represent a daily intake level of 0 mg isoflavones, diets 2 and 3 estimate a low soy-containing human diet (e.g. North American), diet 4 would correspond to Asian diets (e.g. Japanese) or adult humans taking isoflavone supplements, diet 5 approximates the isoflavone intake by babies fed soy based infant formula and diet 6 approximates fivefold the intake levels by babies or 10-fold the intake levels of adults consuming high isoflavone containing diets. Serum testosterone (T) from F1 male rats sacrificed on postnatal days (PND) 28, 70, 120, 240 and 360 were low at PND 28 (0.4 ng/ml), increased approximately five to sixfold at PND 70 (2.5-3.0 ng/ml) and thereafter declined to a steady state level of approximately 1 ng/ml by PND 120. However, rats on diets 5 and 6 demonstrated altered serum testosterone profiles such that at days 120, testosterone levels remained significantly elevated at approximately 3 ng/ml (P < 0.05). Serum dihydrotestosterone levels exhibited similar profiles and the levels in PND 120 rats on diet 5 or 6 were also significantly elevated (two to threefold, P < 0.05). The intra-testicular testosterone concentration in rats on diet 5 was also elevated at PND 120 compared with diet 1 (P < 0

A Recombinant Respiratory Syncytial Virus Vaccine Candidate Attenuated by a Low-Fusion F Protein Is Immunogenic and Protective against Challenge in Cotton Rats

PubMed Central

Rostad, Christina A.; Stobart, Christopher C.; Gilbert, Brian E.; Pickles, Ray J.; Hotard, Anne L.; Meng, Jia; Blanco, Jorge C. G.; Moin, Syed M.; Graham, Barney S.; Piedra, Pedro A.

2016-01-01

ABSTRACT Although respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, a safe and effective vaccine is not yet available. Live-attenuated vaccines (LAVs) are the most advanced vaccine candidates in RSV-naive infants. However, designing an LAV with appropriate attenuation yet sufficient immunogenicity has proven challenging. In this study, we implemented reverse genetics to address these obstacles with a multifaceted LAV design that combined the codon deoptimization of genes for nonstructural proteins NS1 and NS2 (dNS), deletion of the small hydrophobic protein (ΔSH) gene, and replacement of the wild-type fusion (F) protein gene with a low-fusion RSV subgroup B F consensus sequence of the Buenos Aires clade (BAF). This vaccine candidate, RSV-A2-dNS-ΔSH-BAF (DB1), was attenuated in two models of primary human airway epithelial cells and in the upper and lower airways of cotton rats. DB1 was also highly immunogenic in cotton rats and elicited broadly neutralizing antibodies against a diverse panel of recombinant RSV strains. When vaccinated cotton rats were challenged with wild-type RSV A, DB1 reduced viral titers in the upper and lower airways by 3.8 log10 total PFU and 2.7 log10 PFU/g of tissue, respectively, compared to those in unvaccinated animals (P < 0.0001). DB1 was thus attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. DB1 is the first RSV LAV to incorporate a low-fusion F protein as a strategy to attenuate viral replication and preserve immunogenicity. IMPORTANCE RSV is a leading cause of infant hospitalizations and deaths. The development of an effective vaccine for this high-risk population is therefore a public health priority. Although live-attenuated vaccines have been safely administered to RSV-naive infants, strategies to balance vaccine attenuation with immunogenicity have been elusive. In this study, we introduced a novel strategy to attenuate a recombinant RSV

Comparison of the Effects of Hexavalent Chromium in the Alimentary Canal of F344 Rats and B6C3F1 Mice Following Exposure in Drinking Water: Implications for Carcinogenic Modes of Action

PubMed Central

Thompson, Chad M.; Proctor, Deborah M.; Suh, Mina; Haws, Laurie C.; Hébert, Charles D.; Mann, Jill F.; Shertzer, Howard G.; Hixon, J. Gregory; Harris, Mark A.

2012-01-01

Exposure to high concentrations of hexavalent chromium (Cr[VI]) in drinking water is reported to induce oral mucosa tumors in F344 rats and intestinal tumors in B6C3F1 mice. To investigate the modes of action underlying these tumors, 90-day drinking water studies (with interim necropsy at day 8) were conducted with concentrations of 0.1–182 mg/l Cr(VI), administered as 0.3–520 mg/l sodium dichromate dihydrate. Blood and tissue samples were analyzed for chromium content, oxidative stress, iron levels, and gross and microscopic lesions. Results for the F344 rats are described herein and compared with results from B6C3F1 mice published previously. After 90 days of exposure, total chromium concentrations in the rat and mouse oral mucosae were comparable, yet significant dose-dependent decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed only in rats. In the duodenum, changes in GSH/GSSG were only observed in mice. Levels of 8-hydroxydeoxyguanosine were not increased in the oral or duodenal mucosae of either species. Glutathione levels were increased in the duodenum but decreased in the jejunum of both species, indicating potential differential responses in the intestinal segments. Histiocytic infiltration was observed in the duodenum of both species, yet duodenal cytokines were repressed in mice but increased in rats. Serum and bone marrow iron levels were more decreased in rats than mice. Collectively, these data suggest that Cr(VI)-induced carcinogenesis in the rodent alimentary canal involves oxidative stress; however, differences in histopathology, cytokines, and iron status suggest potential contributions from other factors as well. PMID:22011396

Comparison of the effects of hexavalent chromium in the alimentary canal of F344 rats and B6C3F1 mice following exposure in drinking water: implications for carcinogenic modes of action.

PubMed

Thompson, Chad M; Proctor, Deborah M; Suh, Mina; Haws, Laurie C; Hébert, Charles D; Mann, Jill F; Shertzer, Howard G; Hixon, J Gregory; Harris, Mark A

2012-01-01

Exposure to high concentrations of hexavalent chromium (Cr[VI]) in drinking water is reported to induce oral mucosa tumors in F344 rats and intestinal tumors in B6C3F1 mice. To investigate the modes of action underlying these tumors, 90-day drinking water studies (with interim necropsy at day 8) were conducted with concentrations of 0.1-182 mg/l Cr(VI), administered as 0.3-520 mg/l sodium dichromate dihydrate. Blood and tissue samples were analyzed for chromium content, oxidative stress, iron levels, and gross and microscopic lesions. Results for the F344 rats are described herein and compared with results from B6C3F1 mice published previously. After 90 days of exposure, total chromium concentrations in the rat and mouse oral mucosae were comparable, yet significant dose-dependent decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed only in rats. In the duodenum, changes in GSH/GSSG were only observed in mice. Levels of 8-hydroxydeoxyguanosine were not increased in the oral or duodenal mucosae of either species. Glutathione levels were increased in the duodenum but decreased in the jejunum of both species, indicating potential differential responses in the intestinal segments. Histiocytic infiltration was observed in the duodenum of both species, yet duodenal cytokines were repressed in mice but increased in rats. Serum and bone marrow iron levels were more decreased in rats than mice. Collectively, these data suggest that Cr(VI)-induced carcinogenesis in the rodent alimentary canal involves oxidative stress; however, differences in histopathology, cytokines, and iron status suggest potential contributions from other factors as well.

PET Tracer 18F-Fluciclovine Can Detect Histologically Proven Bone Metastatic Lesions: A Preclinical Study in Rat Osteolytic and Osteoblastic Bone Metastasis Models.

PubMed

Oka, Shuntaro; Kanagawa, Masaru; Doi, Yoshihiro; Schuster, David M; Goodman, Mark M; Yoshimura, Hirokatsu

2017-01-01

18 F-Fluciclovine ( trans -1-amino-3- 18 F-fluorocyclobutanecarboxylic acid; anti - 18 F-FACBC) is a positron emission tomography (PET) tracer for diagnosing cancers (e.g., prostate and breast cancer). The most frequent metastatic organ of these cancers is bone. Fluciclovine-PET can visualize bony lesions in clinical practice; however, such lesions have not been described histologically. Methods: We investigated the potential of 14 C-fluciclovine in aiding the visualization of osteolytic and osteoblastic bone metastases (with histological analyses), compared with 3 H-2-deoxy-2-fluoro-D-glucose ( 3 H-FDG), 3 H-choline chloride ( 3 H-choline), and 99m Tc-hydroxymethylene diphosphonate ( 99m Tc-HMDP) by using triple-tracer autoradiography in rat breast cancer osteolytic (on day 12 ± 1 postinjection of MRMT-1) and prostate cancer osteoblastic (on day 20 ± 3 postinjection of AT6.1) metastatic models. Results: The distribution patterns of 14 C-fluciclovine, 3 H-FDG, and 3 H-choline, but not 99m Tc-HMDP, were similar in both models, and the lesions where these tracers accumulated were, histologically, typical osteolytic and osteoblastic lesions. 99m Tc-HMDP accumulated mostly in osteoblastic lesions. 14 C-fluciclovine could visualize the osteolytic lesions as early as day 6 postinjection of MRMT-1. However, differential distributions in 14 C-fluciclovine and 3 H-FDG existed, based on histological differences: low 14 C-fluciclovine and high 3 H-FDG accumulation in osteolytic lesions with inflammation. In the osteoblastic metastatic model, visualization of osteoblastic lesions with 14 C-fluciclovine was not clear, yet clearer than with 3 H-FDG. Although half of the osteoblastic lesions with 14 C-fluciclovine accumulation showed negligible 3 H-choline accumulation in comparison, they were histologically similar to lesions with marked 14 C-fluciclovine and 3 H-choline accumulation. Conclusion: These results suggest that fluciclovine-PET can visualize true osteolytic and

PET Tracer 18F-Fluciclovine Can Detect Histologically Proven Bone Metastatic Lesions: A Preclinical Study in Rat Osteolytic and Osteoblastic Bone Metastasis Models

PubMed Central

Oka, Shuntaro; Kanagawa, Masaru; Doi, Yoshihiro; Schuster, David M.; Goodman, Mark M.; Yoshimura, Hirokatsu

2017-01-01

18F-Fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid; anti-18F-FACBC) is a positron emission tomography (PET) tracer for diagnosing cancers (e.g., prostate and breast cancer). The most frequent metastatic organ of these cancers is bone. Fluciclovine-PET can visualize bony lesions in clinical practice; however, such lesions have not been described histologically. Methods: We investigated the potential of 14C-fluciclovine in aiding the visualization of osteolytic and osteoblastic bone metastases (with histological analyses), compared with 3H-2-deoxy-2-fluoro-D-glucose (3H-FDG), 3H-choline chloride (3H-choline), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) by using triple-tracer autoradiography in rat breast cancer osteolytic (on day 12 ± 1 postinjection of MRMT-1) and prostate cancer osteoblastic (on day 20 ± 3 postinjection of AT6.1) metastatic models. Results: The distribution patterns of 14C-fluciclovine, 3H-FDG, and 3H-choline, but not 99mTc-HMDP, were similar in both models, and the lesions where these tracers accumulated were, histologically, typical osteolytic and osteoblastic lesions. 99mTc-HMDP accumulated mostly in osteoblastic lesions. 14C-fluciclovine could visualize the osteolytic lesions as early as day 6 postinjection of MRMT-1. However, differential distributions in 14C-fluciclovine and 3H-FDG existed, based on histological differences: low 14C-fluciclovine and high 3H-FDG accumulation in osteolytic lesions with inflammation. In the osteoblastic metastatic model, visualization of osteoblastic lesions with 14C-fluciclovine was not clear, yet clearer than with 3H-FDG. Although half of the osteoblastic lesions with 14C-fluciclovine accumulation showed negligible 3H-choline accumulation in comparison, they were histologically similar to lesions with marked 14C-fluciclovine and 3H-choline accumulation. Conclusion: These results suggest that fluciclovine-PET can visualize true osteolytic and osteoblastic bone metastatic lesions

Biodisposition and metabolism of [18F]fluorocholine in 9L glioma cells and 9L glioma-bearing Fisher rats

PubMed Central

Bansal, Aditya; Shuyan, Wang; Hara, Toshiko; Harris, Robert A.; DeGrado, Timothy R.

2008-01-01

Purpose [18F]Fluorocholine [18F]FCH) was developed as an analog of [11C]choline for tumor imaging, however, its metabolic handling remains ill-defined. In this study, the metabolism of [18F]FCH is evaluated in cultured 9L glioma cells and Fisher 344 rats bearing 9L glioma tumors. Methods 9L glioma cells were incubated with [18F]FCH and [14C]choline under normoxic and hypoxic (1% O2) conditions and analyzed for metabolic fate. [18F]FCH and [14C]choline kinetics and metabolism were studied in Fisher 344 rats bearing subcutaneous 9L tumors. Results [18F]FCH and [14C]choline were similarly metabolized in 9L cells in both normoxic and hypoxic conditions over a 2 hr incubation period. In normoxia, radioactivity was predominantly in phosphorylated form for both tracers after 5 min incubation. In hypoxia, the tracers remained mainly in nonmetabolized form at early timepoints (< 20 min). Slow dephosphorylation of intracellular [18F]phosphofluorocholine (0.043–0.060 min−1) and [14C]phosphocholine (0.072–0.088 min−1) was evidenced via efflux measurements. In rat, both [18F]FCH and [14C]choline showed high renal and hepatic uptake. Blood clearance of both tracers was rapid with oxidative metabolites, [18F]fluorobetaine and [14C]betaine, representing the majority of radiolabel in plasma after 5 min post-injection. Oxidation (in liver) and lipid incorporation (in lung) were somewhat slower for [18F]FCH relative to [14C]choline. The majority of radiolabel in hypoxic subcutaneous tumor, as in hypoxic cultured 9L cells, was found as nonmetabolized [18F]FCH and [14C]choline. Conclusions [18F]FCH mimics choline uptake and metabolism by 9L glioma cells and tumors. However, subtle changes in biodistribution, oxidative metabolism, dephosphorylation, lipid incorporation and renal excretion show moderate effects of the presence of the radiofluorine atom in [18F]FCH. The decrease in phosphorylation of exogenous choline by cancer cells should be considered in interpretation of PET

DICHLOROACETIC ACID (DCA) INHIBITS PROLIFERATION AND APOPTOSIS IN NORMAL HEPATOCYTES OF MALE F344 RATS

EPA Science Inventory

Dichloroacetic acid (DCA} inhibits proliferation and apoptosis in nonnal hepatocytes of
male F344 rats.

Large segments of the population are chronically exposed to dichloroacetic acid (DCA}: DCA is a by product of the chlorine disinfection of drinking water, a metab...

TOXICITY OF TETRYL (N-METHYL-N,2,4,6-TETRANITROANILINE) IN F344 RATS

EPA Science Inventory

The toxicity of tetryl (N-methyl-N,2,4,6-tetranitroaniline) in male and female F344 rats was evaluated after adminstration in the diet for 14 or 90 days. The 14-day study diet concentrations used were 0, 500, 1250, 2000, 2500, and 5000 ppm; the 90-day study diet concentrations we...

14-Week toxicity and cell proliferation of methyleugenol administered by gavage to F344 rats and B6C3F1 mice.

PubMed

Abdo, K M; Cunningham, M L; Snell, M L; Herbert, R A; Travlos, G S; Eldridge, S R; Bucher, J R

2001-04-01

Methyleugenol, a food flavor and fragrance agent, was tested for toxicity in male and female F344/N rats and B6C3F1 mice. Groups of 10 males and 10 females per sex per species were administered 0, 10, 30, 100, 300 or 1000 mg methyleugenol/kg body weight in 0.5% aqueous methylcellulose by gavage, 5 days per week for 14 weeks. Additional groups of rats and mice of each sex were dosed similarly and used for hematology and clinical chemistry studies. Groups of 10 male and 10 female rats and mice received the vehicle by gavage on the same dosing schedule and served as vehicle controls. For serum gastrin, gastric pH and cell proliferation studies groups of 10 female rats were given 0, 37, 75 or 150 mg/kg, once daily 5 days per week for 30 or 90 days or 300 or 1000 mg/kg for 30 days; male mice were given 0, 9, 18.5, 37, 75, 150 or 300 mg/kg for 30 or 90 days. For the gastrin, pH and cell proliferation studies, groups of 10 female rats and 10 male mice were given the vehicle for 30 or 90 days and served as controls. Methyleugenol administration to rats induced erythrocyte microcytosis and thrombocytosis in male and female rats. It also caused an increase in serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentration, suggesting hepatocellular injury, cholestasis or altered hepatic function. Additionally, methyleugenol induced hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations in both male and female rats, suggesting in inefficiency of dietary protein utilization due to methyleugenol-induced toxic effects on the liver and glandular stomach of rats and mice. The increase in gastrin and gastric pH of rats and mice given methyleugenol suggests that gastrin feedback was impaired and resulted in conditions not conducive to protein digestion. In rats, methyleugenol caused an increase in the incidences of hepatocyte cytologic alteration, cytomegaly, Kupffer cell pigmentation, mixed foci of

Epistatic effects contribute to variation in BMD in Fischer 344 x Lewis F2 rats.

PubMed

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-01-01

To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F(2) progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an alpha level of 0.01. Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture.

Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal

PubMed Central

Hong, Hue-Hua L.; Hoenerhoff, Mark J.; Ton, Thai-Vu; Herbert, Ronald A.; Kissling, Grace E.; Hooth, Michelle J.; Behl, Mamta; Witt, Kristine L.; Smith-Roe, Stephanie L.; Sills, Robert C.; Pandiri, Arun R.

2015-01-01

Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kras, Egfr and Tp53 mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD) induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors, and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors, and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominantly in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assays indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents. PMID:26059825

Age-related Changes in the Fracture Resistance of Male Fischer F344 Rat Bone

PubMed Central

Uppuganti, Sasidhar; Granke, Mathilde; Makowski, Alexander J.; Does, Mark D.; Nyman, Jeffry S.

2015-01-01

In addition to the loss in bone volume that occurs with age, there is a decline in material properties. To test new therapies or diagnostic tools that target such properties as material strength and toughness, a pre-clinical model of aging would be useful in which changes in bone are similar to those that occur with aging in humans. Toward that end, we hypothesized that similar to human bone, the estimated toughness and material strength of cortical bone at the apparent-level decreases with age in the male Fischer F344 rat. In addition, we tested whether the known decline in trabecular architecture in rats translated to an age-related decrease in vertebra (VB) strength and whether non-X-ray techniques could quantify tissue changes at micron and sub-micron length scales. Bones were harvested from 6-, 12-, and 24-month (mo.) old rats (n=12 per age). Despite a loss in trabecular bone with age, VB compressive strength was similar among the age groups. Similarly, whole-bone strength (peak force) in bending was maintained (femur) or increased (radius) with aging. There was though an age-related decrease in post-yield toughness (radius) and bending strength (femur). The ability to resist crack initiation was actually higher for the 12-mo. and 24-mo. than for 6-mo. rats (notch femur), but the estimated work to propagate the crack was less for the aged bone. For the femur diaphysis region, porosity increased while bound water decreased with age. For the radius diaphysis, there was an age-related increase in non-enzymatic and mature enzymatic collagen crosslinks. Both Raman spectroscopy and reference point indentation detected differences in tissue properties with age, though the trends did not necessarily match observations from human tissue. PMID:26610688

Age-related changes in the fracture resistance of male Fischer F344 rat bone.

PubMed

Uppuganti, Sasidhar; Granke, Mathilde; Makowski, Alexander J; Does, Mark D; Nyman, Jeffry S

2016-02-01

In addition to the loss in bone volume that occurs with age, there is a decline in material properties. To test new therapies or diagnostic tools that target such properties as material strength and toughness, a pre-clinical model of aging would be useful in which changes in bone are similar to those that occur with aging in humans. Toward that end, we hypothesized that similar to human bone, the estimated toughness and material strength of cortical bone at the apparent-level decreases with age in the male Fischer F344 rat. In addition, we tested whether the known decline in trabecular architecture in rats translated to an age-related decrease in vertebra (VB) strength and whether non-X-ray techniques could quantify tissue changes at micron and sub-micron length scales. Bones were harvested from 6-, 12-, and 24-month (mo.) old rats (n=12 per age). Despite a loss in trabecular bone with age, VB compressive strength was similar among the age groups. Similarly, whole-bone strength (peak force) in bending was maintained (femur) or increased (radius) with aging. There was though an age-related decrease in post-yield toughness (radius) and bending strength (femur). The ability to resist crack initiation was actually higher for the 12-mo. and 24-mo. than for 6-mo. rats (notch femur), but the estimated work to propagate the crack was less for the aged bone. For the femur diaphysis region, porosity increased while bound water decreased with age. For the radius diaphysis, there was an age-related increase in non-enzymatic and mature enzymatic collagen crosslinks. Raman spectroscopy analysis of embedded cross-sections of the tibia mid-shaft detected an increase in carbonate subsitution with advanced aging for both inner and outer tissue. Published by Elsevier Inc.

The “metabolic sensor” function of rat supraoptic oxytocin and vasopressin neurons is attenuated during lactation but not in diet-induced obesity

PubMed Central

Stevens, Wanida; Song, Zhilin; Johnson, Ginger C.; MacLean, Paul S.

2015-01-01

The oxytocin (OT) and vasopressin (VP) neurons of the supraoptic nucleus (SON) demonstrate characteristics of “metabolic sensors”. They express insulin receptors and glucokinase (GK). They respond to an increase in glucose and insulin with an increase in intracellular [Ca2+] and increased OT and VP release that is GK dependent. Although this is consistent with the established role of OT as an anorectic agent, how these molecules function relative to the important role of OT during lactation and whether deficits in this metabolic sensor function contribute to obesity remain to be examined. Thus, we evaluated whether insulin and glucose-induced OT and VP secretion from perifused explants of the hypothalamo-neurohypophyseal system are altered during lactation and by diet-induced obesity (DIO). In explants from female day 8 lactating rats, increasing glucose (Glu, 5 mM) did not alter OT or VP release. However, insulin (Ins; 3 ng/ml) increased OT release, and increasing the glucose concentration in the presence of insulin (Ins+Glu) resulted in a sustained elevation in both OT and VP release that was not prevented by alloxan, a GK inhibitor. Explants from male DIO rats also responded to Ins+Glu with an increase in OT and VP regardless of whether obesity had been induced by feeding a high-fat diet (HFD). The HFD-DIO rats had elevated body weight, plasma Ins, Glu, leptin, and triglycerides. These findings suggest that the role of SON neurons as metabolic sensors is diminished during lactation, but not in this animal model of obesity. PMID:26661099

Effect of Gestational Intake of Fisetin (3,3',4',7-Tetrahydroxyflavone) on Developmental Methyl Mercury Neurotoxicity in F1 Generation Rats.

PubMed

Jacob, Sherin; Thangarajan, Sumathi

2017-06-01

Methyl mercury (MeHg) is a developmental neurotoxin that causes irreversible cognitive damage in offspring of gestationally exposed mothers. Currently, no preventive drugs are established against MeHg developmental neurotoxicity. The neuroprotective effect of gestational administration of a flavanoid against in utero toxicity of MeHg is not explored much. Hence, the present study validated the effect of a bioactive flavanoid, fisetin, on MeHg developmental neurotoxicity outcomes in rat offspring at postnatal weaning age. Pregnant Wistar rats were simultaneously given MeHg (1.5 mg/kg b.w.) and two doses of fisetin (10 and 50 mg/kg b.w. in two separate groups) orally from gestational day (GD) 5 till parturition. Accordingly, after parturition, on postnatal day (PND) 24, weaning F 1 generation rats were studied for motor and cognitive behavioural changes. Biochemical and histopathological changes were also studied in the cerebral cortex, cerebellum and hippocampus on PND 25. Administration of fisetin during pregnancy prevented behavioural impairment due to transplacental MeHg exposure in weaning rats. Fisetin decreased the levels of oxidative stress markers, increased enzymatic and non-enzymatic antioxidant levels and increased the activity of membrane-bound ATPases and cholinergic function in F 1 generation rats. In light microscopic studies, fisetin treatment protected the specific offspring brain regions from significant morphological aberrations. Between the two doses of fisetin studied, 10 mg/kg b.w. was found to be more satisfactory and effective than 50 mg/kg b.w. The present study shows that intake of fisetin during pregnancy in rats ameliorated in utero MeHg exposure-induced neurotoxicity outcomes in postnatal weaning F 1 generation rats.

Plekhs1 and Prdx3 are candidate genes responsible for mild hyperglycemia associated with obesity in a new animal model of F344-fa-nidd6 rat.

PubMed

Kotoh, Jun; Sasaki, Daiki; Matsumoto, Kozo; Maeda, Akihiko

2016-12-01

Type 2 diabetes is a polygenic disease and characterized by hyperglycemia and insulin resistance, and it is strongly associated with obesity. However, the mechanism by which obesity contributes to onset of type 2 diabetes is not well understood. We generated rat strains with a hyperglycemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr -/- ) locus derived from the Zucker Fatty rat. Phenotypes for plasma glucose, and insulin levels were measured, and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blot analyses, respectively. Compared with the obese control strain F344-fa (Lepr -/- ), plasma glucose levels of the obese F344-fa-nidd6 (Lepr -/- and Nidd6/of) significantly increased, and plasma insulin levels significantly decreased. These phenotypes were not observed in the lean strains, suggesting that the Nidd6/of locus harbors a diabetogenic gene associated with obesity. We measured the expression of 41 genes in the Nidd6/of QTL region of each strain and found that the mRNA expression levels of the two genes significantly differed between the obese strains. The two genes, pleckstrin homology domain-containing, family S member 1 (Plechs1) and peroxiredoxin III (Prdx3), were differentially expressed only in the obese rats, suggesting that these two genes are involved in the mild elevation of blood glucose levels and insulin resistance in obesity.

The altered balance between sympathetic nervous system and nitric oxide in salt hypertensive Dahl rats: ontogenetic and F2 hybrid studies.

PubMed

Dobesová, Zdena; Kunes, Jaroslav; Zicha, Josef

2002-05-01

We have demonstrated earlier that the nitric oxide (NO) system is not able to counterbalance effectively the hyperactivity of the sympathetic nervous system (SNS) in salt hypertension of young Dahl rats in which augmented superoxide anion formation lowers NO bioavailability. The aim of the present study was to determine whether SNS hyperactivity and/or relative NO deficiency are also present in salt hypertension elicited in adult Dahl rats, and whether they are associated with blood pressure (BP) in the F2 population of Dahl rats. The contribution of major vasoactive systems [renin-angiotensin system (RAS), SNS and NO] and superoxide anions to BP maintenance was studied in SS/Jr rats in which salt hypertension was induced either in adulthood or in youth (8% NaCl diet from the age of 12 or 4 weeks). The contribution of particular vasoactive systems was also investigated in 122 young salt-loaded F2hybrids [derived from salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats] which were fed a high-salt diet (8% NaCl) for 6 weeks after weaning. Mean arterial pressure (MAP) was measured in conscious animals subjected to acute consecutive blockade of RAS (captopril 10 mg/kg i.v.), SNS (pentolinium 5 mg/kg i.v.) and NO synthase (l-NAME 30 mg/kg i.v.). Dahl rats with salt hypertension induced in adulthood were also characterized by enhanced pentolinium-induced BP fall (DeltaMAPpento), but their residual BP (recorded after the blockade of both RAS and SNS) was unaltered, in contrast to its elevation seen in young salt-hypertensive rats. The BP rise after NO synthase inhibition by l-NAME (DeltaMAPL-NAME), which was substantially greater in adult than in young hypertensive rats, was not enhanced by superoxide scavenging with tempol in adult hypertensive animals, in which this drug elicited a moderate BP reduction only. Basal MAP of young salt-loaded F2 hybrids was positively associated not only with DeltaMAPpento (P < 0.0001) and residual BP (P < 0.001) but also with

Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats.

PubMed

Devenny, James J; Godonis, Helen E; Harvey, Susan J; Rooney, Suzanne; Cullen, Mary J; Pelleymounter, Mary Ann

2012-08-01

Dapagliflozin is a potent and selective sodium glucose cotransporter-2 (SGLT2) inhibitor which promotes urinary glucose excretion and induces weight loss. Since metabolic compensation can offset a negative energy balance, we explored the potential for a compensatory physiological response to the weight loss induced by dapagliflozin. Dapagliflozin was administered (0.5-5 mpk; p.o.) to diet-induced obese (DIO) rats with or without ad libitum access to food for 38 days. Along with inducing urinary glucose excretion, chronic administration of dapagliflozin dose-dependently increased food and water intake relative to vehicle-treated controls. Despite this, it reduced body weight by 4% (relative to controls) at the highest dose. The degree of weight loss was increased by an additional 9% if hyperphagia was prevented by restricting food intake to that of vehicle controls. Neither oxygen consumption (vO2) or the respiratory exchange ratio (RER) were altered by dapagliflozin treatment alone. Animals treated with dapagliflozin and pair-fed to vehicle controls (5 mpk PF-V) showed a reduction in RER and an elevation in nonfasting β-hydroxybutyrate (BHBA) relative to ad libitum-fed 5 mpk counterparts. Fasting BHBA was elevated in the 1 mpk, 5 mpk, and 5 mpk PF-V groups. Serum glucose was reduced in the fasted, but not the unfasted state. Insulin was reduced in the non-fasted state. These data suggest that in rodents, the persistent urinary glucose excretion induced by dapagliflozin was accompanied by compensatory hyperphagia, which attenuated the weight loss induced by SGLT2 inhibition. Therefore, it is possible that dapagliflozin-induced weight loss could be enhanced with dietary intervention.

NTP Toxicology and Carcinogenesis Studies of Dimethyl Methylphosphonate (CAS No. 756-79-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

PubMed

1987-11-01

Dimethyl methylphosphonate (98% pure) is one of four chemicals nominated by the U.S. Army for toxicology and carcinogenesis studies because it was being considered for use to simulate the physical and spectroscopic (but not the biologic) properties of anticholinesterase (nerve) agents. Dimethyl methylphosphonate is also used as a flame retardant, a preignition additive for gasoline, an antifoam agent, a plasticizer and stabilizer, a textile conditioner and antistatic agent, and an additive for solvents and low-temperature hydraulic fluids. The United States produces 0.2-2 million pounds (91,000-910,000 kg) of per year. Gavage was chosen as the route of administration for all four candidate "simulants" to mimic potential exposure. Experimental Design: Dimethyl methylphosphonate was administered in corn oil by gavage to male and female F344/N rats and B6C3F1 mice in single-administration, 15-day, and 13-week studies to obtain toxicity data, to establish dose levels for the 2-year studies, and to identify target tissues. Additional studies were also performed to determine toxicity to the reproductive system of male F344/N rats and B6C3F1 mice and to study the potential for genetic damage in bacteria, mammalian cells, and Drosophila. Single-Administration Studies: In the single-administration studies, dimethyl methylphosphonate was given to rats and mice at doses up to 6,810 mg/kg body weight. No compound-related deaths were seen in male or female rats or male mice; two high dose female mice died. Rats exhibited inactivity, unsteady gait, and prostration after dosing; mice were inactive after dosing. Fifteen-Day Studies: Rats and mice received doses of 0, 1,250, 2,500, 5,000, 10,000, or 15,000 mg/kg dimethyl methylphosphonate per day. Compound-related deaths occurred in the three highest dose groups of rats and the two highest dose groups of mice. Rats receiving doses of 2,500 mg/kg or higher were inactive and at 5,000 or 10,000 mg/kg had an unsteady gait after dosing

A new animal diet based on human Western diet is a robust diet-induced obesity model: comparison to high-fat and cafeteria diets in term of metabolic and gut microbiota disruption.

PubMed

Bortolin, R C; Vargas, A R; Gasparotto, J; Chaves, P R; Schnorr, C E; Martinello, Kd B; Silveira, A K; Rabelo, T K; Gelain, D P; Moreira, J C F

2018-03-01

Obesity is a metabolic disorder that predisposes patients to numerous diseases and has become a major global public-health concern. Animal models of diet-induced obesity (DIO) are frequently used to study obesity, but which DIO model most accurately reflects the pathology of human obesity remains unclear. In this study, we designed a diet based on the human Western diet (WD) and compared it with the cafeteria diet (CAF) and high-fat diet (HFD) in order to evaluate which diet most closely mirrors human obesity. Wistar rats were fed four different diets (WD, CAF, HFD and a low-fat diet) for 18 weeks. Metabolic parameters and gut microbiota changes were then characterized. Rats fed the four different diets exhibited completely different phenotypes, highlighting the importance of diet selection. This study also revealed that WD most effectively induced obesity and obesity-related disorders, and thus proved to be a robust model of human obesity. Moreover, WD-fed rats developed obesity and obesity-related comorbidities independent of major alterations in gut microbiota composition (dysbiosis), whereas CAF-fed rats developed the greatest dysbiosis independent of obesity. We also characterized gut microbiota after feeding on these four different diets and identified five genera that might be involved in the pathogenesis of obesity. These data suggest that diet, and not the obese state, was the major driving force behind gut microbiota changes. Moreover, the marked dysbiosis observed in CAF-fed rats might have resulted from the presence of several additives present in the CAF diet, or even a lack of essential vitamins and minerals. Based on our findings, we recommend the use of the prototypic WD (designed here) in DIO models. Conversely, CAF could be used to investigate the effects of excessive consumption of industrially produced and highly processed foods, which are characteristic of Western society.

EFFECTS OF BROMODICHLOROMETHANE (BDCM) ON EX VIVO LUTEAL FUNCTION IN THE F344 RAT

EPA Science Inventory

EFFECTS OF BROMODICHLOROMETHANE (BDCM) ON EX VIVO LUTEAL FUNCTION IN THE PREGNANT F344 RAT.

S. R. Bielmeier1, A. S. Murr2, D. S. Best2, J. M. Goldman2, and M. G. Narotsky2

1 Curriculum in Toxicology, Univ. of North Carolina, Chapel Hill, NC, USA
2 Reproductive T...

Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer's disease.

PubMed

Muñoz-Moreno, Emma; Tudela, Raúl; López-Gil, Xavier; Soria, Guadalupe

2018-02-07

Animal models of Alzheimer's disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain connectivity at an early stage (5 months of age) before a significant concentration of β-amyloid plaques is present. Cognitive abilities were assessed by a delayed nonmatch-to-sample (DNMS) task preceded by a training phase where the animals learned the task. The number of training sessions required to achieve a learning criterion was recorded and evaluated. After DNMS, MRI acquisition was performed, including diffusion-weighted MRI and resting-state functional MRI, which were processed to obtain the structural and functional connectomes, respectively. Global and regional graph metrics were computed to evaluate network organization in both transgenic and control rats. The results pointed to a delay in learning the working memory-related task in the AD rats, which also completed a lower number of trials in the DNMS task. Regarding connectivity properties, less efficient organization of the structural brain networks of the transgenic rats with respect to controls was observed. Specific regional differences in connectivity were identified in both structural and functional networks. In addition, a strong correlation was observed between cognitive performance and brain networks, including whole-brain structural connectivity as well as functional and structural network metrics of regions related to memory and reward processes. In this study, connectivity and neurocognitive impairments were identified in TgF344-AD rats at a very early stage of the disease when most of the pathological hallmarks

Effects of perfluorooctane sulfonate on rat thyroid hormone biosynthesis and metabolism.

PubMed

Yu, Wen-Guang; Liu, Wei; Jin, Yi-He

2009-05-01

The potential toxicity of perfluorooctane sulfonate (PFOS), an environmentally persistent organic pollutant, is of great concern. The present study examines the ability of PFOS to disturb thyroid function and the possible mechanisms involved in PFOS-induced thyroid hormone alteration. Male Sprague-Dawley rats were exposed to 1.7, 5.0, and 15.0 mg/L of PFOS in drinking water for 91 consecutive days. Serum was collected for analysis of total and free thyroxine (T4), total triiodothyronine (T3), and thyrotrophin (TSH). Thyroid and liver were removed for the measurement of endpoints closely related to thyroid hormone biosynthesis and metabolism following PFOS exposure. Determined endpoints were the messenger RNA (mRNA) levels for two isoforms of uridine diphosphoglucuronosyl transferases (UGT1A6 and UGT1A1) and type 1 deiodinase (DIO1) in liver, sodium iodide symporter (NIS), TSH receptor (TSHR), and DIO1 in thyroid as well as the activity of thyroid peroxidase (TPO). Serum total T4 level decreased significantly at all applied dosages, whereas total T3 level increased markedly only at 1.7 mg/L of PFOS. No statistically significant toxic effects of PFOS on serum TSH were observed. Hepatic UGTIA1, but not UGT1A6, mRNA was up-regulated at 5.0 and 15.0 mg/L of PFOS. Treatment with PFOS lowered hepatic DIO1 mRNA at 15.0 mg/L but increased thyroidal DIO1 mRNA dose dependently. The activity of TPO, NIS, and TSHR mRNA in thyroid were unaffected by PFOS treatment. These results indicate that increased hepatic T4 glucuronidation via UGT1A1 and increased thyroidal conversion of T4 to T3 via DIO1 were responsible in part for PFOS-induced hypothyroxinemia in rats.

Modeling Alzheimer’s disease in transgenic rats

PubMed Central

2013-01-01

Alzheimer’s disease (AD) is the most common form of dementia. At the diagnostic stage, the AD brain is characterized by the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Despite the large variety of therapeutic approaches, this condition remains incurable, since at the time of clinical diagnosis, the brain has already suffered irreversible and extensive damage. In recent years, it has become evident that AD starts decades prior to its clinical presentation. In this regard, transgenic animal models can shed much light on the mechanisms underlying this “pre-clinical” stage, enabling the identification and validation of new therapeutic targets. This paper summarizes the formidable efforts to create models mimicking the various aspects of AD pathology in the rat. Transgenic rat models offer distinctive advantages over mice. Rats are physiologically, genetically and morphologically closer to humans. More importantly, the rat has a well-characterized, rich behavioral display. Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes. PMID:24161192

NTP Toxicology and Carcinogenesis Studies of Molybdenum Trioxide (CAS No. 1313-27-5) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

PubMed

1997-04-01

Molybdenum is an essential element for the function of nitrogenase in plants and as a cofactor for enzymes including xanthine oxidoreductase, aldehyde oxidase, and sulfide oxidase in animals. Molybdenum trioxide is used primarily as an additive to steel and corrosion-resistant alloys. It is also used as a chemical intermediate for molybdenum products; an industrial catalyst; a pigment; a crop nutrient; components of glass, ceramics, and enamels; a flame retardant for polyester and polyvinyl chloride resins; and a reagent in chemical analyses. Molybdenum trioxide was nominated by the NCI for toxicity and carcinogenicity studies as a representative inorganic molybdenum compound. The production of molybdenum trioxide is the largest of all the molybdenum compounds examined. Male and female F344/N rats and B6C3F1 mice were exposed to molybdenum trioxide (approximately 99% pure) by inhalation for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 3, 10, 30, 100, or 300 mg molybdenum trioxide/m(3). Rats were exposed for 6 hours per day, 5 days per week, for a total of 10 exposure days during a 14-day period. All rats survived to the end of the study. The final mean body weights of male rats exposed to 100 mg/m(3) and male and female rats exposed to 300 mg/m(3) were significantly lower than those of the control groups. Male rats exposed to 300 mg/m(3) lost weight during the study. There were no clinical findings related to exposure to molybdenum trioxide. No chemical-related lesions were observed. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 3, 10, 30, 100, or 300 mg molybdenum trioxide/m(3). Mice were exposed 6 hours per day, 5 days per week, for a total of 10 exposure days during a 14-day period. All mice survived to the end of the study. Final mean

Inflammatory Biomarkers Associated with Lethal Rift Valley Fever Encephalitis in the Lewis Rat Model

PubMed Central

Caroline, Amy L.; Kujawa, Michael R.; Oury, Tim D.; Reed, Douglas S.; Hartman, Amy L.

2016-01-01

Rift Valley fever (RVF) is an emerging viral disease that causes significant human and veterinary illness in Africa and the Arabian Peninsula. Encephalitis is one of the severe complications arising from RVF virus (RVFV) infection of people, and the pathogenesis of this form of RVF is completely unknown. We use a novel reproducible encephalitic disease model in rats to identify biomarkers of lethal infection. Lewis rats were infected with RVFV strain ZH501 by aerosol exposure, then sacrificed daily to determine the course of infection and evaluation of clinical, virological, and immunological parameters. Weight loss, fever, and clinical signs occurred during the last 1–2 days prior to death. Prior to onset of clinical indications of disease, rats displayed marked granulocytosis and thrombocytopenia. In addition, high levels of inflammatory chemokines (MCP-1, MCS-F, Gro/KC, RANTES, and IL-1β) were detected first in serum (3–5 dpi) followed by brain (5–7 dpi). The results of this study are consistent with clinical data from human RVF patients and validate Lewis rats as an appropriate small animal model for RVF encephalitis. The biomarkers we identified here will be useful in future studies evaluating the efficacy of novel vaccines and therapeutics. PMID:26779164

APOPTOSIS AND PROLIFERATION DURING DICHLOROACETIC ACID (DCA) INDUCED HEPTACELLULAR CARCINOGENESIS IN THE F344 MALE RAT

EPA Science Inventory

Apoptosis and Proliferation During DicWoroacetic Acid (DCA) Induced Hepatocellular
Carcinogenesis in the F344 Male Rat

Chlorine, introduced into public drinking \\\\'ater supplies for disinfection, can react with organic compounds in surface waters to form toxic by-prod...

Antioxidant therapy improves non-thyroidal illness syndrome in uremic rats.

PubMed

Yang, Pingping; Li, Yun; Xu, Gaosi

2016-01-01

The roles of antioxidant therapy on non-thyroidal illness syndrome (NTIS) in uremic rats is still unclear. Twenty-four Sprague-Dawley (SD) rats were randomly divided into blank, 5/6 nephrectomy (Nx), pyrrolidine dithiocarbamate (PDTC, 10 mg/100 g), sodium bicarbonate (SB, 0.1 g/100 g), N-acetylcysteine (NAC, 80 mg/100 g) and thyroid hormones (TH, levothyroxine 2 μg/100 g) groups. The serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), advanced oxidation protein products (AOPP), interleukin (IL)-1β, free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) were detected in the sixth week. The expressions of IL-1β and deiodinase type 1 (DIO1) were assessed by western blotting. The nuclear factor kappa B (NF-κB) inflammatory signal pathway was confirmed by electrophoretic mobility shift assay (EMSA). Compared with 5/6 Nx group, PDTC and NAC significantly reduced the levels (p < 0.01, respectively) of serum MDA, AOPP, TSH, and elevated levels of serum SOD (p < 0.01, respectively) and FT3 (p = 0.016 and p < 0.01). Neither had significant effects on serum IL-1β content (p = 0.612 and p = 0.582). PDTC and NAC markedly decreased the protein expression of IL-1β (p < 0.01) and increased the protein expression of DIO1 (p < 0.01), respectively. Both had been considerably blunted NF-κB activity (p < 0.01). In uremic rat model, PDTC and NAC can effectively improve oxidative stress level and NTIS. In terms of improving oxidative stress level, NAC is probably superior to PDTC.

Impact of high-protein diets with either moderate or low carbohydrate on weight loss, body composition, blood pressure and glucose tolerance in rats.

PubMed

Lobley, Gerald E; Bremner, David M; Holtrop, Grietje; Johnstone, Alexandra M; Maloney, Christopher

2007-06-01

One approach to achieve weight loss and decrease both obesity and associated morbidities involves high-protein, low-carbohydrate (HPLC) diets. This study compares the impact on metabolic health of HPLC and high-protein, medium-carbohydrate (HPMC) diets offered to diet-induced obese (DIO) rats. Weanling male rats were fed either a 37 % fat diet (n 48) or stock pellets (n 12) for 22 weeks. Rats fed the 37 % fat diet accumulated more body fat (26.6 versus 14.8 % body weight, P < 0.001) compared with those on stock diet. The DIO rats had higher systolic blood pressure (+6.6 mmHg, P = 0.002), fasting insulin (+63 % P = 0.006) and areas under the glucose (+21 %, P < 0.001) and insulin (+81 %, P < 0.001) curves following an oral glucose tolerance test. DIO rats were then separated into four groups and offered for 8 weeks either: (1) the 37 % fat diet; (2) an HPLC or (3) HPMC diet; or (4) fed the 37 % fat diet to the intake of the HPMC group. Rats offered the 37 % fat or HPLC diets gained while those on HPMC lost body fat. Blood pressure was not altered by the dietary switch. Both HPLC and HPMC rats had lowered fasting insulin (P = 0.027) and improved homeostatic assessment (HOMA; P = 0.011) that was not different from those of stock animals. These improvements occurred despite differences in fat gain, and indicate that both weight loss and macronutrient intake can impact favourably on obesity-associated morbidities.

Chronic toxicity and carcinogenicity studies of chromium picolinate monohydrate administered in feed to F344/N rats and B6C3F1 mice for 2 years.

PubMed

Stout, M D; Nyska, A; Collins, B J; Witt, K L; Kissling, G E; Malarkey, D E; Hooth, M J

2009-04-01

Trivalent chromium (Cr(III)) has been proposed to be an essential element, which may increase sensitivity to insulin and thus participate in carbohydrate and lipid metabolism. Humans ingest Cr(III) both as a natural dietary constituent and in dietary supplements taken for weight loss and antidiabetic effects. Chromium picolinate (CP), a widely used supplement, contains Cr(III) chelated with three molecules of picolinic acid and was formulated in an attempt to improve the absorption of Cr(III). In order to examine the potential for CP to induce chronic toxicity and carcinogenicity, the NTP conducted studies of the monohydrate form (CPM) in groups of 50 male and female F344/N rats and B6C3F1 mice exposed in feed to concentrations of 0, 2000, 10,000 or 50,000 ppm for 2 years; exposure concentrations were selected following review of the data from NTP 3-month toxicity studies. Exposure to CPM did not induce biologically significant changes in survival, body weight, feed consumption, or non-neoplastic lesions in rats or mice. In male rats, a statistically significant increase in the incidence of preputial gland adenoma at 10,000 ppm was considered an equivocal finding. CPM was not carcinogenic to female rats or to male or female mice.

Chronic Toxicity and Carcinogenicity Studies of Chromium Picolinate Monohydrate Administered in Feed to F344/N Rats and B6C3F1 Mice for 2 Years

PubMed Central

Stout, M.D.; Nyska, A.; Collins, B.J.; Witt, K.L.; Kissling, G.E.; Malarkey, D.E.; Hooth, M.J.

2009-01-01

Trivalent chromium (Cr(III)) has been proposed to be an essential element, which may increase sensitivity to insulin and thus participate in carbohydrate and lipid metabolism. Humans ingest Cr(III) both as a natural dietary constituent and in dietary supplements taken for weight loss and antidiabetic effects. Chromium picolinate (CP), a widely used supplement, contains Cr(III) chelated with three molecules of picolinic acid and was formulated in an attempt to improve the absorption of Cr(III). In order to examine the potential for CP to induce chronic toxicity and carcinogenicity, the NTP conducted studies of the monohydrate form (CPM) in groups of 50 male and female F344/N rats and B6C3F1 mice exposed in feed to concentrations of 0, 2,000, 10,000 or 50,000 ppm for 2 years; exposure concentrations were selected following review of the data from NTP 3-month toxicity studies. Exposure to CPM did not induce biologically significant changes in survival, body weight, feed consumption, or non-neoplastic lesions in rats or mice. In male rats, a statistically significant increase in the incidence of preputial gland adenoma at 10,000 ppm was considered an equivocal finding. CPM was not carcinogenic to female rats or to male or female mice. PMID:19166900

Epistatic Effects Contribute to Variation in BMD in Fischer 344 × Lewis F2 Rats

PubMed Central

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-01-01

To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. Introduction The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F2 progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Materials and Methods Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an α level of 0.01. Results and Conclusions Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture. PMID:17907919

Variable pulmonary responses from exposure to concentrated ambient air particles in a rat model of bronchitis.

PubMed

Kodavanti, U P; Mebane, R; Ledbetter, A; Krantz, T; McGee, J; Jackson, M C; Walsh, L; Hilliard, H; Chen, B Y; Richards, J; Costa, D L

2000-04-01

Chronic bronchitis may be considered a risk factor in particulate matter (PM)-induced morbidity. We hypothesized that a rat model of human bronchitis would be more susceptible to the pulmonary effects of concentrated ambient particles (CAPs) from Research Triangle Park, NC. Bronchitis was induced in male Sprague-Dawley rats (90-100 days of age) by exposure to 200 ppm sulfur dioxide (SO2), 6 h/day x 5 days/week x 6 weeks. One day following the last SO2 exposure, both healthy (air-exposed) and bronchitic (SO2-exposed) rats were exposed to filtered air (three healthy; four bronchitic) or CAPs (five healthy; four bronchitic) by whole-body inhalation, 6 h/day x 2 or 3 days. Pulmonary injury was determined either immediately (0h) or 18 h following final CAPs exposure. The study protocol involving 0 h time point was repeated four times (study #A, November, 1997; #B, February, 1998; #C and #D, May, 1998), whereas the study protocol involving 18 h time point was done only once (#F). In an additional study (#E), rats were exposed to residual oil fly ash (ROFA), approximately 1 mg/ m(3)x6 h/day x 3 days to mimic the CAPs protocol (February, 1998). The rats allowed 18 h recovery following CAPs exposure (#F) did not depict any CAPs-related differences in bronchoalveolar lavage fluid (BALF) injury markers. Of the four CAPs studies conducted (0 h time point), the first (#A) study (approximately 650 microg/m3 CAPs) revealed significant changes in the lungs of CAPs-exposed bronchitic rats compared to the clean air controls. These rats had increased BALF protein, albumin, N-acetyl glutaminidase (NAG) activity and neutrophils. The second (#B) study (approximately 475 microg/m3 CAPs) did not reveal any significant effects of CAPs on BALF parameters. Study protocols #C (approximately 869 microg/m3 CAPs) and #D (approximately 907 microg/m3 CAPs) revealed only moderate increases in the above mentioned BALF parameters in bronchitic rats exposed to CAPs. Pulmonary histologic evaluation of

THE FAILURE OF CHLOROFORM ADMINISTERED IN THE DRINKING WATER TO INDUCE RENAL TUBULAR CELL NEOPLASIA IN MALE F344/N RATS

EPA Science Inventory

The failure of chloroform administered in drinking water to induce renal tubular cell neoplasia in male F344/N rats

Chloroform (TCM) has been demonstrated to be a renal carcinogen in the male Osborne-
Mendel rat when administered either by corn oil gavage or in drin...

Carcinogenicity of bromodichloromethane administered in drinking water to Male F344/N Rats and B6C3F1 mice.

PubMed

George, Michael H; Olson, Greg R; Doerfler, Donald; Moore, Tanya; Kilburn, Steve; DeAngelo, Anthony B

2002-01-01

A life-time exposure study was conducted to assess the carcinogenicity of bromodichloromethane (BDCM) administered in the drinking water to male F344/N rats and B6C3F(1) mice. In mouse, the calculated mean daily BDCM concentrations (measured concentrations corrected for on-cage loss of chemical) were 0.06, 0.28 and 0.49 g/l. Time-weighted water consumption of 135, 97, and 89 ml/kg/day resulted in mean daily doses of 8.1, 27.2, and 43.4 mg BDCM/kg/day. No changes in feed consumption, final body weight, or survival were observed. Kidney weights were significantly depressed at 27.2 and 43.4 mg BDCM/kg/day. There was no increase in neoplasia in the liver, kidney, spleen, testis, bladder, sections along the alimentary tract, excised lesions, or at any other organ site. In rat, the corrected mean daily BDCM concentrations were 0.06, 0.33, and 0.62 g/l. Time-weighted water consumption of 65, 63, and 59 ml/kg/day yielded 3.9, 20.6 and 36.3 mg BDCM/kg/day. No alterations in feed consumption, body weight gain, and survival were seen. Kidney weight was significantly depressed in the 36.3-mg/kg/day treatment group. There was a significantly enhanced prevalence and multiplicity of hepatocellular adenomas at 3.9 mg BDCM/kg/day (15.5% and 0.16/animal vs. 2.2% and 0.02/animal for the control). Hepatocellular carcinomas increased from 2.2% and 0.02/animal for the control and 3.9 mg BDCM/kg/day to 8.3% and 0.10/animal at 20.6 mg BDCM/kg/day. The combined neoplasms were enhanced at 3.9 and 20.6 mg BDCM/kg/day. Liver neoplasia was depressed to the control value at 36.3 mg BDCM/kg. The prevalence of basophilic and clear cell, but not eosinophilic cells, altered foci of cells declined with increasing dose. BDCM did not increase cancer in the large bowel, renal tubules, or in any of the other tissues examined. Renal tubular hyperplasia was observed at 36.3 mg BDCM/kg (15.8% vs. 8.7% for the control group). Under the conditions of the study, BDCM in the drinking water was not carcinogenic

The novel monoclonal antibody 9F5 reveals expression of a fragment of GPNMB/osteoactivin processed by furin‐like protease(s) in a subpopulation of microglia in neonatal rat brain

PubMed Central

Hirata, Hiroshi; Ohbuchi, Kengo; Nishi, Kentaro; Maeda, Akira; Kuniyasu, Akihiko; Yamada, Daisuke; Maeda, Takehiko; Tsuji, Akihiko; Sawada, Makoto

2016-01-01

To differentiate subtypes of microglia (MG), we developed a novel monoclonal antibody, 9F5, against one subtype (type 1) of rat primary MG. The 9F5 showed high selectivity for this cell type in Western blot and immunocytochemical analyses and no cross‐reaction with rat peritoneal macrophages (Mφ). We identified the antigen molecule for 9F5: the 50‐ to 70‐kDa fragments of rat glycoprotein nonmetastatic melanoma protein B (GPNMB)/osteoactivin, which started at Lys170. In addition, 9F5 immunoreactivity with GPNMB depended on the activity of furin‐like protease(s). More important, rat type 1 MG expressed the GPNMB fragments, but type 2 MG and Mφ did not, although all these cells expressed mRNA and the full‐length protein for GPNMB. These results suggest that 9F5 reactivity with MG depends greatly on cleavage of GPNMB and that type 1 MG, in contrast to type 2 MG and Mφ, may have furin‐like protease(s) for GPNMB cleavage. In neonatal rat brain, amoeboid 9F5+ MG were observed in specific brain areas including forebrain subventricular zone, corpus callosum, and retina. Double‐immunοstaining with 9F5 antibody and anti‐Iba1 antibody, which reacts with MG throughout the CNS, revealed that 9F5+ MG were a portion of Iba1+ MG, suggesting that MG subtype(s) exist in vivo. We propose that 9F5 is a useful tool to discriminate between rat type 1 MG and other subtypes of MG/Mφ and to reveal the role of the GPNMB fragments during developing brain. GLIA 2016;64:1938–1961 PMID:27464357

Therapeutic effect of Tripterygium wilfordii Hook F multiglycosides on gut barrier dysfunction in rats with acute necrotizing pancreatitis.

PubMed

Wang, Jie; Wu, Gang; Ma, Baojin; Wu, Jianhua; Cai, Duan

2013-02-01

The aim of the current study was to investigate the therapeutic effect of Tripterygium wilfordii Hook F multiglycosides (TWG) on gut barrier dysfunction in rats with acute necrotizing pancreatitis (ANP). ANP was induced in rats using 3.5% sodium taurocholate. The rats were divided into 3 groups: the sham operation (SO), ANP and ANP+TWG groups. Biochemical and pathological change of pancreatic tissue and ileal mucosa, bacterial cultures and the survival rate were measured following surgery and treatment. TWG treatment significantly decreased amylase and lipase activities and plasma endotoxin and D-lactate levels. Edema and inflammation in the pancreas and ileal mucosa were alleviated. Positive bacterial cultures were significantly reduced. The survival rate of the rats in the ANP+TWG group was higher than that of the rats in the ANP group. TWG treatment showed beneficial effects by protecting the pancreas from bacterial infection caused by gut barrier dysfunction and improving the outcomes of the rats with ANP.

A Recombinant Respiratory Syncytial Virus Vaccine Candidate Attenuated by a Low-Fusion F Protein Is Immunogenic and Protective against Challenge in Cotton Rats.

PubMed

Rostad, Christina A; Stobart, Christopher C; Gilbert, Brian E; Pickles, Ray J; Hotard, Anne L; Meng, Jia; Blanco, Jorge C G; Moin, Syed M; Graham, Barney S; Piedra, Pedro A; Moore, Martin L

2016-08-15

Although respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, a safe and effective vaccine is not yet available. Live-attenuated vaccines (LAVs) are the most advanced vaccine candidates in RSV-naive infants. However, designing an LAV with appropriate attenuation yet sufficient immunogenicity has proven challenging. In this study, we implemented reverse genetics to address these obstacles with a multifaceted LAV design that combined the codon deoptimization of genes for nonstructural proteins NS1 and NS2 (dNS), deletion of the small hydrophobic protein (ΔSH) gene, and replacement of the wild-type fusion (F) protein gene with a low-fusion RSV subgroup B F consensus sequence of the Buenos Aires clade (BAF). This vaccine candidate, RSV-A2-dNS-ΔSH-BAF (DB1), was attenuated in two models of primary human airway epithelial cells and in the upper and lower airways of cotton rats. DB1 was also highly immunogenic in cotton rats and elicited broadly neutralizing antibodies against a diverse panel of recombinant RSV strains. When vaccinated cotton rats were challenged with wild-type RSV A, DB1 reduced viral titers in the upper and lower airways by 3.8 log10 total PFU and 2.7 log10 PFU/g of tissue, respectively, compared to those in unvaccinated animals (P < 0.0001). DB1 was thus attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. DB1 is the first RSV LAV to incorporate a low-fusion F protein as a strategy to attenuate viral replication and preserve immunogenicity. RSV is a leading cause of infant hospitalizations and deaths. The development of an effective vaccine for this high-risk population is therefore a public health priority. Although live-attenuated vaccines have been safely administered to RSV-naive infants, strategies to balance vaccine attenuation with immunogenicity have been elusive. In this study, we introduced a novel strategy to attenuate a recombinant RSV vaccine by

ENU mutagenesis to generate genetically modified rat models.

PubMed

van Boxtel, Ruben; Gould, Michael N; Cuppen, Edwin; Smits, Bart M G

2010-01-01

The rat is one of the most preferred model organisms in biomedical research and has been extremely useful for linking physiology and pathology to the genome. However, approaches to genetically modify specific genes in the rat germ line remain relatively scarce. To date, the most efficient approach for generating genetically modified rats has been the target-selected N-ethyl-N-nitrosourea (ENU) mutagenesis-based technology. Here, we describe the detailed protocols for ENU mutagenesis and mutant retrieval in the rat model organism.

18F-FEAnGA for PET of β-glucuronidase activity in neuroinflammation.

PubMed

Antunes, Inês F; Doorduin, Janine; Haisma, Hidde J; Elsinga, Philip H; van Waarde, Aren; Willemsen, Antoon T M; Dierckx, Rudi A; de Vries, Erik F J

2012-03-01

Activation of microglia is a hallmark of inflammatory, infectious, and degenerative diseases of the central nervous system. Several studies have indicated that there is an increase in release of β-glucuronidase by activated microglia into the extracellular space at the site of neuroinflammation. β-glucuronidase is involved in the hydrolysis of glycosaminoglycans on the cell surface and the degradation of the extracellular matrix. Therefore, β-glucuronidase might be a biomarker for ongoing neurodegeneration induced by neuroinflammation. In this study, we investigated whether the PET tracer (18)F-FEAnGA was able to detect β-glucuronidase release during neuroinflammation in a rat model of herpes encephalitis. Male Wistar rats were intranasally inoculated with herpes simplex virus 1 (HSV-1) or phosphate-buffered saline as a control. (11)C-(R)-PK11195 and (18)F-FEAnGA small-animal PET scans were acquired for 60 min. Logan graphical analysis was used to calculate (18)F-FEAnGA distribution volumes (DV(Logan)) in various brain areas. After administration of (18)F-FEAnGA, the area under the activity concentration-versus-time curve of the whole brain was 2 times higher in HSV-1-infected rats than in control rats. In addition, the DV(Logan) of (18)F-FEAnGA was most increased in the frontopolar cortex, frontal cortex, bulbus olfactorius, cerebral cortex, cerebellum, and brainstem of HSV-1-infected rats, when compared with control rats. The conversion of (18)F-FEAnGA to 4-hydroxy-3-nitrobenzyl alcohol was found to be 1.6 times higher in HSV-1-infected rats than in control rats and correlated with the DV(Logan) of (18)F-FEAnGA in the same areas of the brain. Furthermore, the DV(Logan) of (18)F-FEAnGA also correlated with β-glucuronidase activity in the same brain regions. In addition, DV(Logan) of (18)F-FEAnGA showed a tendency to correlate with (11)C-(R)-PK11195 uptake (marker for activated microglia) in the same brain regions. Despite relatively low brain uptake, (18)F

Optimization of the reference region method for dual pharmacokinetic modeling using Gd-DTPA/MRI and (18) F-FDG/PET.

PubMed

Poulin, Éric; Lebel, Réjean; Croteau, Étienne; Blanchette, Marie; Tremblay, Luc; Lecomte, Roger; Bentourkia, M'hamed; Lepage, Martin

2015-02-01

The combination of MRI and positron emission tomography (PET) offers new possibilities for the development of novel methodologies. In pharmacokinetic image analysis, the blood concentration of the imaging compound as a function of time, [i.e., the arterial input function (AIF)] is required for MRI and PET. In this study, we tested whether an AIF extracted from a reference region (RR) in MRI can be used as a surrogate for the manually sampled (18) F-FDG AIF for pharmacokinetic modeling. An MRI contrast agent, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) and a radiotracer, (18) F-fluorodeoxyglucose ((18) F-FDG), were simultaneously injected in a F98 glioblastoma rat model. A correction to the RR AIF for Gd-DTPA is proposed to adequately represent the manually sampled AIF. A previously published conversion method was applied to convert this AIF into a (18) F-FDG AIF. The tumor metabolic rate of glucose (TMRGlc) calculated with the manually sampled (18) F-FDG AIF, the (18) F-FDG AIF converted from the RR AIF and the (18) F-FDG AIF converted from the corrected RR AIF were found not statistically different (P>0.05). An AIF derived from an RR in MRI can be accurately converted into a (18) F-FDG AIF and used in PET pharmacokinetic modeling. © 2014 Wiley Periodicals, Inc.

Preliminary comparative study on the effect of different chinese drugs for strengthening Pi in antagonizing diet induced obesity.

PubMed

Li, Xiao; Jiang, Ping; Fu, Chang-geng

2010-04-01

To observe the difference in fatty degree, glucose-lipid disorder and adipose-hormones between diet induced obesity (DIO) rats and diet induced obesity resistance (DIO-R) rats, and to explore the effect and acting mechanism of Chinese drugs for strengthening Pi (CD-SP) and those for both strengthening Pi and dissolving phlegm (CD-SPDP) in inhibiting obesity. Excepting eight rats allocated in the blank control group, the other 54 rats were fed with high-lipid forage for 12 weeks to establish models of obesity. Finally, 30 DIO rats and 8 DIO-R rats (shown by their body weight) were obtained. The DIO rats were divided into three groups, which were given gastric perfusion, respectively, with normal saline (Group A), CD-SP (Group B), and CD-SPDP (Group C). Fourteen weeks later, the animals' body weight (BW), length (BL), blood levels of fasting insulin (FIn), fasting glucose (FBG), triglyceride (TG), cholesterol (TC), leptin (LP), neuropeptide Y (NPY), C-reactive protein (CRP), tumor necrosis factor-alpha(TNF-alpha), adiponectin (AN), and resistin (RS) were measured; insulin resistance index (IRI) was calculated, and the degree of obesity and lipid content in abdominal cavity of rats were estimated. Moreover, the levels of LP, CRP, TNF-alpha, AN and RS in homogenate of rats' adipose tissues (ATH) were determined. After 12 weeks of high-lipid diet, the BW of DIO rats was higher than that of normal or DIO-R rats. After a 14-week continuous high-lipid diet feeding, in DIO rats, BW, lipid coefficient (LC), and IRI were significantly increased (P<0.01); serum levels of TNF-alpha, LP and AN were lower, NPY was higher, while the ATH levels of LP and AN were lower and TNF-alpha was higher in DIO rats than in DIO-R rats (P<0.05 or P<0.01); blood levels of FBG and lipids in DIO rats showed an increasing trend but was statistically insignificant (P>0.05); no significant difference was found in serum levels of CRP and RS due to the overly high data dispersion. Comparisons of the 3

Moringa olifeira Lam. Stimulates Activation of the Insulin-Dependent Akt Pathway. Antidiabetic Effect in a Diet-Induced Obesity (DIO) Mouse Model.

PubMed

Attakpa, E S; Sangaré, M M; Béhanzin, G J; Ategbo, J-M; Seri, B; Khan, N A

2017-01-01

We investigated the antidiabetic effect of Moringa olifeira Lam. in a diet-induced obesity (DIO) mouse model. Six mice were randomly selected as normal controls. Moringa olifeira Lam. leaf extract at a dose of 200, 400 or 600 mg/kg body weight, glibenclamide (Glib) at the dose of 10 mg/kg (positive control) and distilled water at 10 ml/kg (control group) were administered orally by gastric intubation, and each group consisted of six mice. Insulinsensitive tissues (liver, skeletal muscle) were collected to investigate antidiabetic effects and examine the plant's molecular mechanisms. Moringa olifeira Lam. leaf extract prevented weight gain. It also reduced blood glucose in DIO mice. Glib and Moringa olifeira Lam. leaf extract, 400 mg/kg, treatments restored insulin levels towards normal values (P < 0.05 versus diabetic control group). Western immunoblot analysis of different tissues, collected at the end of the study, demonstrated that Moringa olifeira Lam. stimulated activation of the insulin-dependent Akt pathway and increased the protein content of Glut 4 in skeletal muscle. The improvement of hepatic steatosis observed in DIO-treated mice was associated with a decrease in the hepatic content of SREBP-1, a transcription factor involved in de novo lipogenesis. The hepatic PPARα protein content in the plant extract- treated mice remained significantly higher than those of the control group (P < 0.05). In conclusion, this study provides the first evidence for direct action of Moringa olifeira Lam. on pancreatic β-cells, enhancing glucose-stimulated insulin secretion. This correlated with hypoglycaemic effects in diabetic mice associated with restored levels of plasma insulin.

18F-labeled norepinephrine transporter tracer [18F]NS12137: radiosynthesis and preclinical evaluation.

PubMed

Kirjavainen, Anna K; Forsback, Sarita; López-Picón, Francisco R; Marjamäki, Päivi; Takkinen, Jatta; Haaparanta-Solin, Merja; Peters, Dan; Solin, Olof

2018-01-01

Several psychiatric and neurodegenerative diseases are associated with malfunction of brain norepinephrine transporter (NET). However, current clinical evaluations of NET function are limited by the lack of sufficiently sensitive methods of detection. To this end, we have synthesized exo-3-[(6-[ 18 F]fluoro-2-pyridyl)oxy]-8-azabicyclo[3.2.1]-octane ([ 18 F]NS12137) as a radiotracer for positron emission tomography (PET) and have demonstrated that it is highly specific for in vivo detection of NET-rich regions of rat brain tissue. We applied two methods of electrophilic, aromatic radiofluorination of the precursor molecule, exo-3-[(6-trimethylstannyl-2-pyridyl)oxy]-8-azabicyclo-[3.2.1]octane-8-carboxylate: (1) direct labeling with [ 18 F]F 2 , and (2) labeling with [ 18 F]Selectfluor, a derivative of [ 18 F]F 2 , using post-target produced [ 18 F]F 2 . The time-dependent distribution of [ 18 F]NS12137 in brain tissue of healthy, adult Sprague-Dawley rats was determined by ex vivo autoradiography. The specificity of [ 18 F]NS12137 binding was demonstrated on the basis of competitive binding by nisoxetine, a known NET antagonist of high specificity. [ 18 F]NS12137 was successfully synthesized with radiochemical yields of 3.9% ± 0.3% when labeled with [ 18 F]F 2 and 10.2% ± 2.7% when labeled with [ 18 F]Selectfluor. The molar activity of radiotracer was 8.8 ± 0.7 GBq/μmol with [ 18 F]F 2 labeling and 6.9 ± 0.4 GBq/μmol with [ 18 F]Selectfluor labeling at the end of synthesis of [ 18 F]NS12137. Uptake of [ 18 F]NS12137 in NET-rich areas in rat brain was demonstrated with the locus coeruleus (LCoe) having the highest regional uptake. Prior treatment of rats with nisoxetine showed no detectable [ 18 F]NS12137 in the LCoe. Analyses of whole brain samples for radiometabolites showed only the parent compound [ 18 F]NS12137. Uptake of 18 F-radioactivity in bone increased with time. The two electrophilic 18 F-labeling methods proved to be suitable for synthesis of [ 18 F

SERUM HORMONE CHARACTERIZATION AND EXOGENEOUS HORMONE RESCUE OF BROMODICHLOROMETHANE-INDUCED PREGNANCY LOSS IN THE F344 RAT

EPA Science Inventory

SERUM HORMONE CHARACTERIZATION AND EXOGENEOUS HORMONE RESCUE OF BROMODICHLOROMETHANE-INDUCED
PREGNANCY LOSS IN THE F344 RAT
Susan R. Bielmeier*, Deborah S. Best^, and Michael G. Narotsky^

ABSTRACT
Previously, we demonstrated that bromodichloromethane (BDCM), a d...

Fasting Enhances the Contrast of Bone Metastatic Lesions in 18F-Fluciclovine-PET: Preclinical Study Using a Rat Model of Mixed Osteolytic/Osteoblastic Bone Metastases

PubMed Central

Oka, Shuntaro; Kanagawa, Masaru; Doi, Yoshihiro; Schuster, David M.; Goodman, Mark M.; Yoshimura, Hirokatsu

2017-01-01

18F-fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid) is an amino acid positron emission tomography (PET) tracer used for cancer staging (e.g., prostate and breast). Patients scheduled to undergo amino acid-PET are usually required to fast before PET tracer administration. However, there have been no reports addressing whether fasting improves fluciclovine-PET imaging. In this study, the authors investigated the influence of fasting on fluciclovine-PET using triple-tracer autoradiography with 14C-fluciclovine, [5,6-3H]-2-fluoro-2-deoxy-d-glucose (3H-FDG), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) in a rat breast cancer model of mixed osteolytic/osteoblastic bone metastases in which the animals fasted overnight. Lesion accumulation of each tracer was evaluated using the target-to-background (muscle) ratio. The mean ratios of 14C-fluciclovine in osteolytic lesions were 4.6 ± 0.8 and 2.8 ± 0.6, respectively, with and without fasting, while those for 3H-FDG were 6.9 ± 2.5 and 5.1 ± 2.0, respectively. In the peri-tumor bone formation regions (osteoblastic), where 99mTc-HMDP accumulated, the ratios of 14C-fluciclovine were 4.3 ± 1.4 and 2.4 ± 0.7, respectively, and those of 3H-FDG were 6.2 ± 3.8 and 3.3 ± 2.2, respectively, with and without fasting. These results suggest that fasting before 18F-fluciclovine-PET improves the contrast between osteolytic and osteoblastic bone metastatic lesions and background, as well as 18F-FDG-PET. PMID:28468238

Epistasis between QTLs for bone density variation in Copenhagen × dark agouti F2 rats

PubMed Central

Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J.; Foroud, Tatiana; Turner, Charles H.

2010-01-01

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation. PMID:19153792

Epistasis between QTLs for bone density variation in Copenhagen x dark agouti F2 rats.

PubMed

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2009-03-01

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation.

Damage of hippocampal neurons in rats with chronic alcoholism.

PubMed

Du, Ailin; Jiang, Hongbo; Xu, Lei; An, Na; Liu, Hui; Li, Yinsheng; Zhang, Ruiling

2014-09-01

Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear membrane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin.

PREGNANCY LOSS IN THE F344 RAT CAUSED BY BROMODICHLOROMETHANE: EFFECTS ON SERUM LUTEINIZING HORMONE LEVELS

EPA Science Inventory

PREGNANCY LOSS IN THE F344 RAT CAUSED BY BROMODICHLOROMETHANE: EFFECTS ON SERUM LUTEINIZING HORMONE LEVELS
Bielmeier1, S.R., D.S. Best2, and M.G. Narotsky2; 1University of North Carolina at Chapel Hill, Curriculum in Toxicology, 2Reproductive Toxicology Division, U.S. Enviro...

The novel monoclonal antibody 9F5 reveals expression of a fragment of GPNMB/osteoactivin processed by furin-like protease(s) in a subpopulation of microglia in neonatal rat brain.

PubMed

Kawahara, Kohichi; Hirata, Hiroshi; Ohbuchi, Kengo; Nishi, Kentaro; Maeda, Akira; Kuniyasu, Akihiko; Yamada, Daisuke; Maeda, Takehiko; Tsuji, Akihiko; Sawada, Makoto; Nakayama, Hitoshi

2016-11-01

To differentiate subtypes of microglia (MG), we developed a novel monoclonal antibody, 9F5, against one subtype (type 1) of rat primary MG. The 9F5 showed high selectivity for this cell type in Western blot and immunocytochemical analyses and no cross-reaction with rat peritoneal macrophages (Mφ). We identified the antigen molecule for 9F5: the 50- to 70-kDa fragments of rat glycoprotein nonmetastatic melanoma protein B (GPNMB)/osteoactivin, which started at Lys(170) . In addition, 9F5 immunoreactivity with GPNMB depended on the activity of furin-like protease(s). More important, rat type 1 MG expressed the GPNMB fragments, but type 2 MG and Mφ did not, although all these cells expressed mRNA and the full-length protein for GPNMB. These results suggest that 9F5 reactivity with MG depends greatly on cleavage of GPNMB and that type 1 MG, in contrast to type 2 MG and Mφ, may have furin-like protease(s) for GPNMB cleavage. In neonatal rat brain, amoeboid 9F5+ MG were observed in specific brain areas including forebrain subventricular zone, corpus callosum, and retina. Double-immunοstaining with 9F5 antibody and anti-Iba1 antibody, which reacts with MG throughout the CNS, revealed that 9F5+ MG were a portion of Iba1+ MG, suggesting that MG subtype(s) exist in vivo. We propose that 9F5 is a useful tool to discriminate between rat type 1 MG and other subtypes of MG/Mφ and to reveal the role of the GPNMB fragments during developing brain. GLIA 2016;64:1938-1961. © 2016 The Authors. Glia Published by Wiley Periodicals, Inc.

N-(4-[18F]fluorobenzyl)cholylglycine, a novel tracer for PET of enterohepatic circulation of bile acids: Radiosynthesis and proof-of-concept studies in rats.

PubMed

Frisch, Kim; Stimson, Damion H R; Venkatachalam, Taracad; Pierens, Gregory K; Keiding, Susanne; Reutens, David; Bhalla, Rajiv

2018-05-04

Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for regulation of intracellular concentrations of bile acids and their function as detergents and signal carriers. Only few bile acid-derived imaging agents have been synthesized and hitherto none have been evaluated for studies of EHC. We hypothesized that N-(4-[ 18 F]fluorobenzyl)cholylglycine ([ 18 F]FBCGly), a novel fluorine-18 labeled derivative of endogenous cholylglycine, would be a suitable tracer for PET of the EHC of conjugated bile acids, and we report here a radiosynthesis of [ 18 F]FBCGly and a proof-of-concept study by PET/MR in rats. A radiosynthesis of [ 18 F]FBCGly was developed based on reductive alkylation of glycine with 4-[ 18 F]fluorobenzaldehyde followed by coupling to cholic acid. [ 18 F]FBCGly was investigated in vivo by dynamic PET/MR in anesthetized rats; untreated or treated with cholyltaurine or rifampicin. Possible in vivo metabolites of [ 18 F]FBCGly were investigated by analysis of blood and bile samples, and the stability of [ 18 F]FBCGly towards enzymatic de-conjugation by Cholylglycine Hydrolase was tested in vitro. [ 18 F]FBCGly was produced with a radiochemical purity of 96% ± 1% and a non-decay corrected radiochemical yield of 1.0% ± 0.3% (mean ± SD; n = 12). PET/MR studies showed that i.v.-administrated [ 18 F]FBCGly underwent EHC within 40-60 min with a rapid transhepatic transport from blood to bile. In untreated rats, the radioactivity concentration of [ 18 F]FBCGly was approximately 15 times higher in bile than in liver tissue. Cholyltaurine and rifampicin inhibited the biliary secretion of [ 18 F]FBCGly. No fluorine-18 metabolites of [ 18 F]FBCGly were observed. We have developed a radiosynthesis of a novel fluorine-18 labeled bile acid derivative, [ 18 F]FBCGly, and shown by PET/MR that [ 18 F]FBCGly undergoes continuous EHC in rats without metabolizing. This novel tracer may prove useful in PET

Toxicology and carcinogenesis studies of tetralin (CAS No. 119-64-2) in F344/N rats and B6C3F1 mice (inhalation studies).

PubMed

2011-04-01

Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce 2u-globulin; the NBR rats were included to study the relationship of 2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark

An Optimized IES Method and Its Inhibitory Effects and Mechanisms on Food Intake and Body Weight in Diet-Induced Obese Rats: IES for Obesity.

PubMed

Wan, Xinyue; Yin, Jieyun; Foreman, Robert; Chen, Jiande D Z

2017-12-01

This paper aims to optimize stimulation parameters and durations for intestinal electrical stimulation (IES) and to explore the effects and mechanisms of chronic IES with optimized methodology in obesity rats. Sixteen diet-induced obese (DIO) rats were tested for food intake with four different sets of IES parameters each lasting 1 week. Then, another 12 DIO rats were used to test the effect of IES on food intake with different stimulation durations. Finally, 16 DIO rats were treated with IES or sham-IES for 4 weeks. Meal patterns, food intake, and body weight were observed. Mechanisms involving gastrointestinal motility, ghrelin, and glucagon-like peptide-1 (GLP-1) were studied. (1) Acute IES with different parameters showed different inhibitory effects on food intake, and the most effective parameters were 0.6 s on, 0.9 s off, 80 Hz, 2 ms, and 4 mA with which 26.3% decrease in food intake was noted (p < 0.001). (2) IES with daily treatment of 12 h was most effective in suppressing food intake compared with 1 or 6 h. (3) Four-week IES reduced net weight by 10.9% (p < 0.05 vs. sham-IES) and epididymal fat pad weight by 13.9% (p < 0.001). (4) IES delayed gastric emptying (p < 0.001) and accelerated intestinal transit (p < 0.05). (5) IES increased both fasting and postprandial plasma levels of GLP-1 but not ghrelin. Twelve-hour daily IES using optimized stimulation parameters reduces food intake and body weight in DIO rats by altering gastrointestinal motility and GLP-1. The IES methodology derived in this study may have a therapeutic potential for obesity.

EFFECTS OF BROMODICHLOROMETHANE (BDCM) ON EX VIVO LUTEAL FUNCTION IN THE PREGNANT F344 RAT

EPA Science Inventory

EFFECTS OF BROMODICHLOROMETHANE (BDCM) ON EX VIVO LUTEAL FUNCTION IN THE PREGNANT F344 RAT.

S. R. Bielmeier1, A. S. Murr2, D. S. Best2, J. M. Goldman2, and M. G. Narotsky2

1 Curriculum in Toxicology, Univ. of North Carolina, Chapel Hill, NC, USA
2 Reproductive T...

In vivo genotoxicity of furan in F344 rats at cancer bioassay doses

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

Ding, Wei, E-mail: Wei.Ding@fda.hhs.gov; Petibone, Dayton M.; Latendresse, John R.

2012-06-01

Furan, a potent rodent liver carcinogen, is found in many cooked food items and thus represents a human cancer risk. Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays, combined with analysis of histopathological and gene expression changes. In addition, formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III (EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage. Rats were treated by gavage on four consecutive days with 2, 4, and 8 mg/kg bw furan, doses that were tumorigenic in 2-year cancer bioassays, and with two higher doses, 12 andmore » 16 mg/kg. Rats were killed 3 h after the last dose, a time established as producing maximum levels of DNA damage in livers of furan-treated rats. Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion, with statistically significant increases detected at cancer bioassay doses. No DNA damage was detected in bone marrow, a non-target tissue for cancer, and peripheral blood micronucleus assays were negative. Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation, single-cell necrosis, apoptosis, and cell proliferation. In addition, genes related to apoptosis, cell-cycle checkpoints, and DNA-repair were expressed at a slightly lower level in the furan-treated livers. Although a mixed mode of action involving direct DNA binding cannot be ruled out, the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress, accompanied by inflammation, cell proliferation, and toxicity. -- Highlights: ► Furan is a potent rodent liver carcinogen and represents a human cancer risk. ► Furan induces DNA damage in rat liver at cancer bioassay doses. ► Furan induces oxidative stress, inflammation and cell proliferation in rat liver. �

PBPK MODELING OF DELTAMETHRIN IN RATS

EPA Science Inventory

The pyrethroid pesticide deltamethrin is cleared nearly twice as rapidly in human liver microsomes compared to rat liver microsomes. A species difference such as this could influence the toxic potency of deltamethrin between rats and humans. PBPK modeling is a tool that can be ut...

Novel and existing data for a future physiological toxicokinetic model of ethylene and its metabolite ethylene oxide in mouse, rat, and human.

PubMed

Filser, Johannes Georg; Artati, Anna; Li, Qiang; Pütz, Christian; Semder, Brigitte; Klein, Dominik; Kessler, Winfried

2015-11-05

The olefin ethylene is a ubiquitously found gas. It originates predominantly from plants, combustion processes and industrial sources. In mammals, inhaled ethylene is metabolized by cytochrome P450-dependent monooxygenases, particularly by cytochrome P450 2E1, to ethylene oxide, an epoxide that directly alkylates proteins and DNA. Ethylene oxide was mutagenic in vitro and in vivo in insects and mammals and carcinogenic in rats and mice. A physiological toxicokinetic model is a most useful tool for estimating the ethylene oxide burden in ethylene-exposed rodents and humans. The only published physiological toxicokinetic model for ethylene and metabolically produced ethylene oxide is discussed. Additionally, existing data required for the development of a future model and for testing its predictive accuracy are reviewed and extended by new gas uptake studies with ethylene and ethylene oxide in B6C3F1 mice and with ethylene in F344 rats. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Aberrant Calreticulin Expression in Articular Cartilage of Dio2 Deficient Mice

PubMed Central

Bomer, Nils; Cornelis, Frederique M. F.; Ramos, Yolande F. M.; den Hollander, Wouter; Lakenberg, Nico; van der Breggen, Ruud; Storms, Lies; Slagboom, P. Eline; Lories, Rik J. U.; Meulenbelt, Ingrid

2016-01-01

Objective To identify intrinsic differences in cartilage gene expression profiles between wild-type- and Dio2-/--mice, as a mechanism to investigate factors that contribute to prolonged healthy tissue homeostasis. Methods Previously generated microarray-data (Illumina MouseWG-6 v2) of knee cartilage of wild-type and Dio2 -/- -mice were re-analyzed to identify differential expressed genes independent of mechanical loading conditions by forced treadmill-running. RT-qPCR and western blot analyses of overexpression and knockdown of Calr in mouse chondro-progenitor cells (ATDC5) were applied to assess the direct effect of differential Calr expression on cartilage deposition. Results Differential expression analyses of articular cartilage of Dio2-/- (N = 9) and wild-type-mice (N = 11) while applying a cutoff threshold (P < 0.05 (FDR) and FC > |1,5|) resulted in 1 probe located in Calreticulin (Calr) that was found significantly downregulated in Dio2-/- mice (FC = -1.731; P = 0.044). Furthermore, overexpression of Calr during early chondrogenesis in ATDC5 cells leads to decreased proteoglycan deposition and corresponding lower Aggrecan expression, whereas knocking down Calr expression does not lead to histological differences of matrix composition. Conclusion We here demonstrate that the beneficial homeostatic state of articular cartilage in Dio2-/- mice is accompanied with significant lower expression of Calr. Functional analyses further showed that upregulation of Calr expression could act as an initiator of cartilage destruction. The consistent association between Calr and Dio2 expression suggests that enhanced expression of these genes facilitate detrimental effects on cartilage integrity. PMID:27163789

Dios: The Dark Baryon Exploring Mission

NASA Technical Reports Server (NTRS)

T.Ohashi; Ishisaki, Y.; Yamada, S.; Kuromaru, G.; Suzuki, S.; Tawara, Y.; Mitsuishi, I.; Babazaki, Y.; Mitsuda, K.; Yamasaki, N. Y.;

Duplication of Dio3 genes in teleost fish and their divergent expression in skin during flatfish metamorphosis.

PubMed

Alves, R N; Cardoso, J C R; Harboe, T; Martins, R S T; Manchado, M; Norberg, B; Power, D M

2017-05-15

Deiodinase 3 (Dio3) plays an essential role during early development in vertebrates by controlling tissue thyroid hormone (TH) availability. The Atlantic halibut (Hippoglossus hippoglossus) possesses duplicate dio3 genes (dio3a and dio3b). Expression analysis indicates that dio3b levels change in abocular skin during metamorphosis and this suggests that this enzyme is associated with the divergent development of larval skin to the juvenile phenotype. In larvae exposed to MMI, a chemical that inhibits TH production, expression of dio3b in ocular skin is significantly up-regulated suggesting that THs normally modulate this genes expression during this developmental event. The molecular basis for divergent dio3a and dio3b expression and responsiveness to MMI treatment is explained by the multiple conserved TREs in the proximal promoter region of teleost dio3b and their absence from the promoter of dio3a. We propose that the divergent expression of dio3 in ocular and abocular skin during halibut metamorphosis contributes to the asymmetric pigment development in response to THs. Copyright © 2017 Elsevier Inc. All rights reserved.

NTP technical report on toxicity studies of cadmium oxide (Cas No. 1306-19-0) administered by inhalation to F344/N rats and B6C3f1 mice. Toxicity report series

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

NONE

1995-03-01

Three thousand tons of cadmium are imported or produced annually in the United States, and approximately 90% of this is cadmium oxide. Cadmium oxide is used in batteries, electroplating baths, pigments, plastics, synthetic products, and a variety of other materials. Cadmium oxide was nominated for study by the National Cancer Institute because of its widespread use and to obtain toxicity and carcinogenicity information. This report describes toxicity studies of cadmium oxide aerosol in F344/N rats and B6C3F1 mice, including sperm motility and vaginal cytology evaluations, and developmental toxicity studies of cadmium oxide aerosol in Sprague-Dawley rats and Swiss (CD-1) mice.more » Genetic toxicology studies were done in Salmonella typhimurium and B6C3F1 mice erythrocytes.« less

RESCUE OF BROMODICHLOROMETHANE-INDUCED PREGNANCY LOSS IN THE F344 RAT BY EXOGENOUS PROGESTERONE AND HCG

EPA Science Inventory

Rescue of bromodichloromethane-induced pregnancy loss in the F344 rat by exogenous progesterone and hCG.

Susan R. Bielmeier1, Deborah S. Best2 and Michael G. Narotsky2

1 Curriculum in Toxicology, Univ. of North Carolina, Chapel Hill, NC, USA
2 Reproductive Toxico...

High-fat diet-induced hepatic steatosis reduces glucagon receptor content in rat hepatocytes: potential interaction with acute exercise

PubMed Central

Charbonneau, Alexandre; Unson, Cecilia G; Lavoie, Jean-Marc

2007-01-01

Studies have revealed that high-fat (HF) diets promote hyperglycaemia, whole-body insulin resistance and non-alcoholic fatty liver disease (NAFLD). Recently, hepatic glucagon resistance has been shown to occur in rats fed a HF diet. More precisely, diet-induced obesity (DIO) reduces the number of hepatic plasma membrane glucagon receptors (GR), which results in a diminished response to glucagon during a hyperglucagonaemic clamp. The present study was undertaken to test the hypothesis that a HF-DIO is associated with a desensitization and destruction of the hepatic GR. We also hypothesized that a single bout of endurance exercise would modify the GR cellular distribution under our DIO model. Male rats were either fed a standard (sd) or a HF diet for two weeks. Each group was subdivided into a non-exercised (Rest) and an acute exercised (EX) group. The HF diet resulted in a reduction of total hepatic GR (55%) and hepatic plasma membrane GR protein content (20%). These changes were accompanied by a significant increase in endosomal and lysosomal GR content with the feeding of a HF diet. The reduction of GR plasma membrane as well as the increase in endosomal GR was strongly correlated with an increase of PKC-α, suggesting a role of PKC-α in GR desensitization. EX increased significantly PKC-α protein content in both diets, suggesting a role of PKC-α in EX-induced GR desensitization. The present results suggest that liver lipid infiltration plays a role in reducing glucagon action in the liver through a reduction in total cellular and plasma membrane GR content. Furthermore, the GR desensitization observed in our in vivo model of HF diet-induced hepatic steatosis and in EX individuals may be regulated by PKC-α. PMID:17053032

Impaired insulin secretion in the spontaneous diabetes rats.

PubMed

Kimura, K; Toyota, T; Kakizaki, M; Kudo, M; Takebe, K; Goto, Y

1982-08-01

Dynamics of insulin and glucagon secretion were investigated by using a new model of spontaneous diabetes rats produced by the repetition of selective breeding in our laboratories. The perfusion experiments of the pancreas showed that the early phase of insulin secretion to continuous stimulation with glucose was specifically impaired, although the response of the early phase to arginine was preserved. The glucose-induced insulin secretion in the nineth generation (F8) which had a more remarkably impaired glucose tolerance was more reduced than in the sixth generation (F5). No significant difference of glucagon secretion in response to arginine or norepinephrine was noted between the diabetes rats and control ones. The present data indicate that the defective insulin secretion is a primary derangement in a diabetic state of the spontaneous diabetes rat. This defect in the early phase of glucose-induced insulin secretion suggests the specific impairment of the recognition of glucose by the pancreatic beta-cells. The spontaneous diabetes rats are very useful as a model of disease for investigating pathophysiology of non-insulin dependent diabetes mellitus.

Inflammation and Atrophy Precede Prostate Neoplasia in PhIP Induced Rat Model

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

Borowsky, A D; Dingley, K; Ubick, E

2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) has been implicated as a major mutagenic heterocyclic amine in the human diet and is carcinogenic in the rat prostate. In order to validate PhIP induced rat prostate neoplasia as a model of human prostate cancer progression, we sought to study the earliest histologic and morphologic changes in the prostate and to follow the progressive changes over time. We fed 67 male Fischer F344 5 week old rats with PhIP (400 PPM) or control diets for 20 weeks, and then sacrificed animals for histomorphologic examination at age 25 weeks, 45 weeks, and 65 weeks. Animals treated with PhIPmore » showed significantly more inflammation (P=.002 (25wk), >.001(45wk), .016(65wk)) and atrophy (P=.003(25wk), >.001(45wk), .006 (65wk)) in their prostate glands relative to controls. Prostatic intraepithelial neoplasia (PIN) occurred only in PhIP treated rats. PIN lesions arose in areas of glandular atrophy, most often in the ventral prostate. Atypical cells in areas of atrophy show loss of glutathione S-transferase pi immunostaining preceding development of PIN. None of the animals in this study developed invasive carcinomas differing from previous reports. Overall, these findings suggest that the pathogenesis of prostatic neoplasia in the PhIP treated rat prostate proceeds from inflammation to post-inflammatory proliferative atrophy to PIN.« less

APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION

EPA Science Inventory

APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION.
Evans, M.V1., Power, F.W2., Dary, C.C2., Tornero-Velez, R2., and Blancato, J.N2.
1 NHEERL, US EPA, ORD, ETD, RTP, NC; 2 NERL, US EPA, ORD, EDRB, LV, NV
Re...

A novel rat model for chemotherapy-induced alopecia.

PubMed

Wikramanayake, T C; Amini, S; Simon, J; Mauro, L M; Elgart, G; Schachner, L A; Jimenez, J J

2012-04-01

More than half of all people diagnosed with cancer receive chemotherapy, and approximately 65% of these develop chemotherapy-induced alopecia (CIA), a side-effect that can have considerable negative psychological repercussions. Currently, there are very few animal models available to study the mechanism and prevention of CIA. To develop a clinically relevant adult rat model for CIA. We first tested whether neonatal pigmented Long-Evans (LE) rats developed alopecia in response to the chemotherapeutic agents etoposide and cyclophosphamide. We then determined whether the rats developed CIA as adults. In the latter experiment, rat dorsal hair was clipped during the early telogen stage to synchronize the hair cycle, and starting 15 days later, the rats were treated with etoposide for 3 days. Neonatal LE pups developed CIA in response to etoposide and cyclophosphamide, similar to other murine models for CIA. Clipping of the hair shaft during early telogen resulted in synchronized anagen induction and subsequent alopecia after etoposide treatment in the clipped areas only. Hair follicles in the clipped areas had the typical chemotherapy-induced follicular dystrophy (dystrophic catagen). When the hair in the pigmented alopecic areas regrew, it had normal pigmentation. A novel, pigmented adult rat model has been established for CIA. By hair-shaft clipping during early telogen, synchronized anagen entry was induced, which resulted in alopecia in response to chemotherapy. This is the first clinically relevant adult rat model for CIA, and will be a useful tool to test agents for the prevention and treatment of CIA. © The Author(s). CED © 2012 British Association of Dermatologists.

On the rat model of human osteopenias and osteoporoses

NASA Technical Reports Server (NTRS)

Frost, Harold M.; Jee, Webster S. S.

1992-01-01

The idea that rats cannot model human osteopenias errs. The same mechanisms control gains in bone mass (longitudinal bone growth and modeling drifts) and losses (BMU-based remodeling), in young and aged rats and humans. Furthermore, they respond similarly in rats and man to mechanical influences, hormones, drugs and other agents.

Quantification of Skeletal Blood Flow and Fluoride Metabolism in Rats using PET in a Pre-Clinical Stress Fracture Model

PubMed Central

Tomlinson, Ryan E.; Silva, Matthew J.; Shoghi, Kooresh I.

2013-01-01

Purpose Blood flow is an important factor in bone production and repair, but its role in osteogenesis induced by mechanical loading is unknown. Here, we present techniques for evaluating blood flow and fluoride metabolism in a pre-clinical stress fracture model of osteogenesis in rats. Procedures Bone formation was induced by forelimb compression in adult rats. 15O water and 18F fluoride PET imaging were used to evaluate blood flow and fluoride kinetics 7 days after loading. 15O water was modeled using a one-compartment, two-parameter model, while a two-compartment, three-parameter model was used to model 18F fluoride. Input functions were created from the heart, and a stochastic search algorithm was implemented to provide initial parameter values in conjunction with a Levenberg–Marquardt optimization algorithm. Results Loaded limbs are shown to have a 26% increase in blood flow rate, 113% increase in fluoride flow rate, 133% increase in fluoride flux, and 13% increase in fluoride incorporation into bone as compared to non-loaded limbs (p < 0.05 for all results). Conclusions The results shown here are consistent with previous studies, confirming this technique is suitable for evaluating the vascular response and mineral kinetics of osteogenic mechanical loading. PMID:21785919

EFFECTS OF BROMODICHLOROMETHANE (BDCM) ON EX VIVO LUTEAL FUNCTION IN THE F344 RAT DURING PREGNANCY

EPA Science Inventory

Effects of Bromodichloromethane (BDCM) on Ex Vivo Luteal Function In the Pregnant F344 Rat

Susan R. Bielmeier1, Ashley S. Murr2, Deborah S. Best2, Jerome M. Goldman2, and Michael G. Narotsky2

1Curriculum in Toxicology, Univ. of North Carolina, Chapel Hill, NC 27599,...

Imaging grafted cells with [18F]FHBG using an optimized HSV1-TK mammalian expression vector in a brain injury rodent model.

PubMed

Salabert, Anne-Sophie; Vaysse, Laurence; Beaurain, Marie; Alonso, Mathieu; Arribarat, Germain; Lotterie, Jean-Albert; Loubinoux, Isabelle; Tafani, Mathieu; Payoux, Pierre

2017-01-01

Cell transplantation is an innovative therapeutic approach after brain injury to compensate for tissue damage. To have real-time longitudinal monitoring of intracerebrally grafted cells, we explored the feasibility of a molecular imaging approach using thymidine kinase HSV1-TK gene encoding and [18F]FHBG as a reporter probe to image enzyme expression. A stable neuronal cell line expressing HSV1-TK was developed with an optimised mammalian expression vector to ensure long-term transgene expression. After [18F]FHBG incubation under defined parameters, calibration ranges from 1 X 104 to 3 X 106 Neuro2A-TK cells were analysed by gamma counter or by PET-camera. In parallel, grafting with different quantities of [18F]FHBG prelabelled Neuro2A-TK cells was carried out in a rat brain injury model induced by stereotaxic injection of malonate toxin. Image acquisition of the rats was then performed with PET/CT camera to study the [18F]FHBG signal of transplanted cells in vivo. Under the optimised incubation conditions, [18F]FHBG cell uptake rate was around 2.52%. In-vitro calibration range analysis shows a clear linear correlation between the number of cells and the signal intensity. The PET signal emitted into rat brain correlated well with the number of cells injected and the number of surviving grafted cells was recorded via the in-vitro calibration range. PET/CT acquisitions also allowed validation of the stereotaxic injection procedure. Technique sensitivity was evaluated under 5 X 104 grafted cells in vivo. No [18F]FHBG or [18F]metabolite release was observed showing a stable cell uptake even 2 h post-graft. The development of this kind of approach will allow grafting to be controlled and ensure longitudinal follow-up of cell viability and biodistribution after intracerebral injection.

A Single-Dose Recombinant Parainfluenza Virus 5-Vectored Vaccine Expressing Respiratory Syncytial Virus (RSV) F or G Protein Protected Cotton Rats and African Green Monkeys from RSV Challenge.

PubMed

Wang, Dai; Phan, Shannon; DiStefano, Daniel J; Citron, Michael P; Callahan, Cheryl L; Indrawati, Lani; Dubey, Sheri A; Heidecker, Gwendolyn J; Govindarajan, Dhanasekaran; Liang, Xiaoping; He, Biao; Espeseth, Amy S

2017-06-01

Human respiratory syncytial virus (RSV) is a common cause of severe respiratory disease among infants, immunocompromised individuals, and the elderly. No licensed vaccine is currently available. In this study, we evaluated two parainfluenza virus 5 (PIV5)-vectored vaccines expressing RSV F (PIV5/F) or G (PIV5/G) protein in the cotton rat and African green monkey models for their replication, immunogenicity, and efficacy of protection against RSV challenge. Following a single intranasal inoculation, both animal species shed the vaccine viruses for a limited time but without noticeable clinical symptoms. In cotton rats, the vaccines elicited RSV F- or G-specific serum antibodies and conferred complete lung protection against RSV challenge at doses as low as 10 3 PFU. Neither vaccine produced the enhanced lung pathology observed in animals immunized with formalin-inactivated RSV. In African green monkeys, vaccine-induced serum and mucosal antibody responses were readily detected, as well. PIV5/F provided nearly complete protection against RSV infection in the upper and lower respiratory tract at a dose of 10 6 PFU of vaccine. At the same dose levels, PIV5/G was less efficacious. Both PIV5/F and PIV5/G were also able to boost neutralization titers in RSV-preexposed African green monkeys. Overall, our data indicated that PIV5/F is a promising RSV vaccine candidate. IMPORTANCE A safe and efficacious respiratory syncytial virus (RSV) vaccine remains elusive. We tested the recombinant parainfluenza virus 5 (PIV5) vectors expressing RSV glycoproteins for their immunogenicity and protective efficacy in cotton rats and African green monkeys, which are among the best available animal models to study RSV infection. In both species, a single dose of intranasal immunization with PIV5-vectored vaccines was able to produce systemic and local immunity and to protect animals from RSV challenge. The vaccines could also boost RSV neutralization antibody titers in African green monkeys

Dark-energy cosmological models in f(G) gravity

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

Shamir, M. F., E-mail: farasat.shamir@nu.edu.pk

We discuss dark-energy cosmological models in f(G) gravity. For this purpose, a locally rotationally symmetric Bianchi type I cosmological model is considered. First, exact solutions with a well-known form of the f(G) model are explored. One general solution is discussed using a power-law f(G) gravity model and physical quantities are calculated. In particular, Kasner’s universe is recovered and the corresponding f(G) gravity models are reported. Second, the energy conditions for the model under consideration are discussed using graphical analysis. It is concluded that solutions with f(G) = G{sup 5/6} support expansion of universe while those with f(G) = G{sup 1/2}more » do not favor the current expansion.« less

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.

F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (II) Activity in models of positive symptoms of schizophrenia

PubMed Central

Depoortère, R; Bardin, L; Auclair, A L; Kleven, M S; Prinssen, E; Colpaert, F; Vacher, B; Newman-Tancredi, A

2007-01-01

Background and purpose: F15063 is a high affinity D2/D3 antagonist, D4 partial agonist, and high efficacy 5-HT1A agonist, with little affinity (40-fold lower than for D2 receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects. Experimental approach: Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and ‘serotonin syndrome'. Key results: F15063 potently (ED50s: 0.23 to 1.10 mg kg−1 i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition (PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing (ED50 = 0.30 mg kg−1 i.p.). F15063, owing to its 5-HT1A agonism, did not produce (ED50 > 40 mg kg−1 i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome (EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg−1 p.o. Furthermore, F15063 did not induce the ‘serotonin syndrome' in rats (flat body posture and forepaw treading: ED50 >32 mg kg−1 i.p.). Conclusions and implications: F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia (companion paper). PMID:17375086

Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a mouse model of diabetes.

PubMed

Lo, Chao-Sheng; Shi, Yixuan; Chang, Shiao-Ying; Abdo, Shaaban; Chenier, Isabelle; Filep, Janos G; Ingelfinger, Julie R; Zhang, Shao-Ling; Chan, John S D

2015-10-01

We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied. Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1-7 receptor [MasR]) expression, and normalised urinary Ang 1-7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-β1 and Tgf-βrII gene expression. Furthermore, hnRNP F overexpression prevented TGF-β1 signalling and TGF-β1 inhibition of Ace-2 gene expression. These data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-β1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes.

USE OF qRTPCR TO IDENTIFY POTENTIAL BIOMARKERS OF BROMATE EXPOSURE IN F344 MALE RAT KIDNEYS

EPA Science Inventory

Potassium bromate (KBrO3) is a drinking water disinfection by-product that is nephrotoxic and carcinogenic. To identify potential biomarkers of carcinogenicity, male F344 rats were chronically exposed to a carcinogenic dose (400mg/l) of KBrO3 in their drinking water. Kidneys were...

Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats

PubMed Central

Haver, Alvin; Chelikani, Prasanth K.; Apenteng, Bettye; Perriotte-Olson, Curtis; Anders, Krista; Steenson, Sharalyn; Blevins, James E.

2012-01-01

Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg−1·h−1)] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg−1·h−1) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats. PMID:22510712

Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats

PubMed Central

Tunc-Ozcan, Elif; Harper, Kathryn M.; Graf, Evan N.; Redei, Eva E.

2016-01-01

The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers. Here we aim to identify whether prenatal ethanol (PE) exposure impairs hippocampus-dependent learning and memory in the second-generation (F2) progeny, and whether T4 administration to the ethanol-consuming dam can prevent it. Sprague-Dawley (S) dams received control diets (ad libitum and nutritional control) or ethanol containing liquid diet with and without simultaneous T4 (0.3mg/l diet) administration. Their offspring (SS F1) were mated with naïve Brown Norway (B) males and females generating the SB F2 and BS F2 progeny. Hippocampus-dependent contextual fear memory and hippocampal expression of the thyroid hormone-regulated type 3 deiodinase, (Dio3) and neurogranin (Nrgn) were assessed. SS F1 PE-exposed females and their SB F2 progeny exhibited fear memory deficits. T4 administration to the mothers of F1 females reversed these deficits. Although SS F1 PE-exposed males also experienced fear memory deficit, this was neither transmitted to their BS F2 offspring nor reversed by prenatal T4 treatment. Hippocampal Dio3 and Nrgn expression showed similar pattern of changes. Grandmaternal ethanol consumption during pregnancy affects fear memory of the matrilineal second-generation progeny. Low dose T4 supplementation prevents this process likely via altering allele-specific and total expression of Dio3 in the hippocampus. PMID:27090562

Metabolic Brain Network Analysis of Hypothyroidism Symptom Based on [18F]FDG-PET of Rats.

PubMed

Wan, Hongkai; Tan, Ziyu; Zheng, Qiang; Yu, Jing

2018-03-12

Recent researches have demonstrated the value of using 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) positron emission tomography (PET) imaging to reveal the hypothyroidism-related damages in local brain regions. However, the influence of hypothyroidism on the entire brain network is barely studied. This study focuses on the application of graph theory on analyzing functional brain networks of the hypothyroidism symptom. For both the hypothyroidism and the control groups of Wistar rats, the functional brain networks were constructed by thresholding the glucose metabolism correlation matrices of 58 brain regions. The network topological properties (including the small-world properties and the nodal centralities) were calculated and compared between the two groups. We found that the rat brains, like human brains, have typical properties of the small-world network in both the hypothyroidism and the control groups. However, the hypothyroidism group demonstrated lower global efficiency and decreased local cliquishness of the brain network, indicating hypothyroidism-related impairment to the brain network. The hypothyroidism group also has decreased nodal centrality in the left posterior hippocampus, the right hypothalamus, pituitary, pons, and medulla. This observation accorded with the hypothyroidism-related functional disorder of hypothalamus-pituitary-thyroid (HPT) feedback regulation mechanism. Our research quantitatively confirms that hypothyroidism hampers brain cognitive function by causing impairment to the brain network of glucose metabolism. This study reveals the feasibility and validity of applying graph theory method to preclinical [ 18 F]FDG-PET images and facilitates future study on human subjects.

Sexual dimorphism in hybrids rats.

PubMed

Garcia-Falgueras, Alicia; Pinos, Helena; Fernández, Rosa; Collado, Paloma; Pasaro, Eduardo; Segovia, Santiago; Guillamon, Antonio

2006-12-06

Laboratory rat strains descend from Wistar rats as a consequence of artificial selection. Previously we reported that the medial posterior division of the bed nucleus of the stria terminalis (BSTMP) was sexually dimorphic in Wistar and Long-Evans strains while the medial anterior division (BSTMA) and the locus coeruleus (LC) only showed sex differences in the ancestor Wistar strain. The lateral posterior division (BSTLP) was isomorphic in both strains. The present work studies the number of neurons in the BSTMP, BSTMA, BSTLP and LC of male and female Wistar and Long-Evans rats (F(0)) and their hybrid F(1) and F(2) generations. The BSTMP is sexually dimorphic in the F(0), F(1) and F(2) generations while sex differences in the LC are only seen in F(0) Wistar rats but not in the F(0) Long-Evans or the F(1) and F(2) hybrid generations. Sex differences in the BSTMA are seen in F(0) Wistar but not in F(0) Long-Evans rats and completely disappear in the F(2) generations. The number of neurons in the LC of both males and females decreased in heterozygotic individuals (F(1)) but increased in homozygotic (F(2)). However, the number of neurons in the BSTMP changes significantly over the generations, although the ratio of neurons (female/male) is stable and unaffected in homo- or heterozygosis. Thus, the mechanism that regulates the neuronal female/male ratio would be different from the one that controls the number of neurons. The facts that sex differences in the BSTMP are not affected by homo- or heterozygosis and that they are seen in several mammalian orders suggest the existence of a "fixed" type of brain sex differences in the Mammalia Class.

Carcinogenicity of 4-methoxyphenol and 4-methylcatechol in F344 rats.

PubMed

Asakawa, E; Hirose, M; Hagiwara, A; Takahashi, S; Ito, N

1994-01-02

The carcinogenic potentials of 4-methoxyphenol (4-MP) and 4-methylcatechol (4-MC), phenolic compounds which are structurally similar to the known forestomach carcinogen BHA and the glandular stomach carcinogen catechol respectively, and cause considerably enhanced cell proliferation and cytotoxicities in rat forestomach and/or glandular stomach epithelium, were examined in male and female F344 rats. Groups of 30 male and female animals were administered diets containing 2% 4-MP or 2% 4-MC for 104 weeks. Histopathological findings in the 4-MP case included atypical hyperplasias (male, 67%, female, 37%), papillomas (50%, 23%) and squamous-cell carcinomas (77%, 20%) in the forestomach. 4-MC induced forestomach papillomas (70%, 93%) and squamous-cell carcinomas (53%, 37%), also glandular stomach submucosal hyperplasias (90%, 93%), adenomas (100%, 100%) and adenocarcinomas (57%, 47%), with ulceration or erosion. The degree of differentiation of the squamous-cell carcinomas induced by 4-MP was less than with 4-MC. The present study demonstrated unequivocal forestomach carcinogenicity for 4-MP and forestomach and glandular stomach carcinogenicity for 4-MC, with cytotoxicity and cell proliferation both appearing as important factors for these non-genotoxic carcinogens.

Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats

PubMed Central

Thatcher, Brendan S.; Reidelberger, Roger D.; Ogimoto, Kayoko; Wolden-Hanson, Tami; Baskin, Denis G.; Schwartz, Michael W.; Blevins, James E.

2012-01-01

Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in diet-induced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dose-dependently reduces food intake and body weight to a similar extent in rats maintained on either diet. Moreover, the effect of oxytocin to induce weight loss remained intact in leptin receptor-deficient Koletsky (fak/fak) rats relative to their lean littermates. To determine whether systemically administered oxytocin activates hindbrain areas that regulate meal size, we measured neuronal c-Fos induction in the nucleus of the solitary tract (NTS) and area postrema (AP). We observed a robust neuronal response to oxytocin in these hindbrain areas that was unexpectedly increased in rats rendered obese on a HFD relative to lean, LFD-fed controls. Finally, we report that repeated daily peripheral administration of oxytocin in DIO animals elicited a sustained reduction of food intake and body weight while preventing the reduction of energy expenditure characteristic of weight-reduced animals. These findings extend recent evidence suggesting that oxytocin circumvents leptin resistance and induces weight-loss in DIO animals through a mechanism involving activation of neurons in the NTS and AP, key hindbrain areas for processing satiety-related inputs. PMID:22008455

NTP technical report on the toxicity studies of Castor Oil (CAS No. 8001-79-4) in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies).

PubMed

Irwin, R

1992-03-01

Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

NTP Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

PubMed

1986-04-01

Benzene ranks 16th in production volume for chemicals produced in the United States, with approximately 9.9 billion pounds being produced in 1984, 9.1 billion pounds in 1983, and 7.8 billion pounds in 1982. This simplest aromatic chemical in used in the synthesis of styrene (polystyrene plastics and synthetic rubber), phenol (phenolic resins), cyclohexane (nylon), aniline, maleic anhydride (polyester resins), alkylbenzenes (detergents), chlorobenzenes, and other products used in the production of drugs, dyes, insecticides, and plastics. Benzene, along with other light, high-octane aromatic hydrocarbons, such as toluene and xylenes, is a component of motor gasoline. Benzene is also used as a solvent, but for most applications, it has been replaced by less hazardous solvents. During the 17-week studies, groups of 10 or 15 male and female F344/N rats and B6C3F1 mice were gavaged 5 days per week with benzene in corn oil (5 ml/kg) at doses of 0 to 600 mg/kg. No benzene-related deaths occurred; in rats that received benzene, final mean body weights were 14%-22% lower compared with vehicle controls and in mice, slight dose-related reductions were observed (less than 10% differences). Doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Two-year toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten additional animals in each of the 16 groups were killed at 12 months and necropsies were performed. Hematologic

Toxicology and carcinogenesis study of styrene-acrylonitrile trimer in F344/N rats (perinatal and postnatal feed studies).

PubMed

2012-07-01

Styrene-acrylonitrile trimer (SAN Trimer) is a mixture of isomers formed by the condensation of two moles of acrylonitrile and one mole of styrene and has a molecular weight of 210. The mixture is composed of two structural forms: 4-cyano-1,2,3,4-tetrahydro-a-methyl-1-naphthaleneacetonitrile (THNA, CAS No. 57964-39-3) and 4-cyano-1,2,3,4-tetrahydro-1-naphthalenepropionitrile (THNP, CAS No. 57964-40-6). The THNA form consists of four stereoisomers. [Structure:see text]. The THNP form consists of two stereoisomers. [Structure:see text]. SAN Trimer is a by-product of the production of acrylonitrile styrene plastics and is created in specific manufacturing processes for polymers of acrylonitrile and styrene. In June 1998, due to community concerns about the toxicity of SAN Trimer, it was nominated to the NTP for carcinogenicity testing by a member of Congress. Male and female F344/N rats were exposed to SAN Trimer in feed in perinatal and postnatal studies for 7 weeks, 18 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, and in rat reticulocytes, leukocytes, liver cells, and brain cells. In vivo comet and micronucleus assays were performed in the juvenile rats. 7-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm SAN Trimer (equivalent to average daily doses of approximately 50, 90, 175, 270, or 410 mg SAN Trimer/kg body weight to males and 45, 90, 185, 295, or 430 mg/kg to females) for 2 weeks postweaning; the dams of these rats were fed the same concentrations of SAN Trimer from gestation day 7 until the pups were weaned. One 4,000 ppm male rat died 3 days after weaning; all other rats that started the postweaning phase survived to the end of the study. Mean body weights of 1,000, 2,000, and 4,000 ppm males and 2,000 and 4,000 ppm females were significantly less than those of the controls; weaning mean body weights were reduced in 4

Simultaneous GCaMP6-based fiber photometry and fMRI in rats.

PubMed

Liang, Zhifeng; Ma, Yuncong; Watson, Glenn D R; Zhang, Nanyin

2017-09-01

Understanding the relationship between neural and vascular signals is essential for interpretation of functional MRI (fMRI) results with respect to underlying neuronal activity. Simultaneously measuring neural activity using electrophysiology with fMRI has been highly valuable in elucidating the neural basis of the blood oxygenation-level dependent (BOLD) signal. However, this approach is also technically challenging due to the electromagnetic interference that is observed in electrophysiological recordings during MRI scanning. Recording optical correlates of neural activity, such as calcium signals, avoids this issue, and has opened a new avenue to simultaneously acquire neural and BOLD signals. The present study is the first to demonstrate the feasibility of simultaneously and repeatedly acquiring calcium and BOLD signals in animals using a genetically encoded calcium indicator, GCaMP6. This approach was validated with a visual stimulation experiment, during which robust increases of both calcium and BOLD signals in the superior colliculus were observed. In addition, repeated measurement in the same animal demonstrated reproducible calcium and BOLD responses to the same stimuli. Taken together, simultaneous GCaMP6-based fiber photometry and fMRI recording presents a novel, artifact-free approach to simultaneously measuring neural and fMRI signals. Furthermore, given the cell-type specificity of GCaMP6, this approach has the potential to mechanistically dissect the contributions of individual neuron populations to BOLD signal, and ultimately reveal its underlying neural mechanisms. The current study established the method for simultaneous GCaMP6-based fiber photometry and fMRI in rats. Copyright © 2017 Elsevier B.V. All rights reserved.

[Effects of telmisartan on resistin expression in a rat model of nonalcoholic steatohepatitis and insulin resistance].

PubMed

Zhang, Qiuzan; Wang, Yanrong; Liu, Yingli; Yang, Qian; Wang, Xiuru; Wang, Qiang; Zhang, Chenming; Wang, Bangmao

2015-04-01

To investigate the effects of telmisartan on expression of resistin in serum and liver under conditions of nonalcoholic steatohepatitis (NASH) and insulin resistance using a rat model system. Forty-five male Sprague-Dawley rats were randomly divided into a normal control group (NC, n=10), a model control group (MC, n=15), a polyene phosphatidylcholine prevention group (PP, n=10), and a telmisartan prevention group (TP, n=10). The NC group was given a standard diet and the other groups were given a high-fat diet for 16 weeks in order to induce NASH. At the end of week 12, 5 rats in the MC group were sacrificed for pathology confirmation of the NASH model. At the end of week 12, the TP group was given telmisartan (8.0 mg/kg/d) and the PP group was given polyene phosphatidylcholine (8.4 mg/kg/d) for an additional 4 weeks by intragastric administration. At the end of week 16, all rats were sacrificed and body weights recorded. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), resistin, insulin and fasting blood glucose were measured. The insulin resistance value, HOMA-IR, was assessed by homeostasis mode assessment. Liver expression of the resistin protein was detected by western blotting and of the resistin mRNA was detected by RT-PCR. The F test and LSD test were used for statistical analyses. Compared to the NC group, the body weight and HOMA-IR of rats in the MC group were significantly increased (P<0.01). The levels of serum resistin, and of resistin protein and mRNA in liver, were significantly higher in the MC group than in the NC group of rats (all P less than 0.01). The body weight of rats in the TP group was significantly lower than those in the MC group (P<0.05). The levels of serrn resistin, resistin protein and mRNA in the liver, and insulin resistance were significantly lower in the TP group than in the MC group of rats (all P<0.01). The PP group did not show significant

Evaluation of a novel sodium borocaptate-containing unnatural amino acid as a boron delivery agent for neutron capture therapy of the F98 rat glioma.

PubMed

Futamura, Gen; Kawabata, Shinji; Nonoguchi, Naosuke; Hiramatsu, Ryo; Toho, Taichiro; Tanaka, Hiroki; Masunaga, Shin-Ichiro; Hattori, Yoshihide; Kirihata, Mitsunori; Ono, Koji; Kuroiwa, Toshihiko; Miyatake, Shin-Ichi

2017-01-23

Boron neutron capture therapy (BNCT) is a unique particle radiation therapy based on the nuclear capture reactions in boron-10. We developed a novel boron-10 containing sodium borocaptate (BSH) derivative, 1-amino-3-fluorocyclobutane-1-carboxylic acid (ACBC)-BSH. ACBC is a tumor selective synthetic amino acid. The purpose of this study was to assess the biodistribution of ACBC-BSH and its therapeutic efficacy following Boron Neutron Capture Therapy (BNCT) of the F98 rat glioma. We evaluated the biodistribution of three boron-10 compounds, ACBC-BSH, BSH and boronophenylalanine (BPA), in vitro and in vivo, following intravenous (i.v.) administration and intratumoral (i.t.) convection-enhanced delivery (CED) in F98 rat glioma bearing rats. For BNCT studies, rats were stratified into five groups: untreated controls, neutron-irradiation controls, BNCT with BPA/i.v., BNCT with ACBC-BSH/CED, and BNCT concomitantly using BPA/i.v. and ACBC-BSH/CED. In vitro, ACBC-BSH attained higher cellular uptake F98 rat glioma cells compared with BSH. In vivo biodistribution studies following i.v. administration and i.t. CED of ACBC-BSH attained significantly higher boron concentrations than that of BSH, but much lower than that of BPA. However, following convection enhanced delivery (CED), ACBC-BSH attained significantly higher tumor concentrations than BPA. The i.t. boron-10 concentrations were almost equal between the ACBC-BSH/CED group and BPA/i.v. group of rats. The tumor/brain boron-10 concentration ratio was higher with ACBC-BSH/CED than that of BPA/i.v. group. Based on these data, BNCT studies were carried out in F98 glioma bearing rats using BPA/i.v. and ACBC-BSH/CED as the delivery agents. The corresponding mean survival times were 37.4 ± 2.6d and 44.3 ± 8.0d, respectively, and although modest, these differences were statistically significant. Our findings suggest that further studies are warranted to evaluate ACBC-BSH/CED as a boron delivery agent.

Efferent projections of NPY expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models

PubMed Central

Lee, Shin J.; Kirigiti, Melissa; Lindsley, Sarah R; Loche, Alberto; Madden, Christopher J.; Morrison, Shaun F.; Smith, M Susan; Grove, Kevin L.

2013-01-01

The dorsomedial hypothalamus (DMH) has long been implicated in feeding behavior and thermogenesis. The DMH contains orexigenic neuropeptide Y (NPY) neurons, but the role of these neurons in the control of energy homeostasis is not well understood. NPY expression in the DMH is low under normal conditions in adult rodents, but is significantly increased during chronic hyperphagic conditions such as lactation and diet-induced obesity (DIO). To better understand the role of DMH-NPY neurons, we characterized the efferent projections of DMH-NPY neurons using the anterograde tracer biotinylated dextran amine (BDA) in lactating rats and DIO mice. In both models, BDA and NPY co-labeled fibers were mainly limited to the hypothalamus including the paraventricular nucleus of the hypothalamus (PVH), lateral hypothalamus/perifornical area (LH/PFA), and anteroventral periventricular nucleus (AVPV). Specifically in lactating rats, BDA and NPY co-labeled axonal swellings were in close apposition to CART expressing neurons in the PVH and AVPV. Although the DMH neurons project to the rostral raphe pallidus (rRPa) these projections did not contain NPY immunoreactivity in either the lactating rat or DIO mouse. Instead, the majority of BDA-labeled fibers in the rRPa were orexin positive. Furthermore, DMH-NPY projections were not observed within the nucleus of the solitary tract (NTS), another brainstem site critical for the regulation of sympathetic outflow. The present data suggest that NPY expression in the DMH during chronic hyperphagic conditions plays important roles in feeding behavior and thermogenesis by modulating neuronal functions within the hypothalamus, but not in the brainstem. PMID:23172177

Bexarotene, a Selective RXRα Agonist, Reverses Hypotension Associated with Inflammation and Tissue Injury in a Rat Model of Septic Shock.

PubMed

Tunctan, Bahar; Kucukkavruk, Sefika P; Temiz-Resitoglu, Meryem; Guden, Demet S; Sari, Ayse N; Sahan-Firat, Seyhan

2018-02-01

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that can activate or inhibit the expression of many target genes by forming a heterodimer complex with the retinoid X receptor (RXR). The aim of this study was to investigate effects of bexarotene, a selective RXRα agonist, on the changes in renal, cardiac, hepatic, and pulmonary expression/activity of inducible nitric oxide synthase (iNOS) and cytochrome P450 (CYP) 4F6 in relation to PPARα/β/γ-RXRα heterodimer formation in a rat model of septic shock. Rats were injected with dimethyl sulfoxide or bexarotene 1 h after administration of saline or lipopolysaccharide (LPS). Mean arterial pressure (MAP) and heart rate (HR) were recorded from rats, which had received either saline or LPS before and after 1, 2, 3, and 4 h. Serum iNOS, LTB 4 , myeloperoxidase (MPO), and lactate dehydrogenase (LDH) levels as well as tissue iNOS and CYP4F6 mRNA expression in addition to PPARα/β/γ and RXRα proteins were measured. LPS-induced decrease in MAP and increase in HR were associated with a decrease in PPARα/β/γ-RXRα heterodimer formation and CYP4F6 mRNA expression. LPS also caused an increase in systemic iNOS, LTB 4 , MPO, and LDH levels as well as iNOS mRNA expression. Bexarotene at 0.1 mg/kg (i.p.) prevented the LPS-induced changes, except tachycardia. The results suggest that increased formation of PPARα/β/γ-RXRα heterodimers and CYP4F6 expression/activity in addition to decreased iNOS expression contributes to the beneficial effect of bexarotene to prevent the hypotension associated with inflammation and tissue injury during rat endotoxemia.

Mechanism of auditory hypersensitivity in human autism using autism model rats.

PubMed

Ida-Eto, Michiru; Hara, Nao; Ohkawara, Takeshi; Narita, Masaaki

2017-04-01

Auditory hypersensitivity is one of the major complications in autism spectrum disorder. The aim of this study was to investigate whether the auditory brain center is affected in autism model rats. Autism model rats were prepared by prenatal exposure to thalidomide on embryonic day 9 and 10 in pregnant rats. The superior olivary complex (SOC), a complex of auditory nuclei, was immunostained with anti-calbindin d28k antibody at postnatal day 50. In autism model rats, SOC immunoreactivity was markedly decreased. Strength of immunostaining of SOC auditory fibers was also weak in autism model rats. Surprisingly, the size of the medial nucleus of trapezoid body, a nucleus exerting inhibitory function in SOC, was significantly decreased in autism model rats. Auditory hypersensitivity may be, in part, due to impairment of inhibitory processing by the auditory brain center. © 2016 Japan Pediatric Society.

Biological characterization of F-18-labeled rhodamine B, a potential positron emission tomography perfusion tracer.

PubMed

Bartholomä, Mark D; He, Huamei; Pacak, Christina A; Dunning, Patricia; Fahey, Frederic H; McGowan, Francis X; Cowan, Douglas B; Treves, S Ted; Packard, Alan B

2013-11-01

Myocardial infarction is the leading cause of death in western countries, and positron emission tomography (PET) plays an increasing role in the diagnosis and treatment planning for this disease. However, the absence of an (18)F-labeled PET myocardial perfusion tracer hampers the widespread use of PET in myocardial perfusion imaging (MPI). We recently reported a potential MPI agent based on (18)F-labeled rhodamine B. The goal of this study was to more completely define the biological properties of (18)F-labeled rhodamine B with respect to uptake and localization in an animal model of myocardial infarction and to evaluate the uptake (18)F-labeled rhodamine B by cardiomyocytes. A total of 12 female Sprague Dawley rats with a permanent ligation of the left anterior descending artery (LAD) were studied with small-animal PET. The animals were injected with 100-150 μCi of (18)F-labeled rhodamine B diethylene glycol ester ([(18)F]RhoBDEGF) and imaged two days before ligation. The animals were imaged again two to ten days post-ligation. After the post-surgery scans, the animals were euthanized and the hearts were sectioned into 1mm slices and myocardial infarct size was determined by phosphorimaging and 2,3,5-triphenyltetrazolium chloride staining (TTC). In addition, the uptake of [(18)F]RhoBDEGF in isolated rat neonatal cardiomyocytes was determined by fluorescence microscopy. Small-animal PET showed intense and uniform uptake of [(18)F]RhoBDEGF throughout the myocardium in healthy rats. After LAD ligation, well defined perfusion defects were observed in the PET images. The defect size was highly correlated with the infarct size as determined ex vivo by phosphorimaging and TTC staining. In vitro, [(18)F]RhoBDEGF was rapidly internalized into rat cardiomyocytes with ~40 % of the initial activity internalized within the 60 min incubation time. Fluorescence microscopy clearly demonstrated localization of [(18)F]RhoBDEGF in the mitochondria of rat cardiomyocytes. Fluorine-18

Biological Characterization of F-18-Labeled Rhodamine B, a Potential Positron Emission Tomography Perfusion Tracer

PubMed Central

Bartholomä, Mark D.; He, Huamei; Pacak, Christina; Dunning, Patricia; Fahey, Frederic H.; McGowan, Francis; Cowan, Douglas; Treves, S. Ted; Packard, Alan B.

2013-01-01

Introduction Myocardial infarction is the leading cause of death in western countries, and positron emission tomography (PET) plays an increasing role in the diagnosis and treatment planning for this disease. However, the absence of an F-18-labeled PET myocardial perfusion tracer hampers the widespread use of PET in myocardial perfusion imaging (MPI). We recently reported a potential MPI agent based on F-18-labeled rhodamine B. The goal of this study was to more completely define the biological properties of F-18-labeled rhodamine B with respect to uptake and localization in an animal model of myocardial infarction and to evaluate the uptake F-18-labeled rhodamine B by cardiomyocytes. Methods A total of 12 female Sprague Dawley rats with a permanent ligation of the left anterior descending artery (LAD) were studied with small-animal PET. The animals were injected with 100–150 µCi of F-18-labeled rhodamine B diethylene glycol ester ([18F]RhoBDEGF) and imaged two days before ligation. The animals were imaged again two to ten days post-ligation. After the post-surgery scans, the animals were euthanized and the hearts were sectioned into 1 mm slices and myocardial infarct size was determined by phosphorimaging and 2,3,5-triphenyltetrazolium chloride staining (TTC). In addition, the uptake of [18F]RhoBDEGF in isolated rat neonatal cardiomyocytes was determined by fluorescence microscopy. Results Small-animal PET showed intense and uniform uptake of [18F]RhoBDEGF throughout the myocardium in healthy rats. After LAD ligation, well defined perfusion defects were observed in the PET images. The defect size was highly correlated with the infarct size as determined ex vivo by phosphorimaging and TTC staining. In vitro, [18F]RhoBDEGF was rapidly internalized into rat cardiomyocytes with ~40 % of the initial activity internalized within the 60 min incubation time. Fluorescence microscopy clearly demonstrated localization of [18F]RhoBDEGF in the mitochondria of rat

Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model.

PubMed

Zoratto, F; Palombelli, G M; Ruocco, L A; Carboni, E; Laviola, G; Sadile, A G; Adriani, W; Canese, R

2017-08-30

Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi-slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats. Copyright © 2017 Elsevier B.V. All rights reserved.

A Comparative Study of the Hypoxia PET Tracers [{sup 18}F]HX4, [{sup 18}F]FAZA, and [{sup 18}F]FMISO in a Preclinical Tumor Model

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

Peeters, Sarah G.J.A., E-mail: sarah.peeters@maastrichtuniversity.nl; Zegers, Catharina M.L.; Lieuwes, Natasja G.

Purpose: Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [{sup 18}F]FMISO, [{sup 18}F]FAZA, and [{sup 18}F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification. Methods and Materials: PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, andmore » reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing. Results: TBR was stabilized and maximal at 2 hours p.i. for [{sup 18}F]FAZA (4.0 ± 0.5) and at 3 hours p.i. for [{sup 18}F]HX4 (7.2 ± 0.7), whereas [{sup 18}F]FMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both [{sup 18}F]FMISO (R = 0.86; Dice coefficient = 0.76) and [{sup 18}F]HX4 (R = 0.76; Dice coefficient = 0.70), whereas [{sup 18}F]FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [{sup 18}F]HX4 and [{sup 18}F]FAZA upon 7% oxygen breathing. Only [{sup 18}F]FMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen. Conclusions: This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be

Identification of brain regions predicting epileptogenesis by serial [18F]GE-180 positron emission tomography imaging of neuroinflammation in a rat model of temporal lobe epilepsy.

PubMed

Russmann, Vera; Brendel, Matthias; Mille, Erik; Helm-Vicidomini, Angela; Beck, Roswitha; Günther, Lisa; Lindner, Simon; Rominger, Axel; Keck, Michael; Salvamoser, Josephine D; Albert, Nathalie L; Bartenstein, Peter; Potschka, Heidrun

2017-01-01

Excessive activation of inflammatory signaling pathways seems to be a hallmark of epileptogenesis. Positron emission tomography (PET) allows in vivo detection of brain inflammation with spatial information and opportunities for longitudinal follow-up scanning protocols. Here, we assessed whether molecular imaging of the 18 kDa translocator protein (TSPO) can serve as a biomarker for the development of epilepsy. Therefore, brain uptake of [ 18 F]GE-180, a highly selective radioligand of TSPO, was investigated in a longitudinal PET study in a chronic rat model of temporal lobe epilepsy. Analyses revealed that the influence of the epileptogenic insult on [ 18 F]GE-180 brain uptake was most pronounced in the earlier phase of epileptogenesis. Differences were evident in various brain regions during earlier phases of epileptogenesis with [ 18 F]GE-180 standardized uptake value enhanced by 2.1 to 2.7fold. In contrast, brain regions exhibiting differences seemed to be more restricted with less pronounced increases of tracer uptake by 1.8-2.5fold four weeks following status epilepticus and by 1.5-1.8fold in the chronic phase. Based on correlation analysis, we were able to identify regions with a predictive value showing a correlation with seizure development. These regions include the amygdala as well as a cluster of brain areas. This cluster comprises parts of different brain regions, e.g. the hippocampus, parietal cortex, thalamus, and somatosensory cortex. In conclusion, the data provide evidence that [ 18 F]GE-180 PET brain imaging can serve as a biomarker of epileptogenesis. The identification of brain regions with predictive value might facilitate the development of preventive concepts as well as the early assessment of the interventional success. Future studies are necessary to further confirm the predictivity of the approach.

Myrtol ameliorates cartilage lesions in an osteoarthritis rat model.

PubMed

Ying, Binbin; Maimaiti, Abudu Kelimujiang; Song, Donghui; Zhu, Songsong

2015-01-01

The aim of this study is to evaluate the effects of myrtol standardized on cartilage lesions in osteoarthritis (OA) rats. Fifty-six healthy Sprague-Dawley rats were randomly divided into sham group (13 rats) and OA model group (43 rats) with interior meniscus excision. Then serum estradiol (E2) and glycosaminoglycan (GAG) content in cartilage tissue were measured by radioimmunoassay and toluidine blue staining, respectively. After that, the model rats were randomly divided into low dose myrtol (LDM) group, middle dose myrtol (MDM) group and high dose myrtol (HDM) group (10 rats in each group) with treatment of 450 mg/kg, 300 mg/kg and 150 mg/kg myrtol, respectively. Then, Mankin scores were used to evaluate lesion extent of knee joint cartilage. Expression of tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), interleukin (IL)-6, Bax and Bcl-2 were investigated using PCR gel electrophoresis method. Mankin cores were lower in sham group and myrtol group than in model group. There were statistically significant differences (P < 0.01) between sham group and model group in expression of TNF-α, TGF-β1, IL-6, Bax and Bcl-2 in the cartilage tissue. Myrtol significantly reduced the expression of TNF-α, IL-6 and Bax, and increased the expression of TGF-β1 and Bcl-2 in myrtol group, comparing with those in model group (P < 0.01). Myrtol could down-regulate the expression of TNF-α, IL-6 and Bax, and up-regulate the expression of TGF-β1 and Bcl-2. Myrtol standardized is a promising drug to ameliorate knee cartilage lesions in the OA rat model.

Tramadol reduces anxiety-related and depression-associated behaviors presumably induced by pain in the chronic constriction injury model of neuropathic pain in rats.

PubMed

Caspani, Ombretta; Reitz, Marie-Céline; Ceci, Angelo; Kremer, Andreas; Treede, Rolf-Detlef

2014-09-01

Depression and anxiety are common comorbidities of neuropathic pain (NP). Pharmacological preclinical studies on NP have given abundant information on the effects of drugs on reflex measures of stimulus-evoked pain. However, few preclinical studies focus on relief of comorbidities evoked by NP. In this study, we investigated the effects of tramadol on nociceptive reflex, depression-associated and anxiety-related behaviors in a NP model in rats. We used chronic constriction injury (CCI) of the sciatic nerve as an animal model of neuropathic pain. We performed electronic von Frey tests (evF) to measure mechanical sensitivity, elevated plus maze tests (EPM) to record anxiety-related behaviors and forced swimming tests (FST) to evaluate depression-associated behaviors. In the evF, CCI rats showed a decrease of 82% of the paw withdrawal threshold (PWT) compared to sham (P<0.001). Tramadol increased the PWT by 336% in CCI rats (P<0.001) and by 16% in sham (P<0.05). On the EPM, CCI rats spent 45% less time than sham on the open arms of the maze (P<0.05). Tramadol increased the time spent on the open arms of CCI rats by 67% (P<0.05) and had no significant effect on sham. During the FST, CCI rats showed 28% longer immobility than sham (P<0.01). Tramadol reduced the immobility time in CCI rats by 22% (P<0.001), while having no effect on sham. Tramadol reversed the changes in mechanical sensitivity as well as anxiety-related and depression-associated behaviors that are caused by injury of the sciatic nerve with only minor effects in the absence of injury. These data suggest that tramadol relieves chronic pain and its indirect consequences and comorbidities, and that this study also is a model for pharmacological studies seeking to investigate the effect of drugs on the major disabling symptoms of NP. Copyright © 2014 Elsevier Inc. All rights reserved.

(-)-P7C3-S243 Protects a Rat Model of Alzheimer's Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia.

PubMed

Voorhees, Jaymie R; Remy, Matthew T; Cintrón-Pérez, Coral J; El Rassi, Eli; Khan, Michael Z; Dutca, Laura M; Yin, Terry C; McDaniel, Latisha N; Williams, Noelle S; Brat, Daniel J; Pieper, Andrew A

2017-11-06

In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might be uniquely applicable to patients with AD, given the comorbid presentation of depression and cognitive deficits. Aging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered (-)-P7C3-S243 daily for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months. (-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation. Neuronal cell death-specific treatment approaches, such as P7C3 compounds, may represent a new treatment approach for patients experiencing the combination of cognitive deficits and depression associated with AD. Published by Elsevier Inc.

Genetic control of indirect airway responsiveness in the rat.

PubMed

Pauwels, R A; Germonpré, P R; Kips, J C; Joos, G F

1995-11-01

Many of the airway responses to endogenous and exogenous stimuli are caused by indirect mechanisms such as the activation of neurons and/or inflammatory cells. In the present study we compare the bronchoconstrictor and the plasma protein extravasation response to adenosine and tachykinins in two highly inbred rat strains, F344 and BDE. BDE-rats have a bronchoconstrictor response to adenosine at lower doses. Challenge with the A3-adenosine receptor agonist APNEA demonstrates that the difference in airway responsiveness to adenosine between BDE- and F344-rats is probably related to a higher number of A3-receptors on the airway mast cells of BDE-rats. In contrast, F344-rats have a higher airway responsiveness to tachykinins than BDE-rats. Tachykinins cause bronchoconstriction in F344-rats mainly by an indirect mechanism, involving stimulation of NK1-receptors and mast cell activation. In BDE-rats they cause bronchoconstriction by a direct effect on airway smooth muscle via activation of NK2-receptors. Finally we also observed a difference between F344- and BDE-rats with regard to the mechanisms involved in the plasma protein extravasation in the airways caused by substance P or capsaicin. In F344-rats but not in BDE-rats mast cell activation and the release of 5-hydroxytryptamine is partly responsible for this plasma protein extravasation.

Wheel running improves REM sleep and attenuates stress-induced flattening of diurnal rhythms in F344 rats.

PubMed

Thompson, Robert S; Roller, Rachel; Greenwood, Benjamin N; Fleshner, Monika

2016-05-01

Regular physical activity produces resistance to the negative health consequences of stressor exposure. One way that exercise may confer stress resistance is by reducing the impact of stress on diurnal rhythms and sleep; disruptions of which contribute to stress-related disease including mood disorders. Given the link between diurnal rhythm disruptions and stress-related disorders and that exercise both promotes stress resistance and is a powerful non-photic biological entrainment cue, we tested if wheel running could reduce stress-induced disruptions of sleep/wake behavior and diurnal rhythms. Adult, male F344 rats with or without access to running wheels were instrumented for biotelemetric recording of diurnal rhythms of locomotor activity, heart rate, core body temperature (CBT), and sleep (i.e. REM, NREM, and WAKE) in the presence of a 12 h light/dark cycle. Following 6 weeks of sedentary or exercise conditions, rats were exposed to an acute stressor known to disrupt diurnal rhythms and produce behaviors associated with mood disorders. Prior to stressor exposure, exercise rats had higher CBT, more locomotor activity during the dark cycle, and greater %REM during the light cycle relative to sedentary rats. NREM and REM sleep were consolidated immediately following peak running to a greater extent in exercise, compared to sedentary rats. In response to stressor exposure, exercise rats expressed higher stress-induced hyperthermia than sedentary rats. Stressor exposure disrupted diurnal rhythms in sedentary rats; and wheel running reduced these effects. Improvements in sleep and reduced diurnal rhythm disruptions following stress could contribute to the health promoting and stress protective effects of exercise.

Wheel Running Improves REM Sleep and Attenuates Stress-induced Flattening of Diurnal Rhythms in F344 Rats

PubMed Central

Thompson, Robert S.; Roller, Rachel; Greenwood, Benjamin N.; Fleshner, Monika

2016-01-01

Regular physical activity produces resistance to the negative health consequences of stressor exposure. One way that exercise may confer stress resistance is by reducing the impact of stress on diurnal rhythms and sleep; disruptions of which contribute to stress-related disease including mood disorders. Given the link between diurnal rhythm disruptions and stress-related disorders and that exercise both promotes stress resistance and is a powerful non-photic biological entrainment cue, we tested if wheel running could reduce stress-induced disruptions of sleep/wake behavior and diurnal rhythms. Adult, male F344 rats with or without access to running wheels were instrumented for biotelemetric recording of diurnal rhythms of locomotor activity, heart rate, core body temperature (CBT), and sleep (i.e. REM, NREM, and WAKE) in the presence of a 12hr light/dark cycle. Following 6 weeks of sedentary or exercise conditions, rats were exposed to an acute stressor known to disrupt diurnal rhythms and produce behaviors associated with mood disorders. Prior to stressor exposure, exercise rats had higher CBT, more locomotor activity during the dark cycle, and greater %REM during the light cycle relative to sedentary rats. NREM and REM sleep were consolidated immediately following peak running to a greater extent in exercise, compared to sedentary rats. In response to stressor exposure, exercise rats expressed higher stress-induced hyperthermia than sedentary rats. Stressor exposure disrupted diurnal rhythms in sedentary rats; and wheel running reduced these effects. Improvements in sleep and reduced diurnal rhythm disruptions following stress could contribute to the health promoting and stress protective effects of exercise. PMID:27124542

Breeding, husbandry, veterinary care, and hematology of marsh rice rats (Oryzomys palustris), a small animal model for periodontitis.

PubMed

Aguirre, J Ignacio; Edmonds, Kent; Zamora, Bernadette; Pingel, Jennifer; Thomas, Linda; Cancel, Denisse; Schneider, Laura; Reinhard, Mary K; Battles, August H; Akhter, Mohammed P; Kimmel, Donald B; Wronski, Thomas J

2015-01-01

Rice rats (Oryzomys palustris) are a recognized animal model for studying periodontal disease and the photoperiodic regulation of reproduction. Here we share information regarding the breeding, husbandry, veterinary care, and hematologic findings about this animal species to facilitate its use in studies at other research institutions. Rice rats initially were quarantined and monitored for excluded pathogens by using microbiologic, parasitologic, and serologic methods with adult female Mus musculus and Rattus norvegicus sentinel animals. Breeders were paired in a monogamous, continuous-breeding system. Rats were housed in static filter-top cages, maintained on commercial chow under 14:10-h light:dark cycles at 68 to 79 °F (20.0 to 26.1 °C) and 30% to 70% humidity. Rice rats apparently adapt relatively well to standard laboratory conditions, despite their aggressive behavior toward conspecifics and humans. Our analysis of 97 litters revealed that dams gave birth to an average of 5.2 pups per dam and weaned 4.2 pups per dam. Several procedures and biologic reagents normally used in standard laboratory rodents (mice and rats) can be used with rice rats. In addition, we present hematologic and serum chemistry values that can be used as preliminary reference values for future studies involving rice rats.

Breeding, Husbandry, Veterinary Care, and Hematology of Marsh Rice Rats (Oryzomys palustris), a Small Animal Model for Periodontitis

PubMed Central

Aguirre, J Ignacio; Edmonds, Kent; Zamora, Bernadette; Pingel, Jennifer; Thomas, Linda; Cancel, Denisse; Schneider, Laura; Reinhard, Mary K; Battles, August H; Akhter, Mohammed P; Kimmel, Donald B; Wronski, Thomas J

2015-01-01

Rice rats (Oryzomys palustris) are a recognized animal model for studying periodontal disease and the photoperiodic regulation of reproduction. Here we share information regarding the breeding, husbandry, veterinary care, and hematologic findings about this animal species to facilitate its use in studies at other research institutions. Rice rats initially were quarantined and monitored for excluded pathogens by using microbiologic, parasitologic, and serologic methods with adult female Mus musculus and Rattus norvegicus sentinel animals. Breeders were paired in a monogamous, continuous-breeding system. Rats were housed in static filter-top cages, maintained on commercial chow under 14:10-h light:dark cycles at 68 to 79 °F (20.0 to 26.1 °C) and 30% to 70% humidity. Rice rats apparently adapt relatively well to standard laboratory conditions, despite their aggressive behavior toward conspecifics and humans. Our analysis of 97 litters revealed that dams gave birth to an average of 5.2 pups per dam and weaned 4.2 pups per dam. Several procedures and biologic reagents normally used in standard laboratory rodents (mice and rats) can be used with rice rats. In addition, we present hematologic and serum chemistry values that can be used as preliminary reference values for future studies involving rice rats. PMID:25651091

Effects of amphetamine on striatal dopamine release, open-field activity, and play in Fischer 344 and Sprague-Dawley rats.

PubMed

Siviy, Stephen M; McDowell, Lana S; Eck, Samantha R; Turano, Alexandra; Akopian, Garnik; Walsh, John P

2015-12-01

Previous work from our laboratories has shown that juvenile Fischer 344 (F344) rats are less playful than other strains and also appear to be compromised in dopamine (DA) functioning. To determine whether the dysfunctional play in this strain is associated with deficits in the handling and delivery of vesicular DA, the following experiments assessed the extent to which F344 rats are differentially sensitive to the effects of amphetamine. When exposed to amphetamine, striatal slices obtained from F344 rats showed a small increase in unstimulated DA release when compared with slices from Sprague-Dawley rats; they also showed a more rapid high K+-mediated release of DA. These data provide tentative support for the hypothesis that F344 rats have a higher concentration of cytoplasmic DA than Sprague-Dawley rats. When rats were tested for activity in an open field, F344 rats presented a pattern of results that was consistent with either an enhanced response to amphetamine (3 mg/kg) or a more rapid release of DA (10 mg/kg). Although there was some indication that amphetamine had a dose-dependent differential effect on play in the two strains, play in F344 rats was not enhanced to any degree by amphetamine. Although these results are not consistent with our working hypothesis that F344 rats are less playful because of a deficit in vesicular release of DA, they still suggest that this strain may be a useful model for better understanding the role of DA in social behavior during the juvenile period.

High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats.

PubMed

Wang, Lixin; Jacobs, Jonathan P; Lagishetty, Venu; Yuan, Pu-Qing; Wu, Shuping V; Million, Mulugeta; Reeve, Joseph R; Pisegna, Joseph R; Taché, Yvette

2017-10-01

High-protein diet (HPD) curtails obesity and/or fat mass, but it is unknown whether it reverses neuroinflammation or alters glucose levels, CCK sensitivity, and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 wk were switched to a HPD for 6 wk. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK-8S, blood glucose, brain signaling, and cecal microbiota were assessed. When compared with a normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for 6 wk reduced fat mass (15.7%) with a nonsignificantly reduced body weight gain, normalized blood glucose, and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD versus WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those, Akkermansia muciniphila (enriched on a HPD), an unclassified Clostridiales, a member of the RF39 order, and a Phascolarctobacterium were significantly associated with fat mass. The WD increased cytokine expression in the hypothalamus and dorsal medulla that was unchanged by switching to HPD. These data indicate that HPD reduces body fat and restores glucose homeostasis and CCK sensitivity, while not modifying brain inflammation. In addition, expansion of cecal Akkermansia muciniphila correlated to fat mass loss may represent a potential peripheral mechanism of HPD beneficial effects.

Numb rats walk - a behavioural and fMRI comparison of mild and moderate spinal cord injury.

PubMed

Hofstetter, Christoph P; Schweinhardt, Petra; Klason, Tomas; Olson, Lars; Spenger, Christian

2003-12-01

Assessment of sensory function serves as a sensitive measure for predicting the functional outcome following spinal cord injury in patients. However, little is known about loss and recovery of sensory function in rodent spinal cord injury models as most tests of sensory functions rely on behaviour and thus motor function. We used functional magnetic resonance imaging (fMRI) to investigate cortical and thalamic BOLD-signal changes in response to limb stimulation following mild or moderate thoracic spinal cord weight drop injury in Sprague-Dawley rats. While there was recovery of close to normal hindlimb motor function as determined by open field locomotor testing following both degrees of injury, recovery of hindlimb sensory function as determined by fMRI and hot plate testing was only seen following mild injury and not following moderate injury. Thus, moderate injury can lead to near normal hindlimb motor function in animals with major sensory deficits. Recovered fMRI signals following mild injury had a partly altered cortical distribution engaging also ipsilateral somatosensory cortex and the cingulate gyrus. Importantly, thoracic spinal cord injury also affected sensory representation of the upper nonaffected limbs. Thus, cortical and thalamic activation in response to forelimb stimulation was significantly increased 16 weeks after spinal cord injury compared to control animals. We conclude that both forelimb and hindlimb cortical sensory representation is altered following thoracic spinal cord injury. Furthermore tests of sensory function that are independent of motor behaviour are needed in rodent spinal cord injury research.

Novel Rat Model for Neurocysticercosis Using Taenia solium

PubMed Central

Verastegui, Manuela R.; Mejia, Alan; Clark, Taryn; Gavidia, Cesar M.; Mamani, Javier; Ccopa, Fredy; Angulo, Noelia; Chile, Nancy; Carmen, Rogger; Medina, Roxana; García, Hector H.; Rodriguez, Silvia; Ortega, Ynes; Gilman, Robert H.

2016-01-01

Neurocysticercosis is caused by Taenia solium infecting the central nervous system and is the leading cause of acquired epilepsy and convulsive conditions worldwide. Research into the pathophysiology of the disease and appropriate treatment is hindered by lack of cost-effective and physiologically similar animal models. We generated a novel rat neurocysticercosis model using intracranial infection with activated T. solium oncospheres. Holtzman rats were infected in two separate groups: the first group was inoculated extraparenchymally and the second intraparenchymally, with different doses of activated oncospheres. The groups were evaluated at three different ages. Histologic examination of the tissue surrounding T. solium cysticerci was performed. Results indicate that generally infected rats developed cysticerci in the brain tissue after 4 months, and the cysticerci were observed in the parenchymal, ventricle, or submeningeal brain tissue. The route of infection did not have a statistically significant effect on the proportion of rats that developed cysticerci, and there was no dependence on infection dose. However, rat age was crucial to the success of the infection. Epilepsy was observed in 9% of rats with neurocysticercosis. In histologic examination, a layer of collagen tissue, inflammatory infiltrate cells, perivascular infiltrate, angiogenesis, spongy change, and mass effect were observed in the tissue surrounding the cysts. This study presents a suitable animal model for the study of human neurocysticercosis. PMID:26216286

Preclinical characterization of 18F-MAA, a novel PET surrogate of 99mTc-MAA.

PubMed

Wu, Shih-Yen; Kuo, Jia-Wei; Chang, Tien-Kuei; Liu, Ren-Shen; Lee, Rheun-Chuan; Wang, Shyh-Jen; Lin, Wuu-Jyh; Wang, Hsin-Ell

2012-10-01

(99m)Tc-labeled macroaggregated albumin ((99m)Tc-MAA) scintigraphy scan is routinely performed for lung perfusion imaging and for the assessment of in vivo distribution of (90)Y-labeled SIR-Spheres prior to selective internal radiation treatment for hepatocellular carcinoma. Positron emission tomography (PET) imaging is superior to gamma scintigraphy in terms of sensitivity, spatial resolution and accuracy of quantification. This study reported that (18)F-labeled macroaggregated albumin ((18)F-MAA) is an ideal PET imaging surrogate for (99m)Tc-MAA. (18)F-MAA was prepared from the commercial MAA kit via a one-step conjugation with N-succinimidyl 4-(18)F-fluorobenzoate ((18)F-SFB). The biodistribution study and microPET/microSPECT imaging were conducted in normal SD rats after intravenous injection of (18)F-MAA/(99m)Tc-MAA. A comparison study of these two radiotracers was performed after co-injection via the intrahepatic arterial in a N1S1 hepatoma-bearing SD rat model. The optimal condition for (18)F-MAA preparation is coupling MAA (0.5mg) with (18)F-SFB at 45°C for 5 min in a phosphate buffer of pH 8.5. (18)F-MAA was prepared in 60 min with high radiochemical yield (30%-35%) and high radiochemical purity (>95%). The in vivo distribution of (18)F-MAA after intravenous injection meets the specifications of MAA depicted in European Pharmacopeia. Our study demonstrated excellent correlation between (18)F-MAA and (99m)Tc-MAA in the regional distribution of tumor, liver and lungs (R(2)=0.965, 0.886 and 0.991, respectively), and also in the tumor-to-liver and tumor-to-lungs ratio (R(2)=0.965 and 0.987, respectively) in a N1S1 hepatoma-bearing SD rat model. The organ uptakes derived from animal PET/CT and SPECT/CT imaging after administration of these two tracers were in accordance with those obtained in the distribution studies. Starting from commercial MAA kit, an efficient preparation of (18)F-MAA was successfully established. Highly correlated, almost parallel

[18F]-Fluorodeoxyglucose-Positron Emission Tomography in Rats with Prolonged Cocaine Self-Administration Suggests Potential Brain Biomarkers for Addictive Behavior

PubMed Central

Cannella, Nazzareno; Cosa-Linan, Alejandro; Roscher, Mareike; Takahashi, Tatiane T.; Vogler, Nils; Wängler, Björn; Spanagel, Rainer

2017-01-01

The DSM5-based dimensional diagnostic approach defines substance use disorders on a continuum from recreational drug use to habitual and ultimately addicted behavior. Biomarkers that are indicative of recreational drug use and addicted behavior are lacking. We performed a translational [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study in the multi-dimensional 0/3crit model of cocaine addiction. Addict-like (3crit) and non-addict-like (0crit) rats, which shared identical life conditions and levels of cocaine self-administration, were acquired for FDG-PET under baseline conditions and following cocaine and yohimbine challenges. Compared to cocaine-naïve control rats, 0crit animals showed higher glucose uptake in the caudate putamen (CPu) and medial prefrontal cortex (mPFC) respect to naïve controls. 3crit animals did not show this adaptive higher glucose utilization, but had lower uptake in several cortical areas. Both cocaine and yohimbine challenges affected glucose uptake in control rats in several brain sites, but not in 0crit and 3crit rats, indicating that impaired glucose mobilization in response to these challenges is not specifically associated with addictive behavior. Compared to 0crit, 3crit rats showed higher reinstatement responses, which were negatively associated with glucose uptake in the ventral tegmental area. Data indicate that cocaine non-addict- and addict-like phenotypes are associated with several potential biomarkers. Specifically, we propose that increased glucose uptake in the CPu and mPFC is a function of controlled drug use, whereas a loss of striatal and prefrontal metabolic activity and reduced uptake in cortical areas are indicative of addictive behavior. PMID:29163237

[18F]-Fluorodeoxyglucose-Positron Emission Tomography in Rats with Prolonged Cocaine Self-Administration Suggests Potential Brain Biomarkers for Addictive Behavior.

PubMed

Cannella, Nazzareno; Cosa-Linan, Alejandro; Roscher, Mareike; Takahashi, Tatiane T; Vogler, Nils; Wängler, Björn; Spanagel, Rainer

2017-01-01

The DSM5-based dimensional diagnostic approach defines substance use disorders on a continuum from recreational drug use to habitual and ultimately addicted behavior. Biomarkers that are indicative of recreational drug use and addicted behavior are lacking. We performed a translational [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study in the multi-dimensional 0/3crit model of cocaine addiction. Addict-like (3crit) and non-addict-like (0crit) rats, which shared identical life conditions and levels of cocaine self-administration, were acquired for FDG-PET under baseline conditions and following cocaine and yohimbine challenges. Compared to cocaine-naïve control rats, 0crit animals showed higher glucose uptake in the caudate putamen (CPu) and medial prefrontal cortex (mPFC) respect to naïve controls. 3crit animals did not show this adaptive higher glucose utilization, but had lower uptake in several cortical areas. Both cocaine and yohimbine challenges affected glucose uptake in control rats in several brain sites, but not in 0crit and 3crit rats, indicating that impaired glucose mobilization in response to these challenges is not specifically associated with addictive behavior. Compared to 0crit, 3crit rats showed higher reinstatement responses, which were negatively associated with glucose uptake in the ventral tegmental area. Data indicate that cocaine non-addict- and addict-like phenotypes are associated with several potential biomarkers. Specifically, we propose that increased glucose uptake in the CPu and mPFC is a function of controlled drug use, whereas a loss of striatal and prefrontal metabolic activity and reduced uptake in cortical areas are indicative of addictive behavior.

Fourier domain low coherence interferometry for detection of early colorectal cancer development in the AOM rat model

NASA Astrophysics Data System (ADS)

Robles, Francisco E.; Zhu, Yizheng; Lee, Jin; Sharma, Sheela; Wax, Adam

2011-03-01

We present Fourier domain low coherence interferometry (fLCI) applied to the detection of preneoplastic changes in the colon using the ex-vivo azoxymethane (AOM) rat carcinogenesis model. fLCI measures depth resolved spectral oscillations, also known as local oscillations, resulting from coherent fields induced by the scattering of cell nuclei. The depth resolution of fLCI permits nuclear morphology measurements within thick tissues, making the technique sensitive to the earliest stages of precancerous development. To achieve depth resolved spectroscopic analysis, we use the dual window method, which obtains simultaneously high spectral and depth resolution and yields access to the local oscillations. The results show highly statistically significant differences between the AOM-treated and control group samples. Further, the results suggest that fLCI may be used to detect the field effect of carcinogenesis, in addition to identifying specific areas where more advanced neoplastic development has occurred.

[Establishment of rat model with diabetes mellitus and concomitant periodontitis and the carotid artery lesions in the model rats].

PubMed

Ren, X Y; Wang, C; Liu, X; Li, H; Gao, J H; Ge, X J

2017-12-09

Objectives: To establish SD rat model with type 2 diabetes mellitus (DM) and concomitant chronic periodontitis (CP) and to evaluate the influence of periodontitis on the vascular lesions of type 2 diabetes rats. Methods: Totally 241 clean level SD rats were randomly divided into four groups, group A (normal control, NC, n= 27), group B (DM, n= 34), group C (CP, n= 90) and group D (DM+CP, n= 90). The rats of DM group were fed with high-fat and high-sugar diet for 8 to 10 weeks, and then were multiply injected with small dose streptozotocin under the condition of ice bath. Blood sugar levels after the injection were dynamically monitored at 72 h, 1 week, 2 weeks and 4 weeks, respectively. The CP model was established by means of ligation. Bilateral maxillary first and second molars were selected and ligated using 0.2 mm orthodontic wires binding with 4-0 surgical suture soaked with Porphyromonas gingivalis (Pg) suspension. After a period of 14 weeks, all the rats were put to death. Maxillary samples were subjected to methylene blue staining to observe alveolar bone loss. Bilateral carotid artery specimens were collected. The left carotid artery specimens were used to detect the prevalence of Pg using quantitative real-time PCR. The right carotid artery specimens were used to observe pathological changes. Results: Blood sugar levels of rats in group B and D increased and changed sharply after Streptozotocin injection with in 1 week. Symptoms of 'more drink, more food and body weight loss' appeared. The fasting blood glucose (FBG) was more than 7.8 mmol/L and (or) the random blood glucose (RBG) was more than 17.8 mmol/L. Both FBG and RBG became stable after 2 to 3 weeks. Levels of HbA1C in group B and D ([7.32±0.45]%, [9.41±0.45]%) were significantly higher than that of group A ([4.02±0.45]%) ( P< 0.01). Rats of group D were observed the most severe bone loss showing wider interdental space and furcation involvement. Pathological results of carotid artery tissues of

F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy.

PubMed

Le Grand, Bruno; Letienne, Robert; Dupont-Passelaigue, Elisabeth; Lantoine-Adam, Frédérique; Longo, Frédéric; David-Dufilho, Monique; Michael, Georghia; Nishida, Kunihiro; Catheline, Daniel; Legrand, Philippe; Hatem, Stéphane; Nattel, Stanley

2014-07-01

Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989 ± 111 s in the vehicle group to 79 ± 59 s with F 16915, P < 0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P < 0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6 ± 7.4 %, n = 9 vs 17.6 ± 3.4 %, n = 9 in the vehicle group, P < 0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure.

Dynamic causal modelling on infant fNIRS data: A validation study on a simultaneously recorded fNIRS-fMRI dataset.

PubMed

Bulgarelli, Chiara; Blasi, Anna; Arridge, Simon; Powell, Samuel; de Klerk, Carina C J M; Southgate, Victoria; Brigadoi, Sabrina; Penny, William; Tak, Sungho; Hamilton, Antonia

2018-04-12

Tracking the connectivity of the developing brain from infancy through childhood is an area of increasing research interest, and fNIRS provides an ideal method for studying the infant brain as it is compact, safe and robust to motion. However, data analysis methods for fNIRS are still underdeveloped compared to those available for fMRI. Dynamic causal modelling (DCM) is an advanced connectivity technique developed for fMRI data, that aims to estimate the coupling between brain regions and how this might be modulated by changes in experimental conditions. DCM has recently been applied to adult fNIRS, but not to infants. The present paper provides a proof-of-principle for the application of this method to infant fNIRS data and a demonstration of the robustness of this method using a simultaneously recorded fMRI-fNIRS single case study, thereby allowing the use of this technique in future infant studies. fMRI and fNIRS were simultaneously recorded from a 6-month-old sleeping infant, who was presented with auditory stimuli in a block design. Both fMRI and fNIRS data were preprocessed using SPM, and analysed using a general linear model approach. The main challenges that adapting DCM for fNIRS infant data posed included: (i) the import of the structural image of the participant for spatial pre-processing, (ii) the spatial registration of the optodes on the structural image of the infant, (iii) calculation of an accurate 3-layer segmentation of the structural image, (iv) creation of a high-density mesh as well as (v) the estimation of the NIRS optical sensitivity functions. To assess our results, we compared the values obtained for variational Free Energy (F), Bayesian Model Selection (BMS) and Bayesian Model Average (BMA) with the same set of possible models applied to both the fMRI and fNIRS datasets. We found high correspondence in F, BMS, and BMA between fMRI and fNIRS data, therefore showing for the first time high reliability of DCM applied to infant fNIRS data

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency.

PubMed

Kim, Hyun-Bum; Kwon, Byeong-Jae; Cho, Hyun-Ji; Kim, Ji-Won; Chon, Jeong-Woo; Do, Moon-Ho; Park, Sang-Yong; Kim, Sun-Yeou; Maeng, Sung-Ho; Park, Yoo-Kyoung; Park, Ji-Ho

2015-03-01

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders.

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency

PubMed Central

Kim, Hyun-Bum; Kwon, Byeong-Jae; Cho, Hyun-Ji; Kim, Ji-Won; Chon, Jeong-Woo; Do, Moon-Ho; Park, Sang-Yong; Kim, Sun-Yeou; Maeng, Sung-Ho; Park, Yoo-Kyoung

2015-01-01

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders. PMID:25792871

Super DIOS: Future X-ray Spectroscopic Mission to Search for Dark Baryons

NASA Astrophysics Data System (ADS)

Yamada, S.; Ohashi, T.; Ishisaki, Y.; Ezoe, Y.; Ichinohe, Y.; Kitazawa, S.; Kosaka, K.; Hayakawa, R.; Nunomura, K.; Mitsuda, K.; Yamasaki, N. Y.; Kikuchi, T.; Hayashi, T.; Muramatsu, H.; Nakashima, Y.; Tawara, Y.; Mitsuishi, I.; Babazaki, Y.; Seki, D.; Otsuka, K.; Ishihara, M.; Osato, K.; Ota, N.; Tomariguchi, M.; Nagai, D.; Lau, E.; Sato, K.

2018-04-01

The updated program of the future Japanese X-ray satellite mission Diffuse Intergalactic Oxygen Surveyor (DIOS), called as Super DIOS, is planned to search for dark baryons in the form of warm-hot intergalactic medium (WHIM) with high-resolution X-ray spectroscopy. The mission will detect redshifted emission lines from OVII, OVIII and other ions, leading to an overall understanding of the physical nature and spatial distribution of dark baryons as a function of cosmological timescale. We have started the conceptual design of the satellite and onboard instruments, focusing on the era of 2030s. The major change will be an improved angular resolution of the X-ray telescope. Super DIOS will have a 10-arcsec resolution, which is an improvement by a factor of about 20 over DIOS. With this resolution, most of the contaminating X-ray sources will be separated, and the level of the diffuse X-ray background will be much reduced after subtraction of point sources. This will give us higher sensitivity to map out the WHIM in emission.

NTP Toxicology and Carcinogenesis Studies of 1,4-Dichlorobenzene (CAS No. 106-46-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

PubMed

1987-01-01

1,4-Dichlorobenzene is commonly used as a space deodorant in toilets and for moth control. Because of its extensive production and use and the absence of carcinogenicity data, carcinogenesis studies were conducted by administering 1,4-dichlorobenzene (greater than 99% pure) in corn oil by gavage (5 days per week) to male F344/N rats at doses of 0, 150, or 300 mg/kg and to female F344/N rats and male and female B6C3F1 mice at doses of 0, 300, or 600 mg/kg per day for 2 years (50 animals per group). Fourteen-day and 13-week studies were performed to characterize the toxicity, identify affected sites, and set doses for the 2-year studies. Clinical chemistry and hematologic studies were performed during the 13-week studies to assess the effects of 1,4-dichlorobenzene on the liver, kidney, and hematopoietic system and to assess whether the compound produced hepatic porphyria. Two 13-week studies were performed in rats. In the first study, rats were dosed with 300-1,500 mg/kg 1,4-dichlorobenzene. Because histologic changes were observed in the kidney of male rats at all doses, a second 13-week study was performed at doses of 38-600 mg/kg. In the 13-week studies, survival was decreased in groups of male rats given 1,200 or 1,500 mg/kg and in female rats given 1,500 mg/kg. Weight gain was decreased in male rats receiving doses of 300 mg/kg or more and in female rats given doses of 1,200 or 1,500 mg/kg. Doses of 1,200 or 1,500 mg/kg produced degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow, lymphoid depletion of the spleen and thymus, and epithelial necrosis of the nasal turbinates in male and female rats. Renal tubular cell degeneration was observed in male rats receiving 300 mg/kg or more in the first study, but only slight changes were seen at 300 mg/kg in the second study. Liver weight to brain weight ratios were increased at 900 mg/kg or more for both male and female rats. The kidney weight to brain weight ratio was increased in male rats

Diosmin Protects against Ethanol-Induced Gastric Injury in Rats: Novel Anti-Ulcer Actions

PubMed Central

Arab, Hany H.; Salama, Samir A.; Omar, Hany A.; Arafa, El-Shaimaa A.; Maghrabi, Ibrahim A.

2015-01-01

Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses. PMID:25821971

Phase-amplitude coupling and infraslow (<1 Hz) frequencies in the rat brain: relationship to resting state fMRI

PubMed Central

Thompson, Garth J.; Pan, Wen-Ju; Billings, Jacob C. W.; Grooms, Joshua K.; Shakil, Sadia; Jaeger, Dieter; Keilholz, Shella D.

2014-01-01

Resting state functional magnetic resonance imaging (fMRI) can identify network alterations that occur in complex psychiatric diseases and behaviors, but its interpretation is difficult because the neural basis of the infraslow BOLD fluctuations is poorly understood. Previous results link dynamic activity during the resting state to both infraslow frequencies in local field potentials (LFP) (<1 Hz) and band-limited power in higher frequency LFP (>1 Hz). To investigate the relationship between these frequencies, LFPs were recorded from rats under two anesthetics: isoflurane and dexmedetomidine. Signal phases were calculated from low-frequency LFP and compared to signal amplitudes from high-frequency LFP to determine if modulation existed between the two frequency bands (phase-amplitude coupling). Isoflurane showed significant, consistent phase-amplitude coupling at nearly all pairs of frequencies, likely due to the burst-suppression pattern of activity that it induces. However, no consistent phase-amplitude coupling was observed in rats that were anesthetized with dexmedetomidine. fMRI-LFP correlations under isoflurane using high frequency LFP were reduced when the low frequency LFP's influence was accounted for, but not vice-versa, or in any condition under dexmedetomidine. The lack of consistent phase-amplitude coupling under dexmedetomidine and lack of shared variance between high frequency and low frequency LFP as it relates to fMRI suggests that high and low frequency neural electrical signals may contribute differently, possibly even independently, to resting state fMRI. This finding suggests that researchers take care in interpreting the neural basis of resting state fMRI, as multiple dynamic factors in the underlying electrophysiology could be driving any particular observation. PMID:24904325

Negligible Colon Cancer Risk from Food-Borne Acrylamide Exposure in Male F344 Rats and Nude (nu/nu) Mice-Bearing Human Colon Tumor Xenografts

PubMed Central

Raju, Jayadev; Roberts, Jennifer; Sondagar, Chandni; Kapal, Kamla; Aziz, Syed A.; Caldwell, Don; Mehta, Rekha

2013-01-01

Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet) reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control) or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM) or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu) mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control) or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a “complete carcinogen”, but acts as a “co-carcinogen” by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters. PMID:24040114

Novel rat model for neurocysticercosis using Taenia solium.

PubMed

Verastegui, Manuela R; Mejia, Alan; Clark, Taryn; Gavidia, Cesar M; Mamani, Javier; Ccopa, Fredy; Angulo, Noelia; Chile, Nancy; Carmen, Rogger; Medina, Roxana; García, Hector H; Rodriguez, Silvia; Ortega, Ynes; Gilman, Robert H

2015-08-01

Neurocysticercosis is caused by Taenia solium infecting the central nervous system and is the leading cause of acquired epilepsy and convulsive conditions worldwide. Research into the pathophysiology of the disease and appropriate treatment is hindered by lack of cost-effective and physiologically similar animal models. We generated a novel rat neurocysticercosis model using intracranial infection with activated T. solium oncospheres. Holtzman rats were infected in two separate groups: the first group was inoculated extraparenchymally and the second intraparenchymally, with different doses of activated oncospheres. The groups were evaluated at three different ages. Histologic examination of the tissue surrounding T. solium cysticerci was performed. Results indicate that generally infected rats developed cysticerci in the brain tissue after 4 months, and the cysticerci were observed in the parenchymal, ventricle, or submeningeal brain tissue. The route of infection did not have a statistically significant effect on the proportion of rats that developed cysticerci, and there was no dependence on infection dose. However, rat age was crucial to the success of the infection. Epilepsy was observed in 9% of rats with neurocysticercosis. In histologic examination, a layer of collagen tissue, inflammatory infiltrate cells, perivascular infiltrate, angiogenesis, spongy change, and mass effect were observed in the tissue surrounding the cysts. This study presents a suitable animal model for the study of human neurocysticercosis. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The Peptide Oxytocin Antagonist F-792, When Given Systemically, Does Not Act Centrally in Lactating Rats.

PubMed

Leng, G; Russell, J A

2016-04-01

Oxytocin secreted by nerve terminals in the posterior pituitary has important actions for ensuring a successful outcome of pregnancy: it stimulates uterine contractions that lead to birth and it is essential in the milk-ejection reflex, enabling milk to be expelled from the mammary glands into the mouths of suckling young. Oxytocin also has important actions in the brain: released from dendrites of neurones that innervate the posterior pituitary, oxytocin auto-excites the neurones to fire action potentials in co-ordinated bursts, causing secretion of pulses of oxytocin. Central oxytocin actions are blocked by an oxytocin antagonist given into the brain and, consequently, milk transfer stops. Systemic peptide oxytocin antagonist (atosiban) treatment is used clinically in management of pre-term labour, a major obstetric problem. Hence, it is important to know whether an oxytocin antagonist given peripherally can enter the brain and interfere with central oxytocin actions. In the present study, we tested F792, a peptide oxytocin antagonist. In urethane-anaesthetised suckled rats, we show that the mammary gland responsiveness to oxytocin is blocked by i.v. injections of 7 μg/kg of F792, and the milk-ejection reflex is blocked when F792 is given directly into the brain at a dose of 0.2 μg. To critically test whether F792 given systemically can enter the brain, we recorded the suckling- and oxytocin-induced burst-firing of individual antidromically identified oxytocin neurones in the paraventricular nucleus. Given systemically at 100 μg/kg i.v., F792 acted only peripherally, blocking the milk-ejecting actions of oxytocin, but not the burst-firing of oxytocin neurones during suckling (n = 5 neurones in five rats). Hence, this peptide oxytocin antagonist does not enter the brain from the circulation to interfere with an essential oxytocin function in the brain. Furthermore, the functions of oxytocin in the brain evidently cannot be explored with a systemic peptide

NTP toxicology and carcinogenesis studies of chromium picolinate monohydrate (CAS No. 27882-76-4) in F344/N rats and B6C3F1 mice (feed studies).

PubMed

2010-06-01

Chromium picolinate monohydrate is the commercially available form of chromium picolinate. Chromium picolinate is one of a number of compounds that contain chromium in the trivalent state (Cr III), which is the predominant form of chromium in nature. Humans ingest Cr III in food and dietary supplements. The major uses of Cr III in the chemical and manufacturing industries include production of chromium pigments and leather tanning. Chromium picolinate was nominated by the National Cancer Institute and a private individual for testing based on the potential for widespread consumer exposure from use as a dietary supplement. Male and female F344/N rats and B6C3F1 mice were exposed to chromium picolinate monohydrate (95% to 96% pure) in feed for 3 months or 2 years. Genetic toxicology studies with chromium picolinate monohydrate were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. Genetic toxicology studies with chromium picolinate were conducted in S. typhimurium and rat bone marrow cells. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 80, 240, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 7, 20, 160, 800, and 4,240 mg chromium picolinate monohydrate/kg body weight to males and 6, 20, 160, 780, and 4,250 mg/kg to females) for 14 weeks. All rats survived to the end of the study. Mean body weights and feed consumption of all exposed groups of males and females were similar to those of the control groups throughout the study. No exposure-related lesions occurred in males or females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 80, 240, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 17, 50, 450, 2,300, and 11,900 mg chromium picolinate monohydrate/kg body weight to males and 14, 40, 370, 1,775, and 9,140 mg/kg to females) for 14

Dose–response assessment of nephrotoxicity from a twenty-eight-day combined-exposure to melamine and cyanuric acid in F344 rats

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

Gamboa da Costa, Gonçalo, E-mail: goncalo.gamboa@fda.hhs.gov; Jacob, Cristina C.; Von Tungeln, Linda S.

The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6 mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4–10.9 mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28 days. Groups of male and female rats weremore » fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360 ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120 ppm, versus 229 ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60 ppm dose and in one female rat at the 30 ppm dose, establishing a NOAEL of 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females, and BMDL values as low as 1.6 mg/kg bw/day for both sexes. These data demonstrate that the length of exposure is an important component in the threshold of toxicity from a co-exposure to these compounds and suggest that the current risk assessments based on exposures to melamine alone may not reflect sufficiently the risk of a co-exposure to melamine and cyanuric acid. -- Highlights: ► A 28-day dietary co-exposure to melamine and cyanuric acid was conducted in F344 rats. ► The NOAELs were 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females. ► BMDL values as low as 1.6 mg/kg bw/day for both sexes were determined. ► The length of exposure plays an important role in the threshold of toxicity. ► Current assessments may underestimate the risk of melamine and cyanuric acid.« less

Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model.

PubMed

Huang, Feng-Yun J; Lee, Te-Wei; Chang, Chih-Hsien; Chen, Liang-Cheng; Hsu, Wei-Hsin; Chang, Chien-Wen; Lo, Jem-Mau

2015-01-01

In this study, the (188)Re-labeled PEGylated nanoliposome ((188)Re-liposome) was prepared and evaluated as a therapeutic agent for glioma. The reporter cell line, F98(luc) was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of (188)Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered (188)Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the (188)Re-liposome-treated rats. By using bioluminescent imaging, the well-established reporter cell line (F98(luc)) showed a high relationship between cell number and its bioluminescent intensity (R(2)=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of (188)Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the (188)Re-liposome-treated group than the control group (P<0.05). As a result, the lifespan of glioma-bearing rats treated with (188)Re-liposome was prolonged 10.67% compared to the control group. The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting (188)Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma

Slc15a1 is involved in the transport of synthetic F5-peptide into the seminiferous epithelium in adult rat testes.

PubMed

Su, Linlin; Zhang, Yufei; Cheng, Yan C; Lee, Will M; Ye, Keping; Hu, Dahai

2015-11-05

Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-γ3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising male contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective male contraceptive.

The Anti-(+)-Methamphetamine Monoclonal Antibody mAb7F9 Attenuates Acute (+)-Methamphetamine Effects on Intracranial Self-Stimulation in Rats

PubMed Central

Harris, Andrew C.; LeSage, Mark G.; Shelley, David; Perry, Jennifer L.; Pentel, Paul R.; Owens, S. Michael

2015-01-01

Passive immunization with monoclonal antibodies (mAbs) against (+)-methamphetamine (METH) is being evaluated for the treatment of METH addiction. A human/mouse chimeric form of the murine anti-METH mAb7F9 has entered clinical trials. This study examined the effects of murine mAb7F9 on certain addiction-related behavioral effects of METH in rats as measured using intracranial self-stimulation (ICSS). Initial studies indicated that acute METH (0.1-0.56 mg/kg, s.c.) lowered the minimal (threshold) stimulation intensity that maintained ICSS. METH (0.3 mg/kg, s.c.) also blocked elevations in ICSS thresholds (anhedonia-like behavior) during spontaneous withdrawal from a chronic METH infusion (10 mg/kg/day x 7 days). In studies examining effects of i.v. pretreatment with mAb7F9 (at 30, 100, or 200 mg/kg), 200 mg/kg blocked the ability of an initial injection of METH (0.3 mg/kg, s.c.) to reduce baseline ICSS thresholds, but was less capable of attenuating the effect of subsequent daily injections of METH. MAb7F9 (200 mg/kg) also produced a small but significant reduction in the ability of METH (0.3 mg/kg, s.c.) to reverse METH withdrawal-induced elevations in ICSS thresholds. These studies demonstrate that mAb7F9 can partially attenuate some addiction-related effects of acute METH in an ICSS model, and provide some support for the therapeutic potential of mAb7F9 for the treatment of METH addiction. PMID:25742165

Aging increases amyloid beta-peptide-induced 8-iso-prostaglandin F2alpha release from rat brain.

PubMed

Brunetti, Luigi; Michelotto, Barbara; Orlando, Giustino; Recinella, Lucia; Di Nisio, Chiara; Ciabattoni, Giovanni; Vacca, Michele

2004-01-01

In order to investigate whether amyloid beta-peptide-induced oxidative damage in the brain could be related to aging, we studied the release of 8-iso-prostaglandin (PG)F2alpha, a stable marker of cellular oxidative stress, in brain synaptosomes from Wistar rats of different ages (3, 6, 12, 18 months old), both basally and after amyloid beta-peptide (1-40) perfusion. We found that basal release of 8-iso-PGF2alpha was not significantly different among all age groups of rats. Either phospholipase A2 activation induced by calcium ionophore A23187 (10 nM) or amyloid beta-peptide (5 microM) did not modify isoprostane release, when these substances were used alone. In contrast, amyloid beta-peptide (1-5 microM) preincubation caused a dose-dependent increase of A23187-stimulated 8-iso-PGF2alpha release in each age group, which was also strikingly correlated to aging of rats. Furthermore, ferric ammonium sulfate stimulates isoprostane production to levels comparable to those induced by amyloid beta-peptide. In conclusion, although 8-iso-PGF2alpha production from rat brain synaptosomes is independent from aging in the basal state, aging renders neurons more vulnerable to amyloid beta-peptide-induced oxidative toxicity.

Quercetin and pioglitazone synergistically reverse endothelial dysfunction in isolated aorta from fructose-streptozotocin (F-STZ)-induced diabetic rats.

PubMed

Kunasegaran, Thubasni; Mustafa, Mohd Rais; Achike, Francis I; Murugan, Dharmani Devi

2017-03-15

Pioglitazone is an anti-diabetic drug with potential to cause adverse effects following prolonged use. This study, therefore, investigated the effects of combination treatment of a subliminal concentration of pioglitazone and quercetin, a potent antioxidant, on vascular reactivity of aorta isolated from fructose-streptozotocin (F-STZ)-induced diabetic rats. Relaxation to acetylcholine and sodium nitroprusside, and contraction to phenylephrine were tested in organ bath chambers following pre-incubation with vehicle (DMSO; 0.05%), quercetin (10-7 M), pioglitazone (10-7 M), or their combination (P+Q; 10-7 M each drug). Subliminal concentration of quercetin or pioglitazone did not alter the acetylcholine- induced relaxation nor the phenylephrine-induced contraction in both normal rat and diabetic F-STZ induced tissues. However, P+Q combination synergistically improved the impaired acetylcholine-induced relaxation and decreased the elevated phenylephrine-induced contraction in aortic rings from diabetic, but not in the normal rats. Neither mono nor combination treatment altered sodium nitroprusside-induced relaxation. The combination also synergistically decreased superoxide anion and increased nitric oxide production compared to the individual treatments in aorta from diabetic rats. Overall, these data demonstrated a synergistic effect, in which, a combination (P+Q; 10-7 M each drug) caused a significantly greater effect than 10-6 M of either agent in improving endothelial function of isolated diabetic aorta. In conclusion, a combination of subliminal concentrations of pioglitazone and quercetin is able to decrease oxidative stress and provide synergistic vascular protection in type 2 diabetes mellitus and thus the possibility of using quercetin as a supplement to pioglitazone in the treatment of diabetes with the goal of reducing pioglitazone toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Down-regulation of A-type potassium channel in gastric-specific DRG neurons in a rat model of functional dyspepsia.

PubMed

Li, S; Chen, J D Z

2014-07-01

Although without evidence of organic structural abnormalities, pain or discomfort is a prominent symptom of functional dyspepsia and considered to reflect visceral hypersensitivity whose underlying mechanism is poorly understood. Here, we studied electrophysiological properties and expression of voltage-gated potassium channels in dorsal root ganglion (DRG) neurons in a rat model of functional dyspepsia induced by neonatal gastric irritation. Male Sprague-Dawley rat pups at 10-day old received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days and studied at adulthood. Retrograde tracer-labeled gastric-specific T8 -T12 DRG neurons were harvested for the patch-clamp study in voltage and current-clamp modes and protein expression of K(+) channel in T8 -T12 DRGs was examined by western blotting. (1) Gastric specific but not non-gastric DRG neurons showed an enhanced excitability in neonatal IA-treated rats compared to the control: depolarized resting membrane potentials, a lower current threshold for action potential (AP) activation, and an increase in the number of APs in response to current stimulation. (2) The current density of tetraethylammonium insensitive (transiently inactivating A-type current), but not the tetraethylammonium sensitive (slow-inactivating delayed rectifier K(+) currents), was significantly smaller in IA-treated rats (65.4 ± 6.9 pA/pF), compared to that of control (93.1 ± 8.3 pA/pF). (3) Protein expression of KV 4.3 was down-regulated in IA-treated rats. A-type potassium channels are significantly down-regulated in the gastric-specific DRG neurons in adult rats with mild neonatal gastric irritation, which in part contribute to the enhanced DRG neuron excitabilities that leads to the development of gastric hypersensitivity. © 2014 John Wiley & Sons Ltd.

Structure-Activity Relationship Models for Rat Carcinogenesis and Assessing the Role Mutagens Play in Model Predictivity

PubMed Central

Carrasquer, C. Alex; Batey, Kaylind; Qamar, Shahid; Cunningham, Albert R.; Cunningham, Suzanne L.

2016-01-01

We previously demonstrated that fragment based cat-SAR carcinogenesis models consisting solely of mutagenic or non-mutagenic carcinogens varied greatly in terms of their predictive accuracy. This led us to investigate how well the rat cancer cat-SAR model predicted mutagens and non-mutagens in their learning set. Four rat cancer cat-SAR models were developed: Complete Rat, Transgender Rat, Male Rat, and Female Rat, with leave-one-out (LOO) validation concordance values of 69%, 74%, 67%, and 73%, respectively. The mutagenic carcinogens produced concordance values in the range of 69–76% as compared to only 47–53% for non-mutagenic carcinogens. As a surrogate for mutagenicity comparisons between single site and multiple site carcinogen SAR models was analyzed. The LOO concordance values for models consisting of 1-site, 2-site, and 4+-site carcinogens were 66%, 71%, and 79%, respectively. As expected, the proportion of mutagens to non-mutagens also increased, rising from 54% for 1-site to 80% for 4+-site carcinogens. This study demonstrates that mutagenic chemicals, in both SAR learning sets and test sets, are influential in assessing model accuracy. This suggests that SAR models for carcinogens may require a two-step process in which mutagenicity is first determined before carcinogenicity can be accurately predicted. PMID:24697549

Chronic Carcinogenicity Study of Gasoline Vapor Condensate (GVC) and GVC Containing Methyl Tertiary-Butyl Ether in F344 Rats

PubMed Central

Benson, Janet M.; Gigliotti, Andrew P.; March, Thomas H.; Barr, Edward B.; Tibbetts, Brad M.; Skipper, Betty J.; Clark, Charles R.; Twerdok, Lorraine

2011-01-01

Chronic inhalation studies were conducted to compare the toxicity and potential carcinogenicity of evaporative emissions from unleaded gasoline (GVC) and gasoline containing the oxygenate methyl tertiary-butyl ether (MTBE; GMVC). The test materials were manufactured to mimic vapors people would be exposed to during refueling at gas stations. Fifty F344 rats per gender per exposure level per test article were exposed 6 h/d, 5 d/wk for 104 wk in whole body chambers. Target total vapor concentrations were 0, 2, 10, or 20 g/m3 for the control, low-, mid-, and high-level exposures, respectively. Endpoints included survival, body weights, clinical observations, organs weights, and histopathology. GVC and GMVC exerted no marked effects on survival or clinical observations and few effects on organ weights. Terminal body weights were reduced in all mid- and high-level GVC groups and high-level GMVC groups. The major proliferative lesions attributable to gasoline exposure with or without MTBE were renal tubule adenomas and carcinomas in male rats. GMV exposure led to elevated testicular mesothelioma incidence and an increased trend for thyroid carcinomas in males. GVMC inhalation caused an increased trend for testicular tumors with exposure concentration. Mid- and high-level exposures of GVC and GMVC led to elevated incidences of nasal respiratory epithelial degeneration. Overall, in these chronic studies conducted under identical conditions, the health effects in F344 rats following 2 yr of GVC or GMVC exposure were comparable in the production of renal adenomas and carcinomas in male rats and similar in other endpoints. PMID:21432714

Chronic carcinogenicity study of gasoline vapor condensate (GVC) and GVC containing methyl tertiary-butyl ether in F344 rats.

PubMed

Benson, Janet M; Gigliotti, Andrew P; March, Thomas H; Barr, Edward B; Tibbetts, Brad M; Skipper, Betty J; Clark, Charles R; Twerdok, Lorraine

2011-01-01

Chronic inhalation studies were conducted to compare the toxicity and potential carcinogenicity of evaporative emissions from unleaded gasoline (GVC) and gasoline containing the oxygenate methyl tertiary-butyl ether (MTBE; GMVC). The test materials were manufactured to mimic vapors people would be exposed to during refueling at gas stations. Fifty F344 rats per gender per exposure level per test article were exposed 6 h/d, 5 d/wk for 104 wk in whole body chambers. Target total vapor concentrations were 0, 2, 10, or 20 g/m³ for the control, low-, mid-, and high-level exposures, respectively. Endpoints included survival, body weights, clinical observations, organs weights, and histopathology. GVC and GMVC exerted no marked effects on survival or clinical observations and few effects on organ weights. Terminal body weights were reduced in all mid- and high-level GVC groups and high-level GMVC groups. The major proliferative lesions attributable to gasoline exposure with or without MTBE were renal tubule adenomas and carcinomas in male rats. GMV exposure led to elevated testicular mesothelioma incidence and an increased trend for thyroid carcinomas in males. GVMC inhalation caused an increased trend for testicular tumors with exposure concentration. Mid- and high-level exposures of GVC and GMVC led to elevated incidences of nasal respiratory epithelial degeneration. Overall, in these chronic studies conducted under identical conditions, the health effects in F344 rats following 2 yr of GVC or GMVC exposure were comparable in the production of renal adenomas and carcinomas in male rats and similar in other endpoints.

Transgenic Rat Models for Breast Cancer Research

DTIC Science & Technology

1998-10-01

animals with mammary adenocarcinoma (1 out of 26 p53 null mice) whereas there was a high incidence of malignant lymphomas (20 out of 26). These studies...heir capacity to develop in utero . To this end, Dr. Warren has cultured various stages of rat embryos and 10 *~cý t. ?V& ks, 9A LA 6"r Eiac,’X4vrý...hyperplasia and adenocarcinomas in male and female mice. Cell 55: 619-625. 13. Andres, A.C., M.A. VanderValk, C.-A. Schoenenberger, F. Fluckinger, M

The structure of the coding and 5'-flanking region of the type 1 iodothyronine deiodinase (dio1) gene is normal in a patient with suspected congenital dio1 deficiency.

PubMed

Toyoda, N; Kleinhaus, N; Larsen, P R

1996-06-01

We analyzed the exon-intron structure of the human type 1 deiodinase gene (dio1) and compared it with that of a patient with suspected congenital type 1 deiodinase (D1) deficiency. The hdio1 gene is identical in exon-intron arrangement to the mouse gene, with coding sequences and a selenocysteine insertion sequence (SECIS) element contained in four exons. There were no mutations in the sequences of exons 1-4 of the patient's genomic DNA. Functional studies by transient expression techniques showed no difference in basal promoter activity or T3 responsiveness between the patient's and the normal dio1 gene. A structural abnormality in the dio1 gene is not a likely explanation for this patient's D1-deficient phenotype.

High-protein diet selectively reduces fat mass and improves glucose tolerance in Western-type diet-induced obese rats

PubMed Central

Stengel, Andreas; Goebel-Stengel, Miriam; Wang, Lixin; Hu, Eugenia; Karasawa, Hiroshi; Pisegna, Joseph R.

2013-01-01

Obesity is an increasing health problem. Because drug treatments are limited, diets remain popular. High-protein diets (HPD) reduce body weight (BW), although the mechanisms are unclear. We investigated physiological mechanisms altered by switching diet induced obesity (DIO) rats from Western-type diet (WTD) to HPD. Male rats were fed standard (SD) or WTD (45% calories from fat). After developing DIO (50% of rats), they were switched to SD (15% calories from protein) or HPD (52% calories from protein) for up to 4 weeks. Food intake (FI), BW, body composition, glucose tolerance, insulin sensitivity, and intestinal hormone plasma levels were monitored. Rats fed WTD showed an increased FI and had a 25% greater BW gain after 9 wk compared with SD (P < 0.05). Diet-induced obese rats switched from WTD to HPD reduced daily FI by 30% on day 1, which lasted to day 9 (−9%) and decreased BW during the 2-wk period compared with SD/SD (P < 0.05). During these 2 wk, WTD/HPD rats lost 72% more fat mass than WTD/SD (P < 0.05), whereas lean mass was unaltered. WTD/HPD rats had lower blood glucose than WTD/SD at 30 min postglucose gavage (P < 0.05). The increase of pancreatic polypeptide and peptide YY during the 2-h dark-phase feeding was higher in WTD/HPD compared with WTD/SD (P < 0.05). These data indicate that HPD reduces BW in WTD rats, which may be related to decreased FI and the selective reduction of fat mass accompanied by improved glucose tolerance, suggesting relevant benefits of HPD in the treatment of obesity. PMID:23883680

Phenotypic characterization of the Komeda miniature rat Ishikawa, an animal model of dwarfism caused by a mutation in Prkg2.

PubMed

Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

2008-12-01

The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BNxKMI-mri/mri)F1xKMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII.

Phenotypic Characterization of the Komeda Miniature Rat Ishikawa, an Animal Model of Dwarfism Caused by a Mutation in Prkg2

PubMed Central

Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

2008-01-01

The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BN×KMI-mri/mri)F1×KMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII. PMID:19149413

World class Devonian potential seen in eastern Madre de Dios basin

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

Peters, K.E.; Wagner, J.B.; Carpenter, D.G.

The Madre de Dios basin in northern Bolivia contains thick, laterally extensive, organic-rich Upper Devonian source rocks that reached the oil-generative stage of thermal maturity after trap and seal formation. Despite these facts, less than one dozen exploration wells have been drilled in the Madre de Dios basin, and no significant reserves have been discovered. Mobil geoscientists conducted a regional geological, geophysical, and geochemical study of the Madre de Dios basin. The work reported here was designed to assess the distribution, richness, depositional environment, and thermal maturity of Devonian source rocks. It is supported by data from over 3,000 mmore » of continuous slimhole core in two of the five Mobil wells in the basin. Source potential also exists in Cretaceous, Mississippian, and Permian intervals. The results of this study have important implications for future exploration in Bolivia and Peru.« less

NTP Toxicology and Carcinogenesis Studies of Benzyl Acetate (CAS No. 140-11-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

PubMed

1986-08-01

Benzyl acetate, a water-white liquid with a pear-like odor, is a natural constituent of several essential oils and flower absolutes extracted from jasmine, hyacinth, gardenia, tuberose, ylang-ylang, cananga, and neroli. Commercial benzyl acetate, a liquid prepared synthetically from benzyl chloride, acetic acid, and triethylamine is used primarily as a component of perfumes for soaps and as a flavoring ingredient. This compound is practically insoluble in water but is miscible in alcohol and ether and soluble in benzene and chloroform. Toxicology and carcinogenesis studies of benzyl acetate (>99% pure) were conducted by administering benzyl acetate in corn oil gavage to groups of 50 male and 50 female F344/N rats at doses of 0, 250, or 500 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 500, or 1,000 mg/kg once daily five days per week for 103 weeks. Dose selection for the 2-year study was based on mean body weight gain depression and decreased survival observed at higher doses in 13 week studies. The absence of any observable adverse effect of benzyl acetate on the survival or mean body weight gains of the rats or mice in the 2-year studies suggests that both the rats and the mice of each sex could have tolerated higher doses. An infection in the genital tract was probably responsible for the deaths of 26/35 control, 14/32 low-dose, and 8/20 high-dose female mice before the end of the study. Acinar-cell adenomas in the pancreas of male rats occurred with a positive trend (P<0.01), and the incidence in the high-dose group (37/49, 76%) was significantly (P<0.01) higher than in the vehicle controls (22/50, 40%). The incidence of these tumors in the low-dose group (27/50, 54%) was comparable to that in the gavage controls. Acinar-cell hyperplasia of the pancreas was observed in 37/50 control, 34/50 low-dose, and 36/49 high-dose male rats. No acinar-cell hyperplasia or adenoma of the pancreas was observed in female rats. The

A viable logarithmic f(R) model for inflation

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

Amin, M.; Khalil, S.; Salah, M.

2016-08-18

Inflation in the framework of f(R) modified gravity is revisited. We study the conditions that f(R) should satisfy in order to lead to a viable inflationary model in the original form and in the Einstein frame. Based on these criteria we propose a new logarithmic model as a potential candidate for f(R) theories aiming to describe inflation consistent with observations from Planck satellite (2015). The model predicts scalar spectral index 0.9615

Oxidative stress of crystalline lens in rat menopausal model.

PubMed

Acer, Semra; Pekel, Gökhan; Küçükatay, Vural; Karabulut, Aysun; Yağcı, Ramazan; Çetin, Ebru Nevin; Akyer, Şahika Pınar; Şahin, Barbaros

2016-01-01

To evaluate lenticular oxidative stress in rat menopausal models. Forty Wistar female albino rats were included in this study. A total of thirty rats underwent oophorectomy to generate a menopausal model. Ten rats that did not undergo oophorectomy formed the control group (Group 1). From the rats that underwent oophorectomy, 10 formed the menopause control group (Group 2), 10 were administered a daily injection of methylprednisolone until the end of the study (Group 3), and the remaining 10 rats were administered intraperitoneal streptozocin to induce diabetes mellitus (Group 4). Total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) measurements of the crystalline lenses were analyzed. The mean OSI was the lowest in group 1 and highest in group 4. Nevertheless, the difference between the groups was not statistically significant in terms of OSI (p >0.05). The mean TOS values were similar between the groups (p >0.05), whereas the mean TAC of group 1 was significantly higher than that of the other groups (p <0.001). Our results indicate that menopause may not promote cataract formation.

A novel respiratory syncytial virus (RSV) F subunit vaccine adjuvanted with GLA-SE elicits robust protective TH1-type humoral and cellular immunity in rodent models.

PubMed

Lambert, Stacie L; Aslam, Shahin; Stillman, Elizabeth; MacPhail, Mia; Nelson, Christine; Ro, Bodrey; Sweetwood, Rosemary; Lei, Yuk Man; Woo, Jennifer C; Tang, Roderick S

2015-01-01

Illness associated with Respiratory Syncytial Virus (RSV) remains an unmet medical need in both full-term infants and older adults. The fusion glycoprotein (F) of RSV, which plays a key role in RSV infection and is a target of neutralizing antibodies, is an attractive vaccine target for inducing RSV-specific immunity. BALB/c mice and cotton rats, two well-characterized rodent models of RSV infection, were used to evaluate the immunogenicity of intramuscularly administered RSV vaccine candidates consisting of purified soluble F (sF) protein formulated with TLR4 agonist glucopyranosyl lipid A (GLA), stable emulsion (SE), GLA-SE, or alum adjuvants. Protection from RSV challenge, serum RSV neutralizing responses, and anti-F IgG responses were induced by all of the tested adjuvanted RSV sF vaccine formulations. However, only RSV sF + GLA-SE induced robust F-specific TH1-biased humoral and cellular responses. In mice, these F-specific cellular responses include both CD4 and CD8 T cells, with F-specific polyfunctional CD8 T cells that traffic to the mouse lung following RSV challenge. This RSV sF + GLA-SE vaccine formulation can also induce robust RSV neutralizing titers and prime IFNγ-producing T cell responses in Sprague Dawley rats. These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA-SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism. This vaccine may benefit older populations at risk for RSV disease.

A Novel Respiratory Syncytial Virus (RSV) F Subunit Vaccine Adjuvanted with GLA-SE Elicits Robust Protective TH1-Type Humoral and Cellular Immunity In Rodent Models

PubMed Central

Lambert, Stacie L.; Aslam, Shahin; Stillman, Elizabeth; MacPhail, Mia; Nelson, Christine; Ro, Bodrey; Sweetwood, Rosemary; Lei, Yuk Man; Woo, Jennifer C.; Tang, Roderick S.

2015-01-01

Background Illness associated with Respiratory Syncytial Virus (RSV) remains an unmet medical need in both full-term infants and older adults. The fusion glycoprotein (F) of RSV, which plays a key role in RSV infection and is a target of neutralizing antibodies, is an attractive vaccine target for inducing RSV-specific immunity. Methodology and Principal Findings BALB/c mice and cotton rats, two well-characterized rodent models of RSV infection, were used to evaluate the immunogenicity of intramuscularly administered RSV vaccine candidates consisting of purified soluble F (sF) protein formulated with TLR4 agonist glucopyranosyl lipid A (GLA), stable emulsion (SE), GLA-SE, or alum adjuvants. Protection from RSV challenge, serum RSV neutralizing responses, and anti-F IgG responses were induced by all of the tested adjuvanted RSV sF vaccine formulations. However, only RSV sF + GLA-SE induced robust F-specific TH1-biased humoral and cellular responses. In mice, these F-specific cellular responses include both CD4 and CD8 T cells, with F-specific polyfunctional CD8 T cells that traffic to the mouse lung following RSV challenge. This RSV sF + GLA-SE vaccine formulation can also induce robust RSV neutralizing titers and prime IFNγ-producing T cell responses in Sprague Dawley rats. Conclusions/Significance These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA-SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism. This vaccine may benefit older populations at risk for RSV disease. PMID:25793508

Respiratory Tract Lung Geometry and Dosimetry Model for Male Sprague-Dawley Rats

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

Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.

2015-07-24

While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract modelmore » for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague-Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.« less

Respiratory tract lung geometry and dosimetry model for male Sprague-Dawley rats.

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

Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.

2014-08-26

While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract modelmore » for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague- Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.« less

Intracerebroventricular Injection of Rats. A Sensitive Assay Method for Endogenous Pyrogen Circulating in Rats (41015)

DTIC Science & Technology

1981-01-01

Rats:1A Sensitive Assay Method for Endogenous Pyrogen Circulating in Rats (41015)1-- / WALTER J.CRITZ ~fI~ U.S. Army Medical Resetirch Inshfute- riak...8217ohn iases. F’oPy Detrick, Frederick. Maryland 21701 OI! Abstract, Intracerebroventricular tics) injection of endogenous pyrogen (EPI into rats causes...the lower the con- in an alteration of the "set-point" for body centration at which the pyrogen can be temperature (2). Endogenous pyrogen is a

MODELING OPERANT BEHAVIOR IN THE PARKINSONIAN RAT

PubMed Central

Avila, Irene; Reilly, Mark P.; Sanabria, Federico; Posadas-Sánchez, Diana; Chavez, Claudia L.; Banerjee, Nikhil; Killeen, Peter; Castañeda, Edward

2009-01-01

Mathematical principles of reinforcement (MPR; Killeen, 1994) is a quantitative model of operant behavior that contains 3 parameters representing motor capacity (δ), motivation (a), and short term memory (λ). The present study applied MPR to characterize the effects of bilateral infusions of 6-OHDA into the substantia nigra pars compacta in the rat, a model of Parkinson’s disease. Rats were trained to lever press under a 5-component fixed ratio (5, 15, 30, 60, and 100) schedule of food reinforcement. Rats were tested for 15 days prior to dopamine lesions and again for 15 days post-lesion. To characterize functional loss relative to lesion size, rats were grouped according to the extent and the degree of lateralization of their dopamine loss. Response rates decreased as a function of dopamine depletion, primarily at intermediate ratios. MPR accounted for 98% of variance in pre- and post-lesion response rates. Consistent with reported disruptions in motor behavior induced by dopaminergic lesions, estimates of δ increased when dopamine was severely depleted. There was no support for different estimates of a based on pre- and post-lesion performance of any lesion group, suggesting that dopamine loss has negligible effects on incentive motivation. The present study demonstrates the usefulness of combining operant techniques with a theoretical model to better understand the effects of a neurochemical manipulation. PMID:19073222

NTP 3-month toxicity studies of estragole (CAS No. 140-67-0) administered by gavage to F344/N rats and B6C3F1 mice.

PubMed

Bristol, D W

2011-01-01

Estragole is a natural organic compound that is used as an additive, flavoring agent, or fragrance in a variety of food, cleaning, and cosmetic products; as an herbal medicine; as an antimicrobial agent against acid-tolerant food microflora; and to produce synthetic anise oil. Estragole was nominated for toxicity testing by the National Institute of Environmental Health Sciences to characterize its toxicity when administered by gavage to F344/N rats and B6C3F1 mice and to determine how similar its effects might be to those of the structurally related compound, methyleugenol. Male and female F344/N rats and B6C3F1 mice were given estragole (greater than 99% pure) in corn oil by gavage for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. Core and special study (rats only) groups of 10 male and 10 female rats and mice were administered 37.5, 75, 150, 300, or 600 mg estragole/kg body weight in corn oil by gavage, 5 days per week. The core study groups were given estragole for 3 months and the special study groups for 30 days. All core study rats survived the 3-month exposure period. Mean body weights of the 300 and 600 mg/kg groups were 73% to 92%, respectively, of those of the vehicle control groups. A staining pattern on the ventral surface anterior to the genitalia beginning at week 9 in the 300 and 600 mg/kg groups was attributed to residue of estragole or metabolites in the urine. Alterations in the erythron related to estragole administration occurred in male and female rats; male rats demonstrated a stronger response. The changes in the erythron were characterized as a microcytic, normochromic, nonresponsive anemia. There were decreases in serum iron concentration in the 300 mg/kg females and 600 mg/kg males and females. The average percent saturation of total iron binding capacity was decreased in the 600 mg/kg males and females. Dose-related increases in platelet counts occurred in most of

Calcium Balance in Mature Rats Exposed to a Space Flight Model

NASA Technical Reports Server (NTRS)

Wolinsky, Ira

1996-01-01

Negative calcium balances are seen in humans during spaceflight and bed rest, an analog of space flight. Due to the infrequency and costliness of space flight and the difficulties, cost, and restraints in using invasive procedures in bed rest studies, several ground based animal models of space flight have been employed. The most useful and well developed of these models is hind limb unloading in the rat. In this model the hind limbs are non-weight bearing (unloaded) but still mobile; there is a cephalad fluid shift similar to that seen in astronauts in flight; the animals are able to feed, groom and locomote using their front limbs; the procedure is reversible; and, importantly, the model has been validated by comparison to space flight. Several laboratories have studied calcium balance using rats in hind limb unweighting. Roer and Dillaman used young male rats to study calcium balance in this model for 25 days. They found no differences in dietary calcium intake, percent calcium absorption, urinary and fecal excretion, hence indicating no differences in calcium balance between control and unloaded rats. In another study, employing 120 day old females, rats' hind limbs were unloaded for 28 days. While negative calcium balances were observed during a 25 day recovery period no balance measurements were possible during unweighting since the researchers did not employ appropriate metabolic cages. In a recent study from this laboratory, using 200 g rats in the space flight model for two weeks, we found depressed intestinal calcium absorption and increased fecal calcium excretion (indicating less positive calcium balances) and lower circulating 1,25-dihydroxyvitamin D. The above studies indicate that there remains a dearth of information on calcium balance during the hind limb unloading rat space flight model, especially in mature rats, whose use is a better model for planned manned space flight than juvenile or growing animals. With the aid of a newly designed

Lactobacillus salivarius Ren prevent the early colorectal carcinogenesis in 1, 2-dimethylhydrazine-induced rat model.

PubMed

Zhu, J; Zhu, C; Ge, S; Zhang, M; Jiang, L; Cui, J; Ren, F

2014-07-01

The objective of this study was to investigate the impact of Lactobacillus salivarius Ren (LS) on modulating colonic micro flora structure and influencing host colonic health in a rat model with colorectal precancerous lesions. Male F344 rats were injected with 1, 2-dimethylhydrazine (DMH) and treated with LS of two doses (5 × 10(8) and 1 × 10(10) CFU kg(-1) body weight) for 15 weeks. The colonic microflora profiles, luminal metabolites, epithelial proliferation and precancerous lesions [aberrant crypt foci (ACF)] were determined. A distinct segregation of colonic microflora structures was observed in LS-treated group. The abundance of one Prevotella-related strain was increased, and the abundance of one Bacillus-related strain was decreased by LS treatment. These changes were accompanied by increased short-chain fatty acid levels and decreased azoreductase activity. LS treatment also reduced the number of ACF by c. 40% and suppressed epithelial proliferation. Lactobacillus salivarius Ren improved the colonic microflora structures and the luminal metabolisms in addition preventing the early colorectal carcinogenesis in DMH-induced rat model. Colonic microflora is an important factor in colorectal carcinogenesis. Modulating the structural shifts of microflora may provide a novel option for preventing colorectal carcinogenesis. This study suggested a potential probiotic-based approach to modulate the intestinal microflora in the prevention of colorectal carcinogenesis. © 2014 The Society for Applied Microbiology.

Rating of CCl(4)-induced rat liver fibrosis by blood serum glycomics.

PubMed

Desmyter, Liesbeth; Fan, Ye-Dong; Praet, Marleen; Jaworski, Tomasz; Vervecken, Wouter; De Hemptinne, Bernard; Contreras, Roland; Chen, Cuiying

2007-07-01

Non-invasive staging of human liver fibrosis is a desirable objective that remains under extensive evaluation. Animal model systems are often used for studying human liver disease and screening antifibrotic compounds. The aim of the present study was to investigate the potential use of serum N-glycan profiles to evaluate liver fibrosis in a rat model. Liver fibrosis and cirrhosis were induced in rats by oral administration of CCl(4). Liver injury was assessed biochemically (alanine aminotransferase [ALT] activity, aspartate aminotransferase [AST] activity and total bilirubin) and histologically. The N-glycan profile (GlycoTest) was performed using DNA sequencer-assisted-fluorophore-assisted carbohydrate electrophoresis technology. In parallel, the effect of cotreatment with antifibrotic interferon-gamma (IFN-gamma) was studied. The biopsy scoring system showed that CCl(4) induced early fibrosis (F < 1-2) in rats after 3 weeks of treatment, and cirrhosis (F4) after 12 weeks. Significant increases in ALT activity, AST activity and total bilirubin levels were detected only after 12 weeks of CCl(4) treatment. GlycoTest showed three glycans were significantly altered in the CCl(4)-goup. Peak 3 started at week 6, at an early stage in fibrosis development (F < 1-2), whereas peaks 4 and 5 occurred at week 9, at which time mild liver fibrosis (F = 1-2) had developed. The changes in the CCl(4)-IFN-gamma group were intermediate between the CCl(4)- and the control groups. The GlycoTest is much more sensitive than biochemical tests for evaluating liver fibrosis/cirrhosis in the rat model. The test can also be used as a non-invasive marker for screening and monitoring the antifibrotic activity of potential therapeutic compounds.

High intake of palatable food predicts binge-eating independent of susceptibility to obesity: an animal model of lean vs obese binge-eating and obesity with and without binge-eating.

PubMed

Boggiano, M M; Artiga, A I; Pritchett, C E; Chandler-Laney, P C; Smith, M L; Eldridge, A J

2007-09-01

To determine the stability of individual differences in non-nutritive 'junk' palatable food (PF) intake in rats; assess the relationship of these differences to binge-eating characteristics and susceptibility to obesity; and evaluate the practicality of using these differences to model binge-eating and obesity. Binge-eating prone (BEP) and resistant (BER) groups were identified. Differential responses to stress, hunger, macronutrient-varied PFs, a diet-induced obesity (DIO) regimen and daily vs intermittent access to a PF+chow diet, were assessed. One hundred and twenty female Sprague-Dawley rats. Reliability of intake patterns within rats; food intake and body weight after various challenges over acute (1, 2, 4 h), 24-h and 2-week periods. Although BEP and BER rats did not differ in amount of chow consumed, BEPs consumed >50% more intermittent PF than BERs (P<0.001) and consistently so (alpha=0.86). BEPs suppressed chow but not PF intake when stressed, and ate as much when sated as when hungry. Conversely, BERs were more affected by stress and ate less PF, not chow, when stressed and were normally hyperphagic to energy deficit. BEP overeating generalized to other PFs varying in sucrose, fat and nutrition content. Half the rats in each group proved to be obesity prone after a no-choice high fat diet (DIO diet) but a continuous diet of PF+chow normalized the BEPs high drive for PF. Greater intermittent intake of PF predicts binge-eating independent of susceptibility to weight gain. Daily fat consumption in a nutritious source (DIO-diet; analogous to a fatty meal) promoted overeating and weight gain but limiting fat to daily non-nutritive food (PF+chow; analogous to a snack with a low fat meal), did not. The data offer an animal model of lean and obese binge-eating, and obesity with and without binge-eating that can be used to identify the unique physiology of these groups and henceforth suggest more specifically targeted treatments for binge-eating and obesity.

Slc15a1 is involved in the transport of synthetic F5-peptide into the seminiferous epithelium in adult rat testes

PubMed Central

Su, Linlin; Zhang, Yufei; Cheng, Yan C.; Lee, Will M.; Ye, Keping; Hu, Dahai

2015-01-01

Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-γ3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising male contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective male contraceptive. PMID:26537751

A physiologically based model of chromium kinetics in the rat.

PubMed

O'Flaherty, E J

1996-05-01

A physiologically based model of chromium kinetics in rats has been developed. The general structure of the model is similar to that of a model of lead kinetics in rats. Like lead chromium exchanges between plasma and the bone surfaces in contact with plasma, and also like lead, although with much lower efficiency, it can become incorporated into actively mineralizing bone. Both processes are included in the model. Parallel absorption and disposition schemes for chromium(VI) and chromium(III) are linked in the model by reduction processes occurring throughout the body, including the lung and gastrointestinal tract. Examination of a number of data sets from studies in which chromium salts were administered to rats intravenously, orally, or by intratracheal instillation established that intravenous administration, on the one hand, and oral or pulmonary administration, on the other hand, result in different disposition patterns. The model was calibrated based on published oral and intratracheal kinetic studies in rats given soluble chromium(III) and chromium(VI) salts. In the most complete of these studies, chromium concentrations were monitored in individual tissues for 42 days following intratracheal administration of a soluble chromium(VI) salt. Inclusion in the model of a urinary excretion delay was necessary in order to fit excretion data from two other intratracheal studies. Model predictions of blood chromium concentrations are compared with the results of a published kinetic study in which rats were administered a soluble chromium(VI) salt by inhalation.

[Establishment and evaluation of extracorporeal circulation model in rats].

PubMed

Xie, Xiao-Jun; Tao, Kai-Yu; Tang, Meng-Lin; Du, Lei; An, Qi; Lin, Ke; Gan, Chang-Ping; Chen, You-Wen; Luo, Shu-Hua

2012-09-01

To establish an extracorporeal circulation (ECC) rat model, and evaluate the inflammatory response and organ injury induced in the model. SD rats were anesthetized and cannulated from right common carotid artery to left femoral vein to establish the bypass of extracorporeal circulation. Then the rats were randomly divided into ECC group and sham group. The rats in ECC group were subjected to extracorporeal circulation for 2 hours and then rest for 2 hours, while the rats in sham group were only observed for 4 hours without extracorporeal circulation. After that, blood routine examination, blood gas analysis, the measurement of pro-inflammatory factors in bronchoalveolar lavage fluid and lung tissue were performed to evaluate the lung injury induced by ECC. Circulating endothelial cells were also calculated by flow cytometry to assess the vascular endothelial injury. At 2 hours after ECC, red blood cell counts in both groups kept normal, while leukocyte and neutrophil counts, plasmatic tumor necrosis factor-a level and neutrophil elastase level, circulating endothelial cells in the rats of ECC group were significantly higher than those in sham group. Tumor necrosis factor-alpha in bronchoalveolar lavage fluid and water content in lung of the ECC rats were also significantly higher, while the oxygenation index was significantly lower. Neutrophil infiltration was also observed in lung tissues with increased thickness of alveolar membrane in ECC group. The ECC model established from right common carotid artery to left femoral vein in our study can successfully induce systemic inflammatory response, and acute lung injury associated with inflammation.

EFFECTS OF BROMODICHLOROMETHANE ON EX VIVO AND IN VITRO LUTEAL FUNCTION AND BROMODICHLOROMETHANE TISSUE DOSIMETRY IN THE PREGNANT F344 RAT

EPA Science Inventory

Bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss, i.e. full-litter resorption, in F344 rats when treated during the luteinizing hormone (LH)-dependent period. This effect is associated with reduced maternal serum progesterone (P) and LH...

NTP Toxicology and Carcinogenesis Studies of l-Epinephrine Hydrochloride (CAS No. 55-31-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

PubMed

1990-03-01

l-Epinephrine, an endogenous neurotransmitter hormone, is widely used for the treatment of allergic and respiratory disorders. NTP Toxicology and Carcinogenesis studies of epinephrine hydrochloride were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to an aerosol containing epinephrine hydrochloride for 14 days, 13 weeks, 15 months, or 2 years. During the 14-day and 13-week studies, control animals were exposed to dilute aerosols of hydrochloric acid (pH 2.8), whereas during the 15-month and 2-year studies, controls were exposed to aerosols of water. Genetic toxicology studies of epinephrine were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Rats and mice were exposed to 0 or 12.5-200 mg/m3 epinephrine hydrochloride. Deaths occurred in male rats exposed to 12.5 mg/m3 or more and in females exposed to 25 mg/m3 or more. Deaths of mice occurred at concentrations of 50 mg/m3 or higher. Compound-related clinical signs included an increased respiratory rate in all groups of epinephrine-exposed rats and mice. At higher concentrations (100 and 200 mg/m3), excessive lacrimation and dyspnea in rats and exaggerated visual and auditory reflexes in mice were observed. Thirteen-Week Studies: Rats and mice were exposed to 0 or 2.5-40 mg/m3 epinephrine hydrochloride. Deaths in rats and mice were not concentration related. Final mean body weights of chemically exposed and hydrochloric acid aerosol control rats and mice were generally similar. Increased respiratory rates were noted in rats and mice exposed to 40 mg/m3. Heart and adrenal gland weights of rats and mice and liver weights of mice exposed to 40 mg/m3 were greater than those of aerosol controls. Squamous metaplasia occurred in the respiratory epithelium of the nasal mucosa of rats and mice exposed to 40 mg/m3. Degenerative lesions of the laryngeal muscle were seen in male and female rats exposed to 20 or 40 mg/m3. Inflammation in the glandular

Effect of neomycin on azoxymethane-induced colon carcinogenesis in F344 rats.

PubMed

Reddy, B S; Furuya, K; Lowenfels, A

1984-07-01

The effect of oral administration of neomycin (100 and 200 micrograms/ml in drinking water) on colon tumors induced by azoxymethane [(AOM); CAS: 25843-45-2] was studied in female F344 rats. Five-week-old rats were fed NIH-07 diet and given daily in drinking water 0, 100, and 200 micrograms neomycin/ml (0, 100, and 200 ppm). At 7 weeks of age, all animals except vehicle-treated groups received weekly sc injections of 8 mg AOM/kg body weight for 8 weeks. The AOM- or vehicle-treated groups were necropsied 30 weeks after the last injection of AOM. The combined incidence of adenomas and adenocarcinomas of the colon did not differ significantly among the 3 groups. The animals in the groups given 100 and 200 micrograms neomycin had a higher incidence of colon adenocarcinomas than did those in the control group. Colonic and cecal bacterial beta-glucuronidase activity was significantly lower in the group given 200 micrograms neomycin than it was in the control group. The excretion of fecal cholesterol, total bile acids, and deoxycholic acid was increased significantly in animals given 100 and 200 micrograms neomycin as compared to animals given no neomycin. These results suggest that long-term oral administration of neomycin increases the incidence of colon adenocarcinomas.

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.

The Characterization of Obese Polycystic Ovary Syndrome Rat Model Suitable for Exercise Intervention

PubMed Central

Qiu, Shuwei; Jiang, Zhongli

2014-01-01

Objective To develop a new polycystic ovary syndrome (PCOS) rat model suitable for exercise intervention. Method 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. Results 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. Conclusion 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. PMID:24905232

Large enhancement of perfusion contribution on fMRI signal

PubMed Central

Wang, Xiao; Zhu, Xiao-Hong; Zhang, Yi; Chen, Wei

2012-01-01

The perfusion contribution to the total functional magnetic resonance imaging (fMRI) signal was investigated using a rat model with mild hypercapnia at 9.4 T, and human subjects with visual stimulation at 4 T. It was found that the total fMRI signal change could be approximated as a linear superposition of ‘true' blood oxygenation level-dependent (BOLD; T2/T2*) effect and the blood flow-related (T1) effect. The latter effect was significantly enhanced by using short repetition time and large radiofrequency pulse flip angle and became comparable to the ‘true' BOLD signal in response to a mild hypercapnia in the rat brain, resulting in an improved contrast-to-noise ratio (CNR). Bipolar diffusion gradients suppressed the intravascular signals but had no significant effect on the flow-related signal. Similar results of enhanced fMRI signal were observed in the human study. The overall results suggest that the observed flow-related signal enhancement is likely originated from perfusion, and this enhancement can improve CNR and the spatial specificity for mapping brain activity and physiology changes. The nature of mixed BOLD and perfusion-related contributions in the total fMRI signal also has implication on BOLD quantification, in particular, the BOLD calibration model commonly used to estimate the change of cerebral metabolic rate of oxygen. PMID:22395206

Gestational exposure to hydroxyprogesterone caproate suppresses reproductive potential in male rats

NASA Astrophysics Data System (ADS)

Pushpalatha, T.; Reddy, P. Ramachandra; Reddy, P. Sreenivasula

2005-08-01

Hydroxyprogesterone caproate was administered to pregnant rats at a dose level of 10 and 25 mg/kg body weight on 1st, 7th and 14th gestational day and the male pups (F1 generation) were allowed to grow for 90 days. The effect of gestational exposure to hydroxyprogesterone caproate on fertility was assessed by breeding F1 male rats with control female rats besides analyzing sperm quality and quantity in F1 male rats. The number of implantation sites and viable fetuses was significantly reduced in females mated with F1 males that were exposed to hydroxyprogesterone caproate during embryonic development. The decrease in sperm function was associated with a decrease in sperm motility, sperm viability and sperm count in F1 rats. The study clearly indicates that in utero exposure to hydroxyprogesterone caproate affects fertility in male rats.

A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric Aβ and frank neuronal loss

PubMed Central

Cohen, Robert M.; Rezai-Zadeh, Kavon; Weitz, Tara M.; Rentsendorj, Altan; Gate, David; Spivak, Inna; Bholat, Yasmin; Vasilevko, Vitaly; Glabe, Charles G.; Breunig, Joshua J.; Rakic, Pasko; Davtyan, Hayk; Agadjanyan, Michael G.; Kepe, Vladimir; Barrio, Jorge; Bannykh, Serguei; Szekely, Christine A.; Pechnick, Robert N.; Town, Terrence

2013-01-01

Alzheimer’s disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The ‘amyloid cascade hypothesis’ posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research. PMID:23575824

Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model

PubMed Central

Yaacob, Nik Soriani; Yankuzo, Hassan Muhammad; Devaraj, Sutha; Wong, Jimmy Ka Ming; Lai, Choon-Sheen

2015-01-01

Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3) using N-methyl-N-Nitrosourea (NMU)-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, β-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3. PMID:26000968

Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model.

PubMed

Yaacob, Nik Soriani; Yankuzo, Hassan Muhammad; Devaraj, Sutha; Wong, Jimmy Ka Ming; Lai, Choon-Sheen

2015-01-01

Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3) using N-methyl-N-Nitrosourea (NMU)-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, β-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3.

Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress.

PubMed