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Sample records for chronic uremic rats

  1. Emodin via colonic irrigation modulates gut microbiota and reduces uremic toxins in rats with chronic kidney disease.

    PubMed

    Zeng, Yu-Qun; Dai, Zhenhua; Lu, Fuhua; Lu, Zhaoyu; Liu, Xusheng; Chen, Cha; Qu, Pinghua; Li, Dingcheng; Hua, Zhengshuang; Qu, Yanni; Zou, Chuan

    2016-04-05

    Gut microbiota plays a dual role in chronic kidney disease (CKD) and is closely linked to production of uremic toxins. Strategies of reducing uremic toxins by targeting gut microbiota are emerging. It is known that Chinese medicine rhubarb enema can reduce uremic toxins and improve renal function. However, it remains unknown which ingredient or mechanism mediates its effect. Here we utilized a rat CKD model of 5/6 nephrectomy to evaluate the effect of emodin, a main ingredient of rhubarb, on gut microbiota and uremic toxins in CKD. Emodin was administered via colonic irrigation at 5ml (1mg/day) for four weeks. We found that emodin via colonic irrigation (ECI) altered levels of two important uremic toxins, urea and indoxyl sulfate (IS), and changed gut microbiota in rats with CKD. ECI remarkably reduced urea and IS and improved renal function. Pyrosequencing and Real-Time qPCR analyses revealed that ECI resumed the microbial balance from an abnormal status in CKD. We also demonstrated that ten genera were positively correlated with Urea while four genera exhibited the negative correlation. Moreover, three genera were positively correlated with IS. Therefore, emodin altered the gut microbiota structure. It reduced the number of harmful bacteria, such as Clostridium spp. that is positively correlated with both urea and IS, but augmented the number of beneficial bacteria, including Lactobacillus spp. that is negatively correlated with urea. Thus, changes in gut microbiota induced by emodin via colonic irrigation are closely associated with reduction in uremic toxins and mitigation of renal injury.

  2. Emodin via colonic irrigation modulates gut microbiota and reduces uremic toxins in rats with chronic kidney disease

    PubMed Central

    Lu, Fuhua; Lu, Zhaoyu; Liu, Xusheng; Chen, Cha; Qu, Pinghua; Li, Dingcheng; Hua, Zhengshuang; Qu, Yanni; Zou, Chuan

    2016-01-01

    Gut microbiota plays a dual role in chronic kidney disease (CKD) and is closely linked to production of uremic toxins. Strategies of reducing uremic toxins by targeting gut microbiota are emerging. It is known that Chinese medicine rhubarb enema can reduce uremic toxins and improve renal function. However, it remains unknown which ingredient or mechanism mediates its effect. Here we utilized a rat CKD model of 5/6 nephrectomy to evaluate the effect of emodin, a main ingredient of rhubarb, on gut microbiota and uremic toxins in CKD. Emodin was administered via colonic irrigation at 5ml (1mg/day) for four weeks. We found that emodin via colonic irrigation (ECI) altered levels of two important uremic toxins, urea and indoxyl sulfate (IS), and changed gut microbiota in rats with CKD. ECI remarkably reduced urea and IS and improved renal function. Pyrosequencing and Real-Time qPCR analyses revealed that ECI resumed the microbial balance from an abnormal status in CKD. We also demonstrated that ten genera were positively correlated with Urea while four genera exhibited the negative correlation. Moreover, three genera were positively correlated with IS. Therefore, emodin altered the gut microbiota structure. It reduced the number of harmful bacteria, such as Clostridium spp. that is positively correlated with both urea and IS, but augmented the number of beneficial bacteria, including Lactobacillus spp. that is negatively correlated with urea. Thus, changes in gut microbiota induced by emodin via colonic irrigation are closely associated with reduction in uremic toxins and mitigation of renal injury. PMID:27003359

  3. Insulin resistance in uremia. Characterization of lipid metabolism in freshly isolated and primary cultures of hepatocytes from chronic uremic rats.

    PubMed Central

    Caro, J F; Lanza-Jacoby, S

    1983-01-01

    We have studied the mechanism(s) of hyperlipidemia and liver insulin sensitivity in a rat model of severe chronic uremia (U). Basal lipid synthesis was decreased in freshly isolated hepatocytes from U when compared with sham-operated ad lib.-fed controls (alfC). Basal lipid synthesis in pair-fed controls (pfC) was in between U and alfC. Similarly, the activity of liver acetyl CoA carboxylase, fatty acid synthetase, citrate cleavage enzyme, malate dehydrogenase, and glucose-6-phosphate dehydrogenase was diminished in U. Muscle and adipose tissue lipoprotein lipase was also decreased. Insulin stimulated lipid synthesis in freshly isolated hepatocytes from alfC. Hepatocytes from U and pfC were resistant to this effect of insulin. To ascertain if the insulin resistance in U was due to starvation (chow intake 50% of alfC) or to uremia itself, the U and pfC were intragastrically fed an isocaloric diet via a Holter pump the last week of the experimental period. Hepatocytes from orally fed U and pfC were also cultured for 24 h in serum-free medium. While freshly isolated and cultured U hepatocytes remained insulin resistant, those from pfC normalized, in vivo and in vitro, when they were provided with enough nutrients. Conclusions: (a) Hyperlipidemia in uremia is not due to increased synthesis, but to defect(s) in clearance. (b) Insulin does not stimulate lipid synthesis in uremia. This finding, along with our recent demonstration that insulin binding and internalization are not decreased in the uremic liver, suggests that a post-binding defect(s) in the liver plays an important role in the mechanism(s) of insulin resistance in uremia. (c) Cultured hepatocytes from uremic rats remain insulin resistant. This quality renders these cells useful in studying the postinsulin binding events responsible for the insulin-resistant state in the absence of complicating hormonal and substrate changes that occur in vivo. PMID:6350367

  4. Uremic pleuritis in chronic hemodialysis patients.

    PubMed

    Rashid-Farokhi, Farin; Pourdowlat, Guitti; Nikoonia, Mohammad-Reza; Behzadnia, Neda; Kahkouee, Shahram; Nassiri, Amir-Ahmad; Masjedi, Mohammad-Reza

    2013-01-01

    Chronic hemodialysis (HD) patients are predisposed to several complications associated with pleural effusion. In addition, uremia can directly cause pleuritis. However, there are inadequate data about pathogenesis and natural course of uremic pleuritis. In this study, 76 chronic HD patients with pleural effusion admitted to the Respiratory Center of Masih Daneshvari Hospital, in Tehran, Iran between June 2005 and May 2011 were evaluated to figure out the etiology of their pleural disease. Among these patients, patients with uremic pleuritis were identified and studied. The rate of uremic pleuritis was 23.7%. Other frequent etiologies of pleural effusion were parapneumonic effusion (23.7%), cardiac failure (19.7%), tuberculosis (6.6%), volume overload, malignancy, and unknown. In patients with uremic pleuritis, dyspnea was the most common symptom, followed by cough, weight loss, anorexia, chest pain, and fever. Compared to patients with parapneumonic effusion, patients with uremic effusion had a significantly higher rate of dyspnea and lower rate of cough and fever. Pleural fluid analysis showed that these patients had a significantly lower pleural to serum lactic dehydrogenase ratio, total pleural leukocytes, and polymorphonuclear count compared to patients with parapneumonic effusion. Improvement was achieved in 94.1% of patients with uremic pleuritis by continuation of HD, chest tube insertion or pleural decortication; an outcome better than the previous reports. Despite the association with an exudative effusion, inflammatory pleural reactions in patients with uremic pleuritis may not be as severe as infection-induced effusions. Owing to the advancement in HD technology and other interventions, outcome of uremic pleuritis may be improved.

  5. Acid-Base Balance in Uremic Rats with Vascular Calcification

    PubMed Central

    Peralta-Ramírez, Alan; Raya, Ana Isabel; Pineda, Carmen; Rodríguez, Mariano; Aguilera-Tejero, Escolástico; López, Ignacio

    2014-01-01

    Background/Aims Vascular calcification (VC), a major complication in humans and animals with chronic kidney disease (CKD), is influenced by changes in acid-base balance. The purpose of this study was to describe the acid-base balance in uremic rats with VC and to correlate the parameters that define acid-base equilibrium with VC. Methods Twenty-two rats with CKD induced by 5/6 nephrectomy (5/6 Nx) and 10 nonuremic control rats were studied. Results The 5/6 Nx rats showed extensive VC as evidenced by a high aortic calcium (9.2 ± 1.7 mg/g of tissue) and phosphorus (20.6 ± 4.9 mg/g of tissue) content. Uremic rats had an increased pH level (7.57 ± 0.03) as a consequence of both respiratory (PaCO2 = 28.4 ± 2.1 mm Hg) and, to a lesser degree, metabolic (base excess = 4.1 ± 1 mmol/l) derangements. A high positive correlation between both anion gap (AG) and strong ion difference (SID) with aortic calcium (AG: r = 0.604, p = 0.02; SID: r = 0.647, p = 0.01) and with aortic phosphorus (AG: r = 0.684, p = 0.007; SID: r = 0.785, p = 0.01) was detected. Conclusions In an experimental model of uremic rats, VC showed high positive correlation with AG and SID. PMID:25177336

  6. Resistant starch alters gut microbiota and reduces uremic retention solutes in rats with adenine-induced chronic kidney disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic kidney disease (CKD) is characterized by the reduced ability to void urine, leading to accumulation of waste products in the body. Recently, it has been observed that patients with CKD have an altered gut microbiome. This may in part be due to reduced fiber intake. Patients with CKD are ofte...

  7. High-phosphorus diet maximizes and low-dose calcitriol attenuates skeletal muscle changes in long-term uremic rats.

    PubMed

    Acevedo, Luz M; López, Ignacio; Peralta-Ramírez, Alan; Pineda, Carmen; Chamizo, Verónica E; Rodríguez, Mariano; Aguilera-Tejero, Escolástico; Rivero, José-Luis L

    2016-05-01

    Although disorders of mineral metabolism and skeletal muscle are common in chronic kidney disease (CKD), their potential relationship remains unexplored. Elevations in plasma phosphate, parathyroid hormone, and fibroblastic growth factor 23 together with decreased calcitriol levels are common features of CKD. High-phosphate intake is a major contributor to progression of CKD. This study was primarily aimed to determine the influence of high-phosphate intake on muscle and to investigate whether calcitriol supplementation counteracts negative skeletal muscle changes associated with long-term uremia. Proportions and metabolic and morphological features of myosin-based muscle fiber types were assessed in the slow-twitch soleus and the fast-twitch tibialis cranialis muscles of uremic rats (5/6 nephrectomy, Nx) and compared with sham-operated (So) controls. Three groups of Nx rats received either a standard diet (0.6% phosphorus, Nx-Sd), or a high-phosphorus diet (0.9% phosphorus, Nx-Pho), or a high-phosphorus diet plus calcitriol (10 ng/kg 3 day/wk ip, Nx-Pho + Cal) for 12 wk. Two groups of So rats received either a standard diet or a high-phosphorus diet (So-Pho) over the same period. A multivariate analysis encompassing all fiber-type characteristics indicated that Nx-Pho + Cal rats displayed skeletal muscle phenotypes intermediate between Nx-Pho and So-Pho rats and that uremia-induced skeletal muscle changes were of greater magnitude in Nx-Pho than in Nx-Sd rats. In uremic rats, treatment with calcitriol preserved fiber-type composition, cross-sectional size, myonuclear domain size, oxidative capacity, and capillarity of muscle fibers. These data demonstrate that a high-phosphorus diet potentiates and low-dose calcitriol attenuates adverse skeletal muscle changes in long-term uremic rats.

  8. Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease

    PubMed Central

    Sato, Emiko; Mori, Takefumi; Mishima, Eikan; Suzuki, Arisa; Sugawara, Sanae; Kurasawa, Naho; Saigusa, Daisuke; Miura, Daisuke; Morikawa-Ichinose, Tomomi; Saito, Ritsumi; Oba-Yabana, Ikuko; Oe, Yuji; Kisu, Kiyomi; Naganuma, Eri; Koizumi, Kenji; Mokudai, Takayuki; Niwano, Yoshimi; Kudo, Tai; Suzuki, Chitose; Takahashi, Nobuyuki; Sato, Hiroshi; Abe, Takaaki; Niwa, Toshimitsu; Ito, Sadayoshi

    2016-01-01

    Sarcopenia is associated with increased morbidity and mortality in chronic kidney disease (CKD). Pathogenic mechanism of skeletal muscle loss in CKD, which is defined as uremic sarcopenia, remains unclear. We found that causative pathological mechanism of uremic sarcopenia is metabolic alterations by uremic toxin indoxyl sulfate. Imaging mass spectrometry revealed indoxyl sulfate accumulated in muscle tissue of a mouse model of CKD. Comprehensive metabolomics revealed that indoxyl sulfate induces metabolic alterations such as upregulation of glycolysis, including pentose phosphate pathway acceleration as antioxidative stress response, via nuclear factor (erythroid-2-related factor)-2. The altered metabolic flow to excess antioxidative response resulted in downregulation of TCA cycle and its effected mitochondrial dysfunction and ATP shortage in muscle cells. In clinical research, a significant inverse association between plasma indoxyl sulfate and skeletal muscle mass in CKD patients was observed. Our results indicate that indoxyl sulfate is a pathogenic factor for sarcopenia in CKD. PMID:27830716

  9. Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition

    PubMed Central

    wu, Min; Tang, Ri-ning; Liu, Hong; Pan, Ming-ming; Liu, Bi-cheng

    2016-01-01

    Aim: Experimental studies found that cinacalcet (CINA) markedly attenuated vascular calcification in uremic rats, but its underlying mechanisms are still largely unknown. Recent evidence have demonstrated that endothelial cells (ECs) participate in ectopic calcification in part by mediating endothelial-to-mesenchymal transition (EndMT). In this study, we investigated whether CINA ameliorated aortic calcification in uremic rats via suppression of EndMT. Methods: Uremia was induced in rats by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, the rats were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats were orally administered CINA (10mg/kg one day) for 12 weeks. The aortic expression of EndMT- and chondrocyte- markers was examined. The effect of elevated PTH on EndMT was also studied in aortic ECs. Results: In uremic rats, CINA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium (Ca), phosphorus (P) and Ca×P product. Besides, CINA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers (SOX9 and COL2A1) and chondrocyte proteoglycan in uremic aortas. Moreover, CINA treatment largely abolished the up-regulation of mesenchymal markers (FSP1 and α-SMA) and down-regulation of the endothelial marker (CD31), which accompanied aortic calcification in uremic aorta samples. In vitro, PTH increased the expression of EndMT-markers in a concentration- and time-dependent manner. Conclusion: These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT. PMID:27593220

  10. The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development.

    PubMed

    Briskey, David; Tucker, Patrick; Johnson, David W; Coombes, Jeff S

    2017-02-01

    It is well-established that uremic toxins are positively correlated with the risk of developing chronic kidney disease and cardiovascular disease. In addition, emerging data suggest that gut bacteria exert an influence over both the production of uremic toxins and the development of chronic kidney disease. As such, modifying the gut microbiota may have the potential as a treatment for chronic kidney disease. This is supported by data that suggest that rescuing microbiota dysbiosis may: reduce uremic toxin production; prevent toxins and pathogens from crossing the intestinal barrier; and, reduce gastrointestinal tract transit time allowing nutrients to reach the microbiota in the distal portion of the gastrointestinal tract. Despite emerging literature, the gut-kidney axis has yet to be fully explored. A special focus should be placed on examining clinically translatable strategies that might encourage improvements to the microbiome, thereby potentially reducing the risk of the development of chronic kidney disease. This review aims to present an overview of literature linking changes to the gastrointestinal tract with microbiota dysbiosis and the development and progression of chronic kidney disease.

  11. Attenuated glomerular arginine transport prevents hyperfiltration and induces HIF-1α in the pregnant uremic rat.

    PubMed

    Schwartz, Idit F; Grupper, Ayelet; Soetendorp, Hila; Hillel, Oren; Laron, Ido; Chernichovski, Tamara; Ingbir, Merav; Shtabski, Allexander; Weinstein, Talia; Chernin, Gil; Shashar, Moshe; Hershkoviz, Rami; Schwartz, Doron

    2012-08-01

    Pregnancy worsens renal function in females with chronic renal failure (CRF) through an unknown mechanism. Reduced nitric oxide (NO) generation induces renal injury. Arginine transport by cationic amino acid transporter-1 (CAT-1), which governs endothelial NO generation, is reduced in both renal failure and pregnancy. We hypothesize that attenuated maternal glomerular arginine transport promotes renal damage in CRF pregnant rats. In uremic rats, pregnancy induced a significant decrease in glomerular arginine transport and cGMP generation (a measure of NO production) compared with CRF or pregnancy alone and these effects were prevented by l-arginine. While CAT-1 abundance was unchanged in all experimental groups, protein kinase C (PKC)-α, phosphorylated PKC-α (CAT-1 inhibitor), and phosphorylated CAT-1 were significantly augmented in CRF, pregnant, and pregnant CRF animals; phenomena that were prevented by coadministrating l-arginine. α-Tocopherol (PKC inhibitor) significantly increased arginine transport in both pregnant and CRF pregnant rats, effects that were attenuated by ex vivo incubation of glomeruli with PMA (a PKC stimulant). Renal histology revealed no differences between all experimental groups. Inulin and p-aminohippurate clearances failed to augment and renal cortical expression of hypoxia inducible factor-1α (HIF-1α) significantly increased in CRF pregnant rat, findings that were prevented by arginine. These studies suggest that in CRF rats, pregnancy induces a profound decrease in glomerular arginine transport, through posttranslational regulation of CAT-1 by PKC-α, resulting in attenuated NO generation. These events provoke renal damage manifested by upregulation of renal HIF-1α and loss of the ability to increase glomerular filtration rate during gestation.

  12. Phosphate binders prevent phosphate-induced cellular senescence of vascular smooth muscle cells and vascular calcification in a modified, adenine-based uremic rat model.

    PubMed

    Yamada, S; Tatsumoto, N; Tokumoto, M; Noguchi, H; Ooboshi, H; Kitazono, T; Tsuruya, K

    2015-04-01

    Clinical and experimental studies have reported that phosphate overload plays a central role in the pathogenesis of vascular calcification in chronic kidney disease. However, it remains undetermined whether phosphate induces cellular senescence during vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3% adenine that showed more slowly progressive kidney failure, more robust vascular calcification, and longer survival than the conventional model (0.75% adenine). To determine the effect of phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified adenine-based diet (CKD); (3) CKD rats treated with 6% lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6% calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased protein expression of senescence-associated β-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders. However, serum levels of oxidative stress and inflammatory markers, serum fibroblast growth factor 23, and aortic calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion, phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and phosphate binders can prevent both cellular senescence and calcification of VSMCs via phosphate unloading. Our modified adenine-based uremic rat model is useful for evaluating uremia-related complications, including vascular calcification.

  13. Hydropic degeneration of the anterior pituitary gland (adenohypophysis) in uremic rats.

    PubMed

    Levine, Seymour; Saltzman, Arthur

    2004-03-01

    We observed hydropic degeneration of the anterior pituitary in rats made uremic by nephrotoxic chemicals, especially when the uremic rats were given a pure carbohydrate diet beforehand. The hydropic degeneration caused loss of nuclear and cytoplasmic content of many or most anterior pituitary cells. It was readily visible in paraffin sections by light microscopy. It was exaggerated when water was injected after the nephrotoxin and it was greatly reduced if saline was injected after the nephrotoxin. Low serum sodium levels in affected rats and the response to saline injection suggested that the mechanism for development of hydropic degeneration of the anterior pituitary gland involved hyponatremia. Depletion of total body sodium probably accounts for the enhancement of hydropic degeneration by the pure carbohydrate diet. Morphologic lesions of the anterior pituitary related to hyponatremia and uremia have not been described previously.

  14. Protein-bound uremic toxins: new culprits of cardiovascular events in chronic kidney disease patients.

    PubMed

    Ito, Shunsuke; Yoshida, Masayuki

    2014-02-20

    Chronic kidney disease (CKD) has been considered a major risk factor for cardiovascular diseases. Although great advances have recently been made in the pathophysiology and treatment of cardiovascular diseases, CKD remains a major global health problem. Moreover, the occurrence rates of cardiovascular events among CKD patients increase even in cases in which patients undergo hemodialysis, and the mechanisms underlying the so-called "cardiorenal syndrome" are not clearly understood. Recently, small-molecule uremic toxins have been associated with cardiovascular mortality in CKD and/or dialysis patients. These toxins range from small uncharged solutes to large protein-bound structures. In this review, we focused on protein-bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which are poorly removed by current dialysis techniques. Several studies have demonstrated that protein-bound uremic toxins, especially indoxyl sulfate, induce vascular inflammation, endothelial dysfunction, and vascular calcification, which may explain the relatively poor prognosis of CKD and dialysis patients. The aim of this review is to provide novel insights into the effects of indoxyl sulfate and p-cresyl sulfate on the pathogenesis of atherosclerosis.

  15. 17beta-estradiol corrects hemostasis in uremic rats by limiting vascular expression of nitric oxide synthases.

    PubMed

    Noris, M; Todeschini, M; Zappella, S; Bonazzola, S; Zoja, C; Corna, D; Gaspari, F; Marchetti, G; Aiello, S; Remuzzi, G; Marchetti, F

    2000-10-01

    Conjugated estrogens shorten the prolonged bleeding time in uremic patients and are similarly effective in a rat model of uremia. We have previously demonstrated that the shortening effect of a conjugated estrogen mixture or 17beta-estradiol on bleeding time was abolished by the nitric oxide (NO) precursor L-arginine, suggesting that the effect of these drugs on hemostasis in uremia might be mediated by changes in the NO synthetic pathway. The present study investigated the biochemical mechanism(s) by which conjugated estrogens limit the excessive formation of NO. 17beta-estradiol (0.6 mg/kg), given to rats made uremic by reduction of renal mass, significantly reduced bleeding time within 24 h and completely normalized plasma concentrations of the NO metabolites, nitrites and nitrates, and of NO synthase (NOS) catalytic activity, determined by NADPH-diaphorase staining in the thoracic aorta. Endothelial NOS (ecNOS) and inducible NOS (iNOS) immunoperoxidase staining in the endothelium of uremic aortas of untreated rats was significantly more intense than in control rats, while in uremic rats receiving 17beta-estradiol staining was comparable to controls. Thus 17beta-estradiol corrected the prolonged bleeding time of uremic rats and fully normalized the formation of NO by reducing the expression of ecNOS and iNOS in vascular endothelium. These results provide a possible biochemical explanation of the well-known effect of estrogens on primary hemostasis in uremia, in experimental animals and humans.

  16. Uremic pruritus.

    PubMed

    Robertson, K E; Mueller, B A

    1996-09-15

    Uremic pruritus and its treatment are reviewed. Pruritus affects 50-90% of patients undergoing peritoneal dialysis or hemodialysis; symptoms usually begin about six months after the start of dialysis and range from localized and mild to generalized and severe. The mechanism underlying uremic pruritus is poorly understood; possibilities include secondary hyperparathyroidism and divalent-ion abnormalities; histamine, allergic sensitization, and proliferation of skin mast cells; hypervitaminosis A; iron-deficiency anemia; neuropathy and neurologic changes; or some combination of these. The cornerstone of therapy for uremic pruritus is regular, intensive, efficient dialysis. Other nonpharmacologic measures consist of the use of non-complement-activating dialysis membranes, compliance with dietary restrictions, electric-needle (acupuncture) therapy, and ultraviolet light therapy. Pharmacologic treatments that have been used include activated charcoal, antihistamines, capsaicin, cholestyramine, emollients and topical corticosteroids, epoetin, pizotyline, ketotifen, and nicergoline. Treatment results have been highly variable, and many of the clinical trials have been flawed. Phosphate-binding agents appear to be the most effective. Although enough is known to determine a reasonable set of steps in approaching a patient's uremic pruritus, more research is needed to understand the pathophysiology of this condition and to establish more reliable treatments. Pruritus is a common and sometimes severe complication of chronic renal failure. Efficient dialysis, dietary restrictions, phosphate-binding therapy, and phototherapy are the most effective treatments currently available.

  17. [Uremic pruritus].

    PubMed

    Corić-Martinović, Valentina; Basić-Jukić, Nikolina

    2008-01-01

    Uremic pruritus is a common and sometimes severe complication of chronic renal failure. Itch affects 50-90% of patients undergoing peritoneal dialysis or hemodialysis and 25% of patients with preterminal chronic renal failure. The mechanism underlying uremic pruritus is poorly understood; possibilities include histamin, proteases, interleukin-2 and TNF- produced by skin mast-cells, substance P, neuropathy and neurological changes, high level of Ca, P, PTH, Al, Mg, divalent ion abnormalities, hypervitaminosis A, inflammation, or some combination of these. Therapeutic measures include regular efficient dialysis, transplantation, topical measures as an emollients, topical steroids, systemic measures as diet, opioids and physical treatment with phototherapy, acupuncture etc. Treatment results are highly variable and more research is needed to understand the patophysiology of this condition and to establish more reliable treatments. Most effective treatments in this moment are efficient dialysis, dietary restrictions, phosphate-binding therapy and phototherapy.

  18. Effect of 2'-phosphophloretin on renal function in chronic renal failure rats.

    PubMed

    Peerce, B E; Weaver, L; Clarke, R D

    2004-07-01

    Hyperhosphatemia and secondary hyperparathyroidism are common and severe complications of chronic renal failure. Therapies to reduce serum phosphate have been shown to reduce serum parathyroid hormone (PTH) and slow the progression of renal failure. The effect of the inhibitor of intestinal phosphate absorption, 2'-phosphophloretin (2'-PP), on serum and urine chemistry, renal histology, and cardiac structure in the uremic rat model of renal failure, 5/6 nephrectomy (5/6 NX), was examined. The effect of 2'-PP on serum phosphate, serum PTH, serum total Ca(2+), and ionized Ca(2+), Ca(2+) x P(i) product, urine protein, urine osmolality, and creatinine clearance in 5/6 NX rats was examined. Uremic rats in chronic renal failure were gavaged daily with 25 microM 2'-PP. Over the course of a 5-wk experiment, serum chemistry in untreated uremic rats, 2'-PP-treated uremic rats, and age-matched control rats with normal renal function was determined twice a week. Urine creatinine, urine osmolality, urine phosphate, and urine protein were determined once a week from 24-h collections. 2'-PP reduced serum phosphate 40 +/- 3% compared with a 17% increase in untreated uremic control rats. 2'-PP did not alter total serum Ca(2+). During 5-wk experiments, serum PTH increased 65 +/- 25% in untreated uremic rats and decreased 70 +/- 7% in uremic rats treated with 25 microM 2'-PP. Creatinine clearance decreased 20% in untreated uremic rats compared with a 100% increase in 2'-PP-treated uremic rats. Urine protein decreased and urine osmolality increased in uremic rats treated with 2'-PP. The mechanism of the effect of 2'-PP on serum phosphate was inhibition of intestinal phosphate absorption. 2-PP inhibited intestinal phosphate absorption 50% without altering dietary protein absorption or intestinal Ca(2+) absorption. Over the course of the 5-wk treatment with 2'-PP, uremic animals treated with 2'-PP had a 2-4% weight gain/wk, similar to the weight gain seen in age-matched control rats

  19. Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins

    PubMed Central

    Florens, Nans; Calzada, Catherine; Lyasko, Egor; Juillard, Laurent; Soulage, Christophe O.

    2016-01-01

    Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity. PMID:27999257

  20. Leptin as an uremic toxin: Deleterious role of leptin in chronic kidney disease.

    PubMed

    Alix, Pascaline M; Guebre-Egziabher, Fitsum; Soulage, Christophe O

    2014-10-01

    White adipose tissue secretes a large variety of compounds named adipokines amongst which, leptin exhibits pleiotropic metabolic actions. Leptin is an anorexigenic hormone, secreted in proportion of fat mass, with additional effects on the regulation of inflammation, cardiovascular system, immunity, hematopoiesis and bone metabolism. Chronic kidney disease (CKD) is characterized by an increase of plasma leptin concentration that may be explained by a lack of renal clearance. Hyperleptinemia plays a key role in the pathogenesis of complications associated with CKD such as cachexia, protein energy wasting, chronic inflammation, insulin resistance, cardiovascular damages and bone complications. Leptin is also involved in the progression of renal disease through its pro-fibrotic and pro-hypertensive actions. Most of the adverse effects of leptin have been documented both experimentally and clinically. Leptin may therefore be considered as an uremic toxin in CKD. The aim of this review is to summarize the pathophysiological and clinical role of leptin in in vitro studies, experimental models, as well as in patients suffering from CKD.

  1. Attenuation of uremia by orally feeding alpha-lipoic acid on acetaminophen induced uremic rats.

    PubMed

    Pradhan, Shrabani; Mandal, Shreya; Roy, Suchismita; Mandal, Arpita; Das, Koushik; Nandi, Dilip K

    2013-04-01

    Uremia means excess nitrogenous waste products in the blood & their toxic effects. An acute acetaminophen (paracetamol, N-acetyl p-aminophenol; APAP) overdose may result into potentially fatal hepatic and renal necrosis in humans and experimental animals. The aims of this present study were to investigate the protective effect of alpha-lipoic acid (ALA) on oxidative stress & uremia on male albino rats induced by acetaminophen. The study was performed by 24 albino male Wister strain rats which were randomly divided into four groups: Group I, control - receives normal food and water, Groups II, III & IV receive acetaminophen interperitoneally at the dose of 500 mg/kg/day for 10 days, from 11th day Groups III & IV were treated with ALA at the dose of 5 mg & 10 mg/100 g/day for 15 days, respectively. After 25 days of treatment, it was observed that there was a significant increase in plasma urea, creatinine, sodium and malondialdehyde (MDA) levels (p < 0.05) but a significant decrease in super oxide dismutase (SOD) & catalase activity & potassium level in uremic group is compared with control group & there was a significant increase in SOD & catalase (p < 0.05) & a significant decrease in serum urea, creatinine & Na and MDA (p < 0.05) in Group III & Group IV is compared with Group II & significant changes were observed in high ALA dose group. In conclusion it was observed that the ALA has nephroprotective activities by biochemical observations against acetaminophen induced uremic rats.

  2. Uremic Solutes in Chronic Kidney Disease and Their Role in Progression

    PubMed Central

    van den Brand, Jan A. J. G.; Mutsaers, Henricus A. M.; van Zuilen, Arjan D.; Blankestijn, Peter J.; van den Broek, Petra H.; Russel, Frans G. M.; Masereeuw, Rosalinde; Wetzels, Jack F. M.

    2016-01-01

    Background To date, over 150 possible uremic solutes have been listed, but their role in the progression of CKD is largely unknown. Here, the association between a selected panel of uremic solutes and progression in CKD patients was investigated. Methods Patients from the MASTERPLAN study, a randomized controlled trial in CKD patients with a creatinine clearance between 20 and 70 ml/min per 1.73m2, were selected based on their rate of eGFR decline during the first five years of follow-up. They were categorized as rapid (decline >5 ml/min per year) or slow progressors. Concentrations of eleven uremic solutes were obtained at baseline and after one year of follow-up. Logistic regression was used to compare the odds for rapid to slow progression by uremic solute concentrations at baseline. Variability in uremic solute levels was assessed using scatter plots, and limits of variability were calculated. Results In total, 40 rapidly and 40 slowly progressing patients were included. Uremic solutes were elevated in all patients compared to reference values for healthy persons. The serum levels of uremic solutes were not associated with rapid progression. Moreover, we observed substantial variability in solute levels over time. Conclusions Elevated concentrations of uremic solutes measured in this study did not explain differences in rate of eGFR decline in CKD patients, possibly due to lack of power as a result of the small sample size, substantial between patient variability, and variability in solute concentrations over time. The etiology of intra-individual variation in uremic solute levels remains to be elucidated. PMID:28033375

  3. Atypical Hemolytic Uremic Syndrome and Chronic Ulcerative Colitis Treated with Eculizumab

    PubMed Central

    Webb, Tennille N.; Griffiths, Heidi; Miyashita, Yosuke; Bhatt, Riha; Jaffe, Ronald; Moritz, Michael; Hofer, Johannes; Swiatecka-Urban, Agnieszka

    2016-01-01

    Background Hemolytic-uremic syndrome (HUS) presents with hemolytic anemia, thrombocytopenia, and thrombotic microangiopathy of the kidney and usually results from Shiga-toxin induced activation of the alternative complement pathway. Gastroenteritis is a common feature of the Shiga-toxin producing Escherichia coli HUS, referred to as STEC-HUS. An inherited or acquired complement dysregulation may lead to HUS referred to as non-STEC or atypical (a)HUS. Although gastroenteritis is not a common presentation of aHUS, some patients develop ischemic colitis and may be misdiagnosed as acute appendicitis or acute ulcerative colitis (UC). Case Diagnosis –Treatment We present a patient with low circulating complement (C) 3 levels who developed aHUS in the course of chronic active UC. Resolution of renal and gastrointestinal manifestations in response to treatment with eculizumab, a humanized monoclonal antibody against terminal C5 protein suggests the role of alternative complement in the pathogenesis of both, aHUS and UC. Conclusion This case illustrates that dysregulation of the alternative complement pathway may manifest in other organs besides the kidney and that the circulating C3 levels do not correlate with the disease activity or the clinical response to eculizumab. PMID:27135055

  4. The Aryl Hydrocarbon Receptor-Activating Effect of Uremic Toxins from Tryptophan Metabolism: A New Concept to Understand Cardiovascular Complications of Chronic Kidney Disease

    PubMed Central

    Sallée, Marion; Dou, Laetitia; Cerini, Claire; Poitevin, Stéphane; Brunet, Philippe; Burtey, Stéphane

    2014-01-01

    Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a “dioxin-like” effect. PMID:24599232

  5. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease.

    PubMed

    Sallée, Marion; Dou, Laetitia; Cerini, Claire; Poitevin, Stéphane; Brunet, Philippe; Burtey, Stéphane

    2014-03-04

    Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a "dioxin-like" effect.

  6. "H" reflex as a measure of subclinical uremic polyneuropathy in children with chronic renal failure.

    PubMed

    Mendoza-Guevara, L; Cervantes, A; Aguilar-Kitsu, A; Rendon, E; Morales, A; Rodriguez, F; Castro, F; Flores, M; Jaramillo, R M; Garcia-Lopez, E

    1997-01-01

    Uremic polyneuropathy (UPNP) is a serious complication of chronic renal failure (CRF) in adults; however, its prevalence is unknown in the pediatric population. An easy-to-perform maneuver for its detection in children is the evaluation of "H" reflex. The objective of this study was to validate the usefulness of the "H" reflex maneuver for the diagnosis of UPNP in pediatric dialysis patients for CRF. Thirty-seven CRF patients were paired with healthy controls by age and sex. The patients were being treated with dialysis or one of its variants. Information was obtained regarding diagnosis, duration, and control of dialysis. Neurological examination was performed, conduction velocities in sensory and motor nerves were measured, and "H" reflex elicited bilaterally. Peripheral polyneuropathy was determined by the presence of at least two nerves with alterations in latency and/or conduction velocities. It was found that 59.4% (22/37) of the children with CRF treated with dialysis developed UPNP, 17 with ambulatory peritoneal dialysis, and 5 with hemodialysis. There was no difference in diagnosis, duration of dialysis, or control of the same in these patients from other CRF patients who did not have UPNP. All patients were clinically asymptomatic. "H" reflex showed a sensibility of 44%, a specificity of 87%, a predictive value positive of 66%, and a predictive value negative of 76%, when measured to 28 msec. With a 30 msec duration specificity rises to 95%. UPNP presents asymptomatically in pediatric patients. "H" reflex is an adequate screening test for the selection of pediatric patients to be tested further.

  7. Effects of chronic renal failure on wound healing in rats. II. Microscopic study and hydroxyproline assay.

    PubMed

    Shindo, K; Kosaki, G

    1982-01-01

    Incisional wounds of the abdominal skin, aponeurosis, stomach and colon were investigated microscopically for a comparison of the findings between uremic and normal rats. The grade of edema and number of inflammatory cells were increased in the rats with uremia and the granulation zone was also larger in the uremics. Hydroxyproline was assayed in the wound tissues by a modification of the technique of Stegemann and Stalder. The hydroxyproline level was lower in the uremics (p less than 0.05) only in the aponeurosis of the 5th postoperative day and in the colon of the 3.5th to 7th day. The correlation coefficient calculated for the blood urea level, biomechanical strength and hydroxyproline level was nil. If these results can validly be extrapolated to patients with chronic renal failure, careful management and avoidance of possible wound infections is of the greatest importance for surgical patients.

  8. Untargeted plasma and tissue metabolomics in rats with chronic kidney disease given AST-120

    PubMed Central

    Velenosi, Thomas J.; Hennop, Anzel; Feere, David A.; Tieu, Alvin; Kucey, Andrew S.; Kyriacou, Polydoros; McCuaig, Laura E.; Nevison, Stephanie E.; Kerr, Michael A.; Urquhart, Bradley L.

    2016-01-01

    Chronic kidney disease (CKD) results in the accumulation of metabolic waste products that are normally cleared by the kidney, known as uremia. Many of these waste products are from bacteria metabolites in the gut. Accumulation of uremic toxins in plasma and tissue, as well as the gut-plasma-tissue metabolic axis are important for understanding pathophysiological mechanisms of comorbidities in CKD. In this study, an untargeted metabolomics approach was used to determine uremic toxin accumulation in plasma, liver, heart and kidney tissue in rats with adenine-induced CKD. Rats with CKD were also given AST-120, a spherical carbon adsorbent, to assess metabolic changes in plasma and tissues with the removal of gut-derived uremic toxins. AST-120 decreased >55% of metabolites that were increased in plasma, liver and heart tissue of rats with CKD. CKD was primarily defined by 8 gut-derived uremic toxins, which were significantly increased in plasma and all tissues. These metabolites were derived from aromatic amino acids and soy protein including: indoxyl sulfate, p-cresyl sulfate, hippuric acid, phenyl sulfate, pyrocatechol sulfate, 4-ethylphenyl sulfate, p-cresol glucuronide and equol 7-glucuronide. Our results highlight the importance of diet and gut-derived metabolites in the accumulation of uremic toxins and define the gut-plasma-tissue metabolic axis in CKD. PMID:26932318

  9. Uremic pruritus.

    PubMed

    Mettang, Thomas; Kremer, Andreas E

    2015-04-01

    Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient's quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) μ-opioid receptor antagonists and κ-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as μ-opioid-receptor-antagonists (i.e., naltrexone) or κ-opioid-receptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on 'high urgency'-status, as successful kidney transplantation will relieve patients from CKD-aP.

  10. Biologic effects of 1,25-dihydroxycholecalciferol (a highly active vitamin D metabolite) in acutely uremic rats

    PubMed Central

    Wong, Richard G.; Norman, Anthony W.; Reddy, Chilumula R.; Coburn, Jack W.

    1972-01-01

    The development of a vitamin D-resistant state in the course of renal failure may be responsible for reduced intestinal absorption of calcium and an impaired response of skeletal tissue. Moreover, the kidney has been shown to carry out the conversion of 25-hydroxycholecalciferol (25-OH-CC) to a highly biologically active metabolite, 1,25-dihydroxycholecalciferol (1,25-diOH-CC). In the present studies, vitamin D-deficient rats, made acutely uremic by either bilateral nephrectomy or urethral ligation, received physiological doses of cholecalciferol (vitamin D3) (CC), 25-OH-CC or 1,25-diOH-CC; 24 hr later intestinal calcium transport, in vitro, and bone calcium mobilization, in vivo, were assessed. Whereas CC and 25-OH-CC stimulated calcium transport in sham-operated controls, they were without effect in the uremic animals. In contrast, administration of 1,25-diOH-CC stimulated calcium transport in both groups of uremic animals. Administration of 1,25-diOH-CC also stimulated calcium mobilization from bone in each group of animals. However, CC and 25-OH-CC were only effective in the sham controls and the uremic group produced by urethral ligation and had little or no effect in animals without kidneys. These results indicate that renal conversion of calciferol to a more biologically active form is necessary for the stimulation of intestinal calcium absorption and calcium mobilization from bone, and that 1,25-diOH-CC may bypass a possible defect in vitamin D metabolism in uremia. From these studies it is likely that uremia, per se, may also impair intestinal calcium transport. PMID:4341503

  11. Protein-energy wasting and uremic failure to thrive in children with chronic kidney disease: they are not small adults.

    PubMed

    Nourbakhsh, Noureddin; Rhee, Connie M; Kalantar-Zadeh, Kamyar

    2014-12-01

    Protein-energy wasting (PEW), a condition of decreased body protein and fat mass, is highly prevalent in patients with chronic kidney disease (CKD) and a potent predictor of mortality in this population. In adults with CKD, PEW has typically been defined on the basis of (1) deranged biochemical parameters, (2) reduced body mass, (3) reduced muscle mass, and (4) decreased dietary protein intake. Emerging data suggest that PEW may also commonly afflict children with CKD and have a negative impact on growth and development ("uremic failure to thrive"), yet it remains comparatively understudied and less well characterized in these patients. Given the challenges of applying adult-defined PEW criteria to the pediatric population, the authors of a recent study entitled "Protein energy wasting in children with chronic kidney disease" [Abraham et al. (2014) Pediatr Nephrol 29:1231-1238] have sought to develop a scoring system and three alterative definitions for this condition using a combination of biochemical markers, clinical measurements, and subjective reporting in children in the CKiD cohort: (1) minimal PEW definition (≥2 adult-defined PEW criteria); (2) standard PEW definition (≥3 adult-defined PEW criteria); (3) modified PEW definition (≥3 adult-defined PEW criteria, plus short stature or poor growth). These authors observed that meeting the modified PEW definition was associated with a significantly increased risk of hospitalization in unadjusted analyses, i.e., a 2.2-fold higher risk, and trended towards increased risk in multivariable adjusted analyses, i.e., 2.0-fold higher risk. At the present time, future studies validating these findings and developing further refined definitions and/or scoring systems for the detection and management of PEW in children and uremic failure to thrive are urgently needed.

  12. Utilization of alpha-ketoisocaproate for protein synthesis in uremic rats

    SciTech Connect

    Tungsanga, K.; Kang, C.W.; Walser, M.

    1986-12-01

    We have recently shown that the nutritional efficiency, R, of alpha-ketoisocaproate (KIC) as a substitute for leucine, defined as the ratio of the dose of leucine to the dose of KIC (on a leucine-free diet) for equal growth, can be evaluated isotopically: /sup 14/C-KIC and /sup 3/H-leucine are administered p.o.; six hours later, /sup 14/C//sup 3/H in the leucine of whole body protein, divided by /sup 14/C//sup 3/H in the injectate, gives a value distinguishable from R assessed in the same animals by growth experiments. To see how chronic uremia affects R, 11/12 nephrectomized rats and sham-operated controls were fed a regular diet for 15 days and then given these isotopes p.o. Six hours later, R, measured in whole body protein, and in the protein of brain, heart, muscle, salivary gland, liver, and the kidney remnant was significantly greater than in sham-operated controls. The greatest difference (39%) was seen in liver protein and the smallest difference (19%) in muscle. Thus, chronic uremia increases the efficiency, relative to leucine, with which KIC is utilized for protein synthesis in all of these organs and in the body as a whole. Possible explanations are discussed.

  13. Effect of water fluoridation on the development of medial vascular calcification in uremic rats.

    PubMed

    Martín-Pardillos, Ana; Sosa, Cecilia; Millán, Ángel; Sorribas, Víctor

    2014-04-06

    Public water fluoridation is a common policy for improving dental health. Fluoride replaces the hydroxyls of hydroxyapatite, thereby improving the strength of tooth enamel, but this process can also occur in other active calcifications. This paper studies the effects of water fluoridation during the course of vascular calcification in renal disease. The effect of fluoride was studied in vitro and in vivo. Rat aortic smooth muscle cells were calcified with 2mM Pi for 5 days. Fluoride concentrations of 5-10 μM--similar to those found in people who drink fluoridated water--partially prevented calcification, death, and osteogene expression in vitro. The anticalcifying mechanism was independent of cell activity, matrix Gla protein, and fetuin A expressions, and it exhibited an IC50 of 8.7 μM fluoride. In vivo, however, fluoridation of drinking water at 1.5mg/L (concentration recommended by the WHO) and 15 mg/L dramatically increased the incipient aortic calcification observed in rats with experimental chronic kidney disease (CKD, 5/6-nephrectomy), fed a Pi-rich fodder (1.2% Pi). Fluoride further declined the remaining renal function of the CKD animals, an effect that most likely overwhelmed the positive effect of fluoride on calcification in vitro. Ultrastructural analysis revealed that fluoride did not modify the Ca/P atomic ratio, but it was incorporated into the lattice of in vivo deposits. Fluoride also converted the crystallization pattern from plate to rode-like structures. In conclusion, while fluoride prevents calcification in vitro, the WHO's recommended concentrations in drinking water become nephrotoxic to CKD rats, thereby aggravating renal disease and making media vascular calcification significant.

  14. Dual-specificity phosphatases are implicated in severe hyperplasia and lack of response to FGF23 of uremic parathyroid glands from rats.

    PubMed

    Román-García, Pablo; Carrillo-López, Natalia; Naves-Díaz, Manuel; Rodríguez, Isabel; Ortiz, Alberto; Cannata-Andía, Jorge B

    2012-04-01

    Phosphate load accelerates the progression of secondary hyperparathyroidism (sHPT). In advanced stages of sHPT, there is a marked hyperplasia and resistance to classical regulatory endocrine factors such as calcium, calcitriol, or fibroblast growth factor 23 (FGF23), which suppresses PTH secretion by an ERK-dependent mechanism. Nephrectomized rats were fed with a high- or normal-phosphorus diet for different periods of time to induce sHPT. Biochemical parameters, parathyroid gland microarrays, quantitative real-time PCR, and immunohistochemistry (ERK/phospho-ERK) were performed. To test the role of dual-specificity phosphatases (Dusp) on parathyroid gland regulation, normal parathyroid glands were cultured with FGF23 and Dusp. Uremic rats fed with a high-phosphorus diet showed more severe sHPT, higher serum FGF23 levels and mortality, and decreased parathyroid Klotho gene expression. In all stages of sHPT, parathyroid microarrays displayed a widespread gene expression down-regulation; only a few genes were overexpressed, among them, Dusp5 and -6. In very severe sHPT, a significant reduction in phospho-ERK (the target of Dusp) and a significant increase of Dusp5 and -6 gene expression were observed. In ex vivo experiments with parathyroid glands, Dusp partially blocked the effect of FGF23 on PTH secretion, suggesting that Dusp might play a role in parathyroid regulation. The overexpression of Dusp and the inactivation of ERK found in the in vivo studies together with the ex vivo results might be indicative of the defense mechanism triggered to counteract hyperplasia, a mechanism that can also contribute to the resistance to the effect of FGF23 on parathyroid gland observed in advanced forms of chronic kidney disease.

  15. Uremic Leontiasis Ossea in a Patient With Chronic Renal Insufficiency Demonstrated on Bone Scintigraphy.

    PubMed

    Han, Yeon-Hee; Jeong, Hwan-Jeong; Lim, Seok Tae; Sohn, Myung-Hee

    2016-08-01

    A 37-year-old woman with chronic renal insufficiency underwent bone scintigraphy to evaluate renal osteodystrophy (ROD). Markedly increased uptakes were shown in the maxilla and the mandible, which suggested extensive maxillary and mandibular hypertrophy. CT image revealed that diffuse bony thickening and ground-glass appearance in the skull, maxilla, and mandible with poor distinction of the corticomedullary junction. Whole-body bone scintigraphy images also demonstrated various skeletal characteristics of ROD. This case emphasizes the utility of bone scintigraphy for the surveillance of the whole body in ROD.

  16. Effect of paricalcitol and cinacalcet on serum phosphate, FGF-23, and bone in rats with chronic kidney disease

    PubMed Central

    Finch, Jane L.; Tokumoto, Masanori; Nakamura, Hironori; Yao, Wei; Shahnazari, Mohammad; Lane, Nancy

    2010-01-01

    Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3–4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances “equivalent” to patients with CKD 3–4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg·kg−1·day−1 po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 μg/kg, 3 × wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca × P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)2D3 was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)2D3, and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies. PMID:20200094

  17. Humoral inhibitors of the immune response in uremia. V. Induction of suppressor cells in vitro by uremic serum.

    PubMed Central

    Raskova, J.; Raska, K.

    1983-01-01

    The mechanism of inhibition of mixed lymphocyte reaction (MLR) by serum of chronically uremic rats has been studied. The inhibitory activity of the serum has been associated with a discrete subset of very low density lipoproteins (VLDL) of Sf 100-400. The degree of the inhibitory activity of uremic serum correlates with the severity of uremia. Spleen cells from normal rats incubated for 20 hours with uremic serum or its VLDL fraction suppress the response of control syngeneic cells in the MLR. Induction of such suppressor activity does not require cell proliferation because it is not inhibited by mitomycin C. although the exact identity of the induced suppressor cells has not been established, they may be macrophages. The suppressor activity of induced spleen cells can be markedly reduced by filtration of spleen cells on glass wool or on nylon wool columns. Reconstruction experiments show that the adherent cell fraction of spleen cells exposed to uremic serum suppresses the response of the nonadherent fraction of control spleen cells. These results indicate that the immunosuppressive effects of rat uremic serum in vitro involve the induction of suppressor cells. PMID:6221666

  18. Dietary L-lysine prevents arterial calcification in adenine-induced uremic rats.

    PubMed

    Shimomura, Akihiro; Matsui, Isao; Hamano, Takayuki; Ishimoto, Takuya; Katou, Yumiko; Takehana, Kenji; Inoue, Kazunori; Kusunoki, Yasuo; Mori, Daisuke; Nakano, Chikako; Obi, Yoshitsugu; Fujii, Naohiko; Takabatake, Yoshitsugu; Nakano, Takayoshi; Tsubakihara, Yoshiharu; Isaka, Yoshitaka; Rakugi, Hiromi

    2014-09-01

    Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.

  19. Dietary l-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

    PubMed Central

    Shimomura, Akihiro; Matsui, Isao; Hamano, Takayuki; Ishimoto, Takuya; Katou, Yumiko; Takehana, Kenji; Inoue, Kazunori; Kusunoki, Yasuo; Mori, Daisuke; Nakano, Chikako; Obi, Yoshitsugu; Fujii, Naohiko; Takabatake, Yoshitsugu; Nakano, Takayoshi; Tsubakihara, Yoshiharu; Rakugi, Hiromi

    2014-01-01

    Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC. PMID:24652795

  20. Colon-derived uremic biomarkers induced by the acute toxicity of Kansui radix: A metabolomics study of rat plasma and intestinal contents by UPLC-QTOF-MS(E).

    PubMed

    Yang, Zhou; Hou, Jin-Jun; Qi, Peng; Yang, Min; Yan, Bing-Peng; Bi, Qi-Rui; Feng, Rui-Hong; Yang, Wen-Zhi; Wu, Wan-Ying; Guo, De-An

    2016-07-15

    Kansui radix (KR) is a poisonous Chinese herbal medicine recorded in the Chinese Pharmacopoeia, and the acute toxicity obstructs its clinical applications. To explore its acute toxicity mechanism to enhance clinical safety, a metabolomics study based on UPLC-ESI-QTOF-MS(E) was performed. Wistar rats were exposed for 4h to the aqueous and ethyl acetate extracts prepared from KR at a high dose (25g/kg). The contents of six different sections of rat intestine, including the duodenum, jejunum, ileum, cecum, colon, and rectum were collected as samples for the first time, as well as the rat plasma. The interesting results showed that only those rats exposed to the ethyl acetate extract showed a watery diarrhea, similar to the observed acute human toxicity. The identified biomarkers found in the plasma, such as phenol sulfate, indoxyl sulfate, and p-cresol sulfate were significantly perturbed in the rats. These biomarkers are known as colon-derived uremic compounds, which were first reported with respect to KR. The three essential amino acids which produced these biomarkers were only found in the contents of colon and rectum. A hypothesis was proposed that only the colon-derived uremic compounds induced by KR might be responsible for the acute toxicity. Three traditional process methods to reduce the toxicity of KR were compared based on these biomarkers, and different levels of toxicity modulation were observed. These results may be helpful to further understand the mechanism of acute toxicity, and the relevance of the traditional process methods to ameliorate the adverse effects of KR.

  1. Effects of 1 alpha,25- and 24R,25-dihydroxyvitamin D3 on aluminum-induced rickets in growing uremic rats.

    PubMed

    Vukicević, S; Krempien, B; Stavljenić, A

    1987-12-01

    Rats were subjected to a two-stage subtotal nephrectomy or sham operation, and treated with aluminum (Al) or both aluminum and vitamin D3 metabolites for 5 weeks with a cumulative dose of 13.6 mg aluminum. Animals were injected with 3H-thymidine and 3H-proline. The following analyses were performed: quantitative histology of tibial metaphyses and cytomorphometric electron microscopy of osteoclasts, quantitative (ICP-spectroscopy) and qualitative determination (histochemical staining) of aluminum within organs, and serum biochemistry (Ca, P, Mg, vitamin D3 metabolites, alkaline phosphatase, urea). The following new facts of the aluminum-related bone disease became evident: (a) Application of aluminum to growing uremic rats induced rickets, whose major epiphyseal growth plate changes were 1 alpha,25(OH)2D3-dependent. Addition of 1 alpha,25(OH)2D3 prevented the formation of rachitic metaphysis, but failed to prevent osteoid accumulation on epiphyseal and metaphyseal trabecular surfaces. Moreover, calcitriol produced hyperosteoidosis and osteosclerosis in the same rats. Aluminum did not alter the function of osteoblasts, while osteoclasts seemed inactivated. (b) The development of rickets was associated with suppressed serum levels of 1,25(OH)2D3, reduced phosphorus level and the high content of aluminum in the bone, kidney, and liver. The addition of 24R,25(OH)2D3 markedly exaggerated the reduction of serum levels of calcitriol. We suggested that aluminum induces rickets in growing uremic rats, which consists of two components: vitamin D refractory osteomalacia and 1 alpha,25(OH)2D3-dependent epiphyseal growth plate changes.

  2. Effects of acute and chronic uremia on active cation transport in rat myocardium

    SciTech Connect

    Druml, W.; Kelly, R.A.; England, B.K.; O'Hara, D.S.; Mitch, W.E. )

    1990-12-01

    As abnormalities of active cation transport could contribute to the genesis of uremic cardiomyopathy, we investigated myocardial sodium pump function in rats with acute renal failure (ARF) and with a model of experimental chronic renal failure (CRF) that has metabolic similarities to advanced chronic uremia in humans. CRF rats were hypertensive and had left ventricular hypertrophy (33% higher heart:body weight ratio; P less than 0.01) at four weeks compared to pair-fed sham-operated rats. Importantly, both ouabain- and furosemide-sensitive 86Rb uptake rates were unchanged in left ventricular myocardial slices from CRF, and the intracellular sodium concentration was not different from that of control rats even though skeletal muscle sodium was increased, as we found previously. Insulin-stimulated, ouabain-sensitive 86Rb influx was also preserved. There also were no abnormalities in myocardium cation transport in rats with ARF. However, (3H)ouabain binding was decreased 45% in CRF rats (P less than 0.01); it was unchanged in acute uremia. Decreased ouabain binding in chronic uremia was due entirely to fewer low affinity (3H)ouabain binding sites (the binding affinity for ouabain was unaffected). We conclude that in chronic, (but not acute) renal failure, sodium pump number is reduced in myocardium but intracellular sodium is unchanged and active cation flux rates are maintained. These results emphasize that in rats with chronic uremia, intracellular sodium homeostasis is preserved in myocardium, despite the presence of marked abnormalities of active cation transport in skeletal muscle that are characteristic of chronic uremia.

  3. Functional Profile of the Isolated Uremic Nephron

    PubMed Central

    Fine, Leon G.; Schlondorff, Detlef; Trizna, Walter; Gilbert, Richard M.; Bricker, Neal S.

    1978-01-01

    Resistance of the chronically diseased kidney to vasopressin has been proposed as a possible explanation for the urinary concentrating defect of uremia. The present studies examined the water permeability and adenylate cyclase responsiveness of isolated cortical collecting tubules (CCT) from remnant kidneys of uremic rabbits to vasopressin. In the absence of vasopressin the CCTs of both normal and uremic rabbits were impermeable to water. At the same osmotic gradient, addition of a supramaximal concentration of vasopressin to the peritubular bathing medium led to a significantly lower net water flux per unit length (and per unit luminal surface area) in uremic CCTs than in normal CCTs. Transepithelial osmotic water permeability coefficient, Pf, was 0.0232 ±0.0043 cm/s in normal CCTs and 0.0059±0.001 cm/s in uremic CCTs (P < 0.001). The impaired vasopressin responsiveness of the uremic CCTs was observed whether normal or uremic serum was present in the bath. Basal adenylate cyclase activity per microgram protein was comparable in normal and uremic CCTs. Stimulation by NaF led to equivalent levels of activity in both, whereas vasopressin-stimulated activity was 50% lower in the uremic than in the normal CCTs (P < 0.025). The cyclic AMP analogue, 8-bromo cyclic AMP, produced an increase in the Pf of normal CCTs closely comparable to that observed with vasopressin. In contrast, the Pf of uremic CCTs was only minimally increased by this analogue and was not further stimulated by theophylline. These studies demonstrate an impaired responsiveness of the uremic CCT to vasopressin. This functional defect appears to be a result, at least in part, of a blunted responsiveness of adenylate cyclase to vasopressin. The data further suggest that an additional defect in the cellular response to vasopressin may exist, involving a step (or steps) subsequent to the formation of cyclic AMP. A unifying concept of the urinary concentrating defect of uremia is proposed which

  4. Rat growth during chronic centrifugation

    NASA Technical Reports Server (NTRS)

    Pitts, G. C.; Oyama, J.

    1978-01-01

    Female weanling rats were chronically centrifuged at 4.15 G with controls at terrestrial gravity. Samples were sacrificed for body composition studies at 0, 28, 63, 105 and 308 days of centrifugation. The centrifuged group approached a significantly lower mature body mass than the controls (251 and 318g) but the rate of approach was the same in both groups. Retirement to 1G on the 60th day resulted in complete recovery. Among individual components muscle, bone, skin, CNS, heart, kidneys, body water and body fat were changed in the centrifuged group. However, an analysis of the growth of individual components relative to growth of the total fat-free compartment revealed that only skin (which increased in mass) was responding to centrifugation per se.

  5. Exploiting the nephrotoxic effects of venom from the sea anemone, Phyllodiscus semoni, to create a hemolytic uremic syndrome model in the rat.

    PubMed

    Mizuno, Masashi; Ito, Yasuhiko; Morgan, B Paul

    2012-07-01

    In the natural world, there are many creatures with venoms that have interesting and varied activities. Although the sea anemone, a member of the phylum Coelenterata, has venom that it uses to capture and immobilise small fishes and shrimp and for protection from predators, most sea anemones are harmless to man. However, a few species are highly toxic; some have venoms containing neurotoxins, recently suggested as potential immune-modulators for therapeutic application in immune diseases. Phyllodiscus semoni is a highly toxic sea anemone; the venom has multiple effects, including lethality, hemolysis and renal injuries. We previously reported that venom extracted from Phyllodiscus semoni induced acute glomerular endothelial injuries in rats resembling hemolytic uremic syndrome (HUS), accompanied with complement dysregulation in glomeruli and suggested that the model might be useful for analyses of pathology and development of therapeutic approaches in HUS. In this mini-review, we describe in detail the venom-induced acute renal injuries in rat and summarize how the venom of Phyllodiscus semoni could have potential as a tool for analyses of complement activation and therapeutic interventions in HUS.

  6. Exploiting the Nephrotoxic Effects of Venom from the Sea Anemone, Phyllodiscus semoni, to Create a Hemolytic Uremic Syndrome Model in the Rat

    PubMed Central

    Mizuno, Masashi; Ito, Yasuhiko; Morgan, B. Paul

    2012-01-01

    In the natural world, there are many creatures with venoms that have interesting and varied activities. Although the sea anemone, a member of the phylum Coelenterata, has venom that it uses to capture and immobilise small fishes and shrimp and for protection from predators, most sea anemones are harmless to man. However, a few species are highly toxic; some have venoms containing neurotoxins, recently suggested as potential immune-modulators for therapeutic application in immune diseases. Phyllodiscus semoni is a highly toxic sea anemone; the venom has multiple effects, including lethality, hemolysis and renal injuries. We previously reported that venom extracted from Phyllodiscus semoni induced acute glomerular endothelial injuries in rats resembling hemolytic uremic syndrome (HUS), accompanied with complement dysregulation in glomeruli and suggested that the model might be useful for analyses of pathology and development of therapeutic approaches in HUS. In this mini-review, we describe in detail the venom-induced acute renal injuries in rat and summarize how the venom of Phyllodiscus semoni could have potential as a tool for analyses of complement activation and therapeutic interventions in HUS. PMID:22851928

  7. An update on uremic toxins.

    PubMed

    Neirynck, N; Vanholder, R; Schepers, E; Eloot, S; Pletinck, A; Glorieux, G

    2013-02-01

    In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.

  8. Treatment with pyrophosphate inhibits uremic vascular calcification.

    PubMed

    O'Neill, W Charles; Lomashvili, Koba A; Malluche, Hartmut H; Faugere, Marie-Claude; Riser, Bruce L

    2011-03-01

    Pyrophosphate, which may be deficient in advanced renal failure, is a potent inhibitor of vascular calcification. To explore its use as a potential therapeutic, we injected exogenous pyrophosphate subcutaneously or intraperitoneally in normal rats and found that their plasma pyrophosphate concentrations peaked within 15 min. There was a single exponential decay with a half-life of 33 min. The kinetics were indistinguishable between the two routes of administration or in anephric rats. The effect of daily intraperitoneal pyrophosphate injections on uremic vascular calcification was then tested in rats fed a high-phosphate diet containing adenine for 28 days to induce uremia. Although the incidence of aortic calcification varied and was not altered by pyrophosphate, the calcium content of calcified aortas was significantly reduced by 70%. Studies were repeated in uremic rats given calcitriol to produce more consistent aortic calcification and treated with sodium pyrophosphate delivered intraperitoneally in a larger volume of glucose-containing solution to prolong plasma pyrophosphate levels. This maneuver significantly reduced both the incidence and amount of calcification. Quantitative histomorphometry of bone samples after double-labeling with calcein indicated that there was no effect of pyrophosphate on the rates of bone formation or mineralization. Thus, exogenous pyrophosphate can inhibit uremic vascular calcification without producing adverse effects on bone.

  9. Elastin Degradation and Vascular Smooth Muscle Cell Phenotype Change Precede Cell Loss and Arterial Medial Calcification in a Uremic Mouse Model of Chronic Kidney Disease

    PubMed Central

    Pai, Ashwini; Leaf, Elizabeth M.; El-Abbadi, Mohga; Giachelli, Cecilia M.

    2011-01-01

    Arterial medial calcification (AMC), a hallmark of vascular disease in uremic patients, is highly correlated with serum phosphate levels and cardiovascular mortality. To determine the mechanisms of AMC, mice were made uremic by partial right-side renal ablation (week 0), followed by left-side nephrectomy at week 2. At 3 weeks, mice were switched to a high-phosphate diet, and various parameters of disease progression were examined over time. Serum phosphate, calcium, and fibroblast growth factor 23 (FGF-23) were up-regulated as early as week 4. Whereas serum phosphate and calcium levels declined to normal by 10 weeks, FGF-23 levels remained elevated through 16 weeks, consistent with an increased phosphate load. Elastin turnover and vascular smooth muscle cell (VSMC) phenotype change were early events, detected by week 4 and before AMC. Both AMC and VSMC loss were significantly elevated by week 8. Matrix metalloprotease 2 (MMP-2) and cathepsin S were present at baseline and were significantly elevated at weeks 8 and 12. In contrast, MMP-9 was not up-regulated until week 12. These findings over time suggest that VSMC phenotype change and VSMC loss (early phosphate-dependent events) may be necessary and sufficient to promote AMC in uremic mice fed a high-phosphate diet, whereas elastin degradation might be necessary but is not sufficient to induce AMC (because elastin degradation occurred also in uremic mice on a normal-phosphate diet, but they did not develop AMC). PMID:21281809

  10. Effects of Sucroferric Oxyhydroxide Compared to Lanthanum Carbonate and Sevelamer Carbonate on Phosphate Homeostasis and Vascular Calcifications in a Rat Model of Chronic Kidney Failure.

    PubMed

    Phan, Olivier; Maillard, Marc; Malluche, Hartmut H; Stehle, Jean-Christophe; Funk, Felix; Burnier, Michel

    2015-01-01

    Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. Hyperphosphatemia and increased serum iPTH were controlled to a similar extent in all phosphate binder-treatment groups. Only sucroferric oxyhydroxide was associated with significantly decreased FGF23. Vascular calcifications of the thoracic aorta were decreased by all three phosphate binders. Calcifications were better prevented at the superior part of the thoracic and abdominal aorta in the PA21 treated rats. In adenine-induced CRF rats, sucroferric oxyhydroxide was as effective as La and Se in controlling hyperphosphatemia, secondary hyperparathyroidism, and vascular calcifications. The role of FGF23 in calcification remains to be confirmed.

  11. Effects of Sucroferric Oxyhydroxide Compared to Lanthanum Carbonate and Sevelamer Carbonate on Phosphate Homeostasis and Vascular Calcifications in a Rat Model of Chronic Kidney Failure

    PubMed Central

    Phan, Olivier; Maillard, Marc; Malluche, Hartmut H.; Stehle, Jean-Christophe; Funk, Felix; Burnier, Michel

    2015-01-01

    Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. Hyperphosphatemia and increased serum iPTH were controlled to a similar extent in all phosphate binder-treatment groups. Only sucroferric oxyhydroxide was associated with significantly decreased FGF23. Vascular calcifications of the thoracic aorta were decreased by all three phosphate binders. Calcifications were better prevented at the superior part of the thoracic and abdominal aorta in the PA21 treated rats. In adenine-induced CRF rats, sucroferric oxyhydroxide was as effective as La and Se in controlling hyperphosphatemia, secondary hyperparathyroidism, and vascular calcifications. The role of FGF23 in calcification remains to be confirmed. PMID:26221597

  12. Acute ischemia/reperfusion injury after isogeneic kidney transplantation is mitigated in a rat model of chronic renal failure.

    PubMed

    Vercauteren, Sven R; Ysebaert, Dirk K; Van Rompay, An R; De Greef, Kathleen E; De Broe, Marc E

    2003-05-01

    The influence of chronic renal failure on renal susceptibility to an acute ischemic insult was evaluated. Recipient Lewis rats were randomly assigned to undergo 5/6 nephrectomy (chronic renal failure, CRF) or sham operation (normal renal function, NRF). After 11 weeks, normal kidneys of Lewis donor rats were transplanted in the recipients. The outcome of the isografts was assessed. Filtration capacity of the isografts in the CRF rats was preserved to approximately one-quarter of its normal capacity on the 1st day post-transplantation, whereas it fell to 0 in the NRF rats. This was reflected by a significantly higher increase in serum creatinine in the latter group. The isografts in the CRF rats had a significantly lower degree of acute tubular necrosis and no increase in the number of macrophages and T lymphocytes in the first 24 h in contrast to the NRF rats. Epithelial regeneration and repair started earlier in the CRF group. In conclusion, the present study indicated that CRF blunted ischemia/reperfusion injury of a transplanted kidney, and that its regeneration capacity was certainly not hampered by the presence of chronic uremia. These results will be the basis for studies on modulation of early leukocyte-endothelial interactions resulting from immunological disturbances inherent to the uremic environment.

  13. Design of a new therapy for patients with chronic kidney disease: use of microarrays for selective hemoadsorption of uremic wastes and toxins to improve homeostasis

    PubMed Central

    Shahidi Bonjar, Mohammad Rashid; Shahidi Bonjar, Leyla

    2015-01-01

    The hypothesis proposed here would provide near to optimum homeostasis for patients with chronic kidney disease (CKD) without the need for hemodialysis. This strategy has not been described previously in the scientific literature. It involves a targeted therapy that may prevent progression of the disease and help to improve the well-being of CKD patients. It proposes a nanotechnological device, ie, a microarray-oriented homeostasis provider (MOHP), to improve homeostasis in CKD patients. MOHP would be an auxiliary kidney aid, and would improve the filtration functions that impaired kidneys cannot perform by their own. MOHP is composed of two main computer-oriented components, ie, a quantitative microarray detector (QMD) and a homeostasis-oriented microarray column (HOMC). QMD detects and HOMC selectively removes defined quantities of uremic wastes, toxins and any other metabolites which is programmed for. The QMD and HOMC would accomplish this with the help of a peristaltic blood pump that would circulate blood aseptically in an extracorporeal closed circuit. During the passage of blood through the QMD, this microarray detector would quantitatively monitor all of the blood compounds that accumulate in the blood of a patient with impaired glomerular filtration, including small-sized, middle-sized and large-sized molecules. The electronic information collected by QMD would be electronically transmitted to the HOMC, which would adjust the molecules to the concentrations they are electronically programmed for and/or receive from QMD. This process of monitoring and removal of waste continues until the programmed homeostasis criteria are reached. Like a conventional kidney machine, MOHP can be used in hospitals and homes under the supervision of a trained technician. The main advantages of this treatment would include improved homeostasis, a reduced likelihood of side effects and of the morbidity resulting from CKD, slower progression of kidney impairment, prevention of

  14. Uremic frost: a harbinger of impending renal failure.

    PubMed

    Saardi, Karl M; Schwartz, Robert A

    2016-01-01

    Uremic frost is a striking cutaneous finding seen in patients with severe kidney disease. Familiarity with this condition can be a life-saving signal to initiate urgent dialysis. Uremic frost generally occurs at blood urea nitrogen levels of approximately 200 mg/dl, although it may arise with less severe uremia. Recently confirmed urea transporters in the skin may play a role in the development of uremic frost. Alternatively, damage to the cutaneous microvasculature and pilosebaceous units, as seen in chronic kidney disease, could account for the high levels of urea deposited outside the skin. The treatment of uremic frost is largely aimed at correcting the underlying cause of uremia and the other life-threatening conditions associated with renal failure.

  15. Targeting the Opioid Pathway for Uremic Pruritus

    PubMed Central

    Jaiswal, Deep; Uzans, Drea; Hayden, Jill; Kiberd, Bryce A.; Tennankore, Karthik K.

    2016-01-01

    Background: Patients undergoing hemodialysis or peritoneal dialysis often experience pruritus which is associated with morbidity and mortality. One proposed treatment approach is to target the opioid pathway using either µ-opioid antagonists or κ-opioid agonists. Objective: To review the efficacy of targeting the opioid pathway for pruritus among dialysis patients (uremic pruritus). Design: Systematic review and meta-analysis. Setting/Methods: The systematic review included randomized controlled and randomized crossover trials identified in the MEDLINE, EMBASE, and Cochrane databases (1990 to June 2014) evaluating the efficacy of µ-opioid antagonists or κ-opioid agonists in the treatment of uremic pruritus. Patients: Adult (≥18 years) chronic dialysis patients. Measurements: The primary outcome being evaluated was reduction in itch severity measured on a patient-reported visual analog scale (VAS). Results: Five studies out of 3587 screened articles met the inclusion criteria. Three studies evaluated the efficacy of naltrexone, a µ-opioid antagonist, and 2 studies evaluated the efficacy of nalfurafine, a κ-opioid agonist. Duration of included studies was short, ranging from 2 to 9 weeks. Limitations: Due to the heterogeneity in reporting of outcomes, data from the studies evaluating naltrexone could not be pooled. Pooled analysis, using a random effects model, found that use of nalfurafine resulted in a 9.50 mm (95% confidence interval [CI], 6.27-12.74, P < .001) greater reduction of itch severity (measured on a 100-mm VAS) than placebo in the treatment of uremic pruritus. Conclusions: Nalfurafine holds some promise with respect to the treatment of uremic pruritus among dialysis patients. However, more long-term randomized controlled trials evaluating the efficacy of therapies targeting the opioid pathway for uremic pruritus are required. PMID:28270926

  16. The role of oxygen free radicals in the development of chronic renal failure

    SciTech Connect

    Trachtman, H.; Wilson, D.; Rao, P.S. )

    1992-01-01

    This study examined whether there is increased production of oxygen free radicals during chronic renal failure. Rats subjected to 3/4 nephrectomy and sham operated controls were killed after 3 weeks. Lipid extracts of plasma and renal tissue were examined by HPLC and kidney specimens were also analyzed by EPR spectroscopy. The redox capacity of blood was assessed using nitroblue tetrazolium and plasma ascorbate levels were measured with HPLC. There was no detectable renal production of oxygen free radicals in rats with chronic renal failure. Kidney parenchymal content of other oxidants and the oxidant: reductant ratio were similar in control and uremic animals. The plasma redox capacity and ascorbate levels were elevated in uremic rats. The authors conclude that early in the course of chronic renal failure, there is not excessive production of oxygen free radicals. There is accumulation of reductants, primarily ascorbate, in the plasma of uremic animals.

  17. Uremic toxins and oral adsorbents.

    PubMed

    Goto, Shunsuke; Yoshiya, Kunihiko; Kita, Tomoyuki; Fujii, Hideki; Fukagawa, Masafumi

    2011-04-01

    Uremic toxins are associated with various disorders in patients with end-stage renal disease and it is difficult to remove some of these toxins by dialysis. Since some uremic toxins are generated by bacterial metabolites in the colon, oral adsorbents that interfere with the absorption of uremic toxins or their precursors are believed to prevent their accumulation in the body. AST-120 adsorbs various uremic retention solutes in the gastrointestinal system and has potential for providing clinical benefit. Sevelamer hydrochloride binds some harmful compounds in addition to phosphate and seems to have pleiotropic effects that include lowering serum LDL cholesterol levels and reduction of inflammation. The effect of sevelamer hydrochloride on indoxyl sulfate and p-cresol has been shown in an in vitro study; however, in vivo studies in mice or humans did not demonstrate this effect on protein-binding uremic toxins. Oral adsorbents are thus one of the important modalities in the treatment of uremic syndrome.

  18. Recent progress in the analysis of uremic toxins by mass spectrometry.

    PubMed

    Niwa, Toshimitsu

    2009-09-01

    Mass spectrometry (MS) has been successfully applied for the identification and quantification of uremic toxins and uremia-associated modified proteins. This review focuses on recent progress in the analysis of uremic toxins by using MS. Uremic toxins include low-molecular-weight compounds (e.g., indoxyl sulfate, p-cresol sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, asymmetric dimethylarginine), middle-molecular-weight peptides, and proteins modified with advanced glycation and oxidation. These uremic toxins are considered to be involved in a variety of symptoms which may appear in patients with stage 5 chronic kidney disease. Based on MS analysis of these uremic toxins, the pathogenesis of the uremic symptoms will be elucidated to prevent and manage the symptoms.

  19. Hemolytic uremic syndrome

    PubMed Central

    Canpolat, Nur

    2015-01-01

    Hemolytic uremic syndrome (HUS) is a clinical syndrome characterized by the triad of thrombotic microangiopathy, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome represents a heterogeneous group of disorders with variable etiologies that result in differences in presentation, management and outcome. In recent years, better understanding of the HUS, especially those due to genetic mutations in the alternative complement pathway have provided an update on the terminology, classification, and treatment of the disease. This review will provide the updated classification of the disease and the current diagnostic and therapeutic approaches on the complement-mediated HUS in addition to STEC-HUS which is the most common cause of the HUS in childhood. PMID:26265890

  20. Ameliorative Effect of Chrysin on Adenine-Induced Chronic Kidney Disease in Rats

    PubMed Central

    Ali, Badreldin H.; Adham, Sirin A.; Al Za’abi, Mohammed; Waly, Mostafa I.; Yasin, Javed; Nemmar, Abderrahim; Schupp, Nicole

    2015-01-01

    Chrysin (5, 7- dihydroxyflavone) is a flavonoid with several pharmacological properties that include antioxidant, anti-inflammatory and antiapoptotic activities. in this work, we investigated some effects of three graded oral doses of chrysin (10, 50 and 250 mg/kg) on kidney structure and function in rats with experimental chronic renal disease (CKD) induced by adenine (0.25% w/w in feed for 35 days), which is known to involve inflammation and oxidative stress. Using several indices in plasma, urine and kidney homogenates, adenine was found to impair kidney function as it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and N-Acetyl-beta-D-glucosaminidase activity. Furthermore, it raised plasma concentrations of the uremic toxin indoxyl sulfate, some inflammatory cytokines and urinary albumin concentration. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activities, total antioxidant capacity and reduced glutathione were all adversely affected. Most of these adenine – induced actions were moderately and dose -dependently mitigated by chrysin, especially at the highest dose. Chrysin did not cause any overt adverse effect on the treated rats. The results suggest that different doses of chrysin produce variable salutary effects against adenine-induced CKD in rats, and that, pending further pharmacological and toxicological studies, its usability as a possible ameliorative agent in human CKD should be considered. PMID:25909514

  1. Ameliorative effect of chrysin on adenine-induced chronic kidney disease in rats.

    PubMed

    Ali, Badreldin H; Adham, Sirin A; Al Za'abi, Mohammed; Waly, Mostafa I; Yasin, Javed; Nemmar, Abderrahim; Schupp, Nicole

    2015-01-01

    Chrysin (5, 7- dihydroxyflavone) is a flavonoid with several pharmacological properties that include antioxidant, anti-inflammatory and antiapoptotic activities. in this work, we investigated some effects of three graded oral doses of chrysin (10, 50 and 250 mg/kg) on kidney structure and function in rats with experimental chronic renal disease (CKD) induced by adenine (0.25% w/w in feed for 35 days), which is known to involve inflammation and oxidative stress. Using several indices in plasma, urine and kidney homogenates, adenine was found to impair kidney function as it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and N-Acetyl-beta-D-glucosaminidase activity. Furthermore, it raised plasma concentrations of the uremic toxin indoxyl sulfate, some inflammatory cytokines and urinary albumin concentration. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activities, total antioxidant capacity and reduced glutathione were all adversely affected. Most of these adenine - induced actions were moderately and dose -dependently mitigated by chrysin, especially at the highest dose. Chrysin did not cause any overt adverse effect on the treated rats. The results suggest that different doses of chrysin produce variable salutary effects against adenine-induced CKD in rats, and that, pending further pharmacological and toxicological studies, its usability as a possible ameliorative agent in human CKD should be considered.

  2. The effect of activated charcoal on adenine-induced chronic renal failure in rats.

    PubMed

    Ali, Badreldin H; Alza'abi, Mohamed; Ramkumar, Aishwarya; Al-Lawati, Intisar; Waly, Mostafa I; Beegam, Sumaya; Nemmar, Abderrahim; Brand, Susanne; Schupp, Nicole

    2014-03-01

    Activated charcoal (AC) is a sorbent that has been shown to remove urinary toxins like urea and indoxyl sulfate. Here, the influence of AC on kidney function of rats with experimental chronic renal failure (CRF) is investigated. CRF was induced in rats by feeding adenine (0.75%) for four weeks. As an intervention, AC was added to the feed at concentrations of 10%, 15% or 20%. Adenine treatment impaired kidney function: it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and vanin-1. Furthermore, it raised plasma concentrations of the uremic toxins indoxyl sulfate, phosphate and uric acid. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activity, total antioxidant capacity and reduced glutathione were adversely affected. Most of these changes were significantly ameliorated by dietary administration of AC at a concentration of 20%, while effects induced by lower doses of dietary AC on adenine nephrotoxicity were not statistically significant. The results suggest that charcoal is a useful sorbent agent in dietary adenine-induced CRF in rats and that its usability as a nephroprotective agent in human kidney disease should be studied.

  3. Azotemia (48 h) decreases the risk of brain damage in rats after correction of chronic hyponatremia.

    PubMed

    Soupart, A; Penninckx, R; Stenuit, A; Decaux, G

    2000-01-03

    Brain myelinolysis complicates excessive correction of chronic hyponatremia in man. Myelinolysis appear in rats for correction levels deltaSNa) > 20 mEq/l/24 h. We previously showed in rats that when chronic hyponatremia was corrected with urea, the incidence and the severity of brain lesions were significantly reduced compared to hypertonic saline. In man, hyponatremia is frequently associated with azotemia and hemo-dialysis usually corrects rapidly the serum sodium (SNa) but only few patients apparently develop demyelination. We hypothesize that uremic state protects brain against myelinolysis. This hypothesis was evaluated in rats developing azotemia by administration of mercuric chloride (HgCl2, 1.5 mg/kg). Severe (SNa < 120 mEq/l) hyponatremia (3 days) was induced by S.C. AVP and i.p. 2.5% D-glucose for 3 days. HgCl2 was injected on day 2. Hyponatremia was corrected on day 4 by i.p. injections of 5% NaCl in order to obtain a correction level largely above the toxic threshold for brain (deltaSNA approximately 30 mEq/l/24 h). Surviving rats were decapitated on day 10 for brain analysis. In the group with renal failure (Group I, n = 15, urea 59 mmol/l) the outcome was remarkably favourable with only three rats (3/15) dying before day 10 and only one of them (1/3) presenting myelinolysis-related neurologic symptoms. The 12 other rats (80%) survived in Group I without symptoms and brain analysis was normal in all of them despite large correction level (deltaSNa: 32 mEq/l/24 h). On the contrary in nine rats in which HgCl, did not produce significant azotemia (control 1, n = 9, urea: 11 mmol/l), all the rats developed severe neurologic symptoms and eight of them died before day 10. Similar catastrophic outcome was observed in the non-azotemic controls (control 2, no HgCl2 administration, n = 15, urea: 5 mmol/l). All of them developed myelinolysis-related neurologic symptoms and only four of them survived with severe brain lesions (survival 12/15 in Group I vs. 5

  4. Protein-bound uremic retention solutes.

    PubMed

    Brunet, Philippe; Dou, Laetitia; Cerini, Claire; Berland, Yvon

    2003-10-01

    Protein-bound uremic retention solutes are molecules with low molecular weight (MW) but should be considered middle or high MW substances. This article describes the best known substances of this group, which include p-cresol, indoxyl sulfate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furan-propionic acid (CMPF), and homocysteine. At concentrations encountered during uremia, p-cresol inhibits phagocyte function and decreases leukocyte adhesion to cytokine-stimulated endothelial cells. CMPF has been implicated in anemia and neurologic abnormalities of uremia. CMPF could alter the metabolism of drugs of inhibiting their binding to albumin and their tubular excretion. Indoxyl sulfate administrated to uremic rats increases the rate of progression of renal failure. Hippuric acid inhibits glucose utilization in the muscle, and its serum concentration is correlated with neurologic symptoms of uremia. Homocysteine predisposes uremic patients to cardiovascular disease through impairment of endothelial and smooth muscle cell functions. The removal of protein-bound compounds by conventional hemodialysis is low. Other strategies to decrease their concentrations include increase in dialyze pore size, daily hemodialysis, peritoneal dialysis, reduction of production or acceleration of degradation, and preservation of residual renal function.

  5. [Compression of the sciatic nerve in uremic tumor calcinosis].

    PubMed

    García, S; Cofán, F; Combalia, A; Casas, A; Campistol, J M; Oppenheimer, F

    1999-02-01

    Tumoral calcinosis is an uncommon and benign condition characterized by the presence of slow-growing calcified periarticular soft tissue masses of varying size. They are usually asymptomatic and nerve compression is rare. We describe the case of a 54-year-old female patient on long-term hemodialysis for chronic renal failure presenting sciatica in the left lower limb secondary to an extensive uremic tumoral calcinosis that affected the hip and thigh. The pathogenesis of uremic tumoral calcinosis as well as the treatment and clinical outcome are analyzed. The uncommon nerve compression due to tumoral calcinosis are reviewed. In conclusion, uremic tumoral calcinosis is a not previously reported infrequent cause of sciatic nerve compression.

  6. The Influence of Prebiotic Arabinoxylan Oligosaccharides on Microbiota Derived Uremic Retention Solutes in Patients with Chronic Kidney Disease: A Randomized Controlled Trial

    PubMed Central

    Evenepoel, Pieter; de Loor, Henriette; Delcour, Jan A.; Courtin, Christophe M.; Kuypers, Dirk; Augustijns, Patrick; Verbeke, Kristin; Meijers, Björn

    2016-01-01

    The colonic microbial metabolism is a key contributor to uremic retention solutes accumulating in patients with CKD, relating to adverse outcomes and insulin resistance. Whether prebiotics can reduce intestinal generation of these microbial metabolites and improve insulin resistance in CKD patients not yet on dialysis remains unknown. We performed a randomized, placebo-controlled, double-blind, cross-over study in 40 patients with eGFR between 15 and 45 ml/min/1.73 m2. Patients were randomized to sequential treatment with prebiotic arabinoxylan oligosaccharides (AXOS) (10 g twice daily) and maltodextrin for 4 weeks, or vice versa, with a 4-week wash-out period between both intervention periods. Serum levels and 24h urinary excretion of p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, trimethylamine N-oxide and phenylacetylglutamine were determined at each time point using liquid chromatography—tandem mass spectrometry. In addition, insulin resistance was estimated by the homeostatic model assessment (HOMA-IR). A total of 39 patients completed the study. We observed no significant effect of AXOS on serum p-cresyl sulfate (P 0.42), p-cresyl glucuronide (P 0.59), indoxyl sulfate (P 0.70) and phenylacetylglutamine (P 0.41) and a small, albeit significant decreasing effect on serum trimethylamine N-oxide (P 0.04). There were neither effect of AXOS on 24h urinary excretion of p-cresyl sulfate (P 0.31), p-cresyl glucuronide (P 0.23), indoxyl sulfate (P 0.87) and phenylacetylglutamine (P 0.43), nor on 24h urinary excretion of trimethylamine N-oxide (P 0.97). In addition, we observed no significant change in HOMA-IR (P 0.93). In conclusion, we could not demonstrate an influence of prebiotic AXOS on microbiota derived uremic retention solutes and insulin resistance in patients with CKD not yet on dialysis. Further study is necessary to elucidate whether prebiotic therapy with other characteristics, higher cumulative exposure or in different patient populations may

  7. Chronic Paraspinal Muscle Injury Model in Rat

    PubMed Central

    Cho, Tack Geun; Kim, Young Baeg

    2016-01-01

    Objective The objective of this study is to establish an animal model of chronic paraspinal muscle injury in rat. Methods Fifty four Sprague-Dawley male rats were divided into experimental group (n=30), sham (n=15), and normal group (n=9). Incision was done from T7 to L2 and paraspinal muscles were detached from spine and tied at each level. The paraspinal muscles were exposed and untied at 2 weeks after surgery. Sham operation was done by paraspinal muscles dissection at the same levels and wound closure was done without tying. Kyphotic index and thoracolumbar Cobb's angle were measured at preoperative, 2, 4, 8, and 12 weeks after the first surgery for all groups. The rats were sacrificed at 4, 8, and 12 weeks after the first surgery, and performed histological examinations. Results At 4 weeks after surgery, the kyphotic index decreased, but, Cobb's angle increased significantly in the experimental group (p<0.05), and then that were maintained until the end of the experiment. However, there were no significant differences of the kyphotic index and Cobb's angle between sham and normal groups. In histological examinations, necrosis and fibrosis were observed definitely and persisted until 12 weeks after surgery. There were also presences of regenerated muscle cells which nucleus is at the center of cytoplasm, centronucleated myofibers. Conclusion Our chronic injury model of paraspinal muscles in rats shows necrosis and fibrosis in the muscles for 12 weeks after surgery, which might be useful to study the pathophysiology of the degenerative thoracolumbar kyphosis or degeneration of paraspinal muscles. PMID:27651859

  8. Damage of hippocampal neurons in rats with chronic alcoholism

    PubMed Central

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

    2014-01-01

    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. PMID:25368648

  9. Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory statesthe examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degeneration.

    PubMed

    Richards, Anna; Kavanagh, David; Atkinson, John P

    2007-01-01

    In this chapter, we examine the role of complement regulatory activity in atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). These diseases are representative of two distinct types of complement-mediated injury, one being acute and self-limited, the other reflecting accumulation of chronic damage. Neither condition was previously thought to have a pathologic relationship to the immune system. However, alterations in complement regulatory protein genes have now been identified as major predisposing factors for the development of both diseases. In aHUS, heterozygous mutations leading to haploinsufficiency and function-altering polymorphisms in complement regulators have been identified, while in AMD, polymorphic haplotypes in complement genes are associated with development of disease. The basic premise is that a loss of function in a plasma or membrane inhibitor of the alternative complement pathway allows for excessive activation of complement on the endothelium of the kidney in aHUS and on retinal debris in AMD. These associations have much to teach us about the host's innate immune response to acute injury and to chronic debris deposition. We all experience cellular injury and, if we live long enough, will deposit debris in blood vessel walls (atherosclerosis leading to heart attacks and strokes), the brain (amyloid proteins leading to Alzheimer's disease), and retina (lipofuscin pigments leading to AMD). These are three common causes of morbidity and mortality in the developed world. The clinical, genetic, and immunopathologic understandings derived from the two examples of aHUS and AMD may illustrate what to anticipate in related conditions. They highlight how a powerful recognition and effector system, the alternative complement pathway, reacts to altered self. A response to acute injury or chronic debris accumulation must be appropriately balanced. In either case, too much activation or too little regulation promotes

  10. Uremic pruritus: a review.

    PubMed

    Lugon, Jocemir R

    2005-04-01

    Pruritus is a major disorder among the skin derangements in advanced renal failure. Its prevalence seems to be diminishing perhaps because of improvements in dialysis treatment. Recent information suggests that interactions between dermal mast cells and distal ends of nonmyelinated C fibers may be important in the precipitation and regulation of the sensory stimuli. The knowledge as to the control of pruritus transmission to cortex areas is still incomplete but endogenous opioid and opioid receptors may have a role in this regard. A recent classification was proposed for pruritus based on the level of its origin. Uremic pruritus, however, seems to be too complex to fit perfectly in any of the suggested modalities. Inflammation and malnutrition are recognized risk factors for cardiovascular death in end-stage renal disease patients, which may be related to the genesis of pruritus. Consistent with this concept, lower serum levels of albumin and higher serum levels of ferritin were found in pruritic patients when compared to nonpruritic ones. Newer treatments for this difficult clinical problem are being developed and tested.

  11. Uremic toxins and peritoneal dialysis.

    PubMed

    Lameire, N; Vanholder, R; De Smet, R

    2001-02-01

    Uremic toxicity is related in part to the accumulation of toxic substances, the nature of which has only partly been characterized. Because of the use of a highly permeable membrane and better preservation of the residual renal function, it could be anticipated that some of these uremic toxins are more efficiently cleared across the peritoneal membrane, and that the plasma and tissue levels of these compounds are lower than in hemodialysis patients. This article analyzes the generation and removal of several uremic toxins in peritoneal dialysis patients. The following uremic toxins are discussed: beta2-microglobulin, advanced glycation end products, advanced oxidation protein products, granulocyte inhibitory proteins, p-Cresol, and hyperhomocysteinemia. Some recent studies are reviewed suggesting that uremic toxins are involved in the progression of renal failure and are at least partially removed by peritoneal dialysis. We conclude that, although the plasma levels of some of these compounds are lower in peritoneal dialysis versus hemodialysis patients, it does not mean that the peritoneal dialysis patient is "better" protected against the numerous disturbances caused by these toxins.

  12. Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats.

    PubMed

    Kieffer, Dorothy A; Piccolo, Brian D; Vaziri, Nosratola D; Liu, Shuman; Lau, Wei L; Khazaeli, Mahyar; Nazertehrani, Sohrab; Moore, Mary E; Marco, Maria L; Martin, Roy J; Adams, Sean H

    2016-05-01

    Patients and animals with chronic kidney disease (CKD) exhibit profound alterations in the gut environment including shifts in microbial composition, increased fecal pH, and increased blood levels of gut microbe-derived metabolites (xenometabolites). The fermentable dietary fiber high amylose maize-resistant starch type 2 (HAMRS2) has been shown to alter the gut milieu and in CKD rat models leads to markedly improved kidney function. The aim of the present study was to identify specific cecal bacteria and cecal, blood, and urinary metabolites that associate with changes in kidney function to identify potential mechanisms involved with CKD amelioration in response to dietary resistant starch. Male Sprague-Dawley rats with adenine-induced CKD were fed a semipurified low-fiber diet or a high-fiber diet [59% (wt/wt) HAMRS2] for 3 wk (n = 9 rats/group). The cecal microbiome was characterized, and cecal contents, serum, and urine metabolites were analyzed. HAMRS2-fed rats displayed decreased cecal pH, decreased microbial diversity, and an increased Bacteroidetes-to-Firmicutes ratio. Several uremic retention solutes were altered in the cecal contents, serum, and urine, many of which had strong correlations with specific gut bacteria abundances, i.e., serum and urine indoxyl sulfate were reduced by 36% and 66%, respectively, in HAMRS2-fed rats and urine p-cresol was reduced by 47% in HAMRS2-fed rats. Outcomes from this study were coincident with improvements in kidney function indexes and amelioration of CKD outcomes previously reported for these rats, suggesting an important role for microbial-derived factors and gut microbe metabolism in regulating host kidney function.

  13. Protein-bound uremic toxins: new insight from clinical studies.

    PubMed

    Liabeuf, Sophie; Drüeke, Tilman B; Massy, Ziad A

    2011-07-01

    The uremic syndrome is attributed to the progressive retention of a large number of compounds which, under normal conditions, are excreted by healthy kidneys. The compounds are called uremic toxins when they interact negatively with biological functions. The present review focuses on a specific class of molecules, namely the family of protein-bound uremic toxins. Recent experimental studies have shown that protein-bound toxins are involved not only in the progression of chronic kidney disease (CKD), but also in the generation and aggravation of cardiovascular disease. Two protein-bound uremic retention solutes, namely indoxyl sulfate and p-cresyl sulfate, have been shown to play a prominent role. However, although these two molecules belong to the same class of molecules, exert toxic effects on the cardiovascular system in experimental animals, and accumulate in the serum of patients with CKD they may have different clinical impacts in terms of cardiovascular disease and other complications. The principal aim of this review is to evaluate the effect of p-cresyl sulfate and indoxyl sulfate retention on CKD patient outcomes, based on recent clinical studies.

  14. The effect of the uremic toxin cyanate (CNO⁻) on anaerobic cysteine metabolism and oxidative processes in the rat liver: a protective effect of lipoate.

    PubMed

    Sokołowska, Maria; Niedzielska, Ewa; Iciek, Małgorzata; Bilska, Anna; Lorenc-Koci, Elżbieta; Włodek, Lidia

    2011-07-01

    Chronic renal failure (CRF) patients have an increased plasma level of urea, which can be a source of cyanate. This compound can cause protein carbamoylation thereby changing biological activity of proteins. Therefore, in renal failure patients, cyanate can disturb metabolism and functioning of the liver. This work presents studies demonstrating that the treatment of rats with cyanate alone causes the following changes in the liver: (1) inhibition of rhodanese (TST), cystathionase (CST) and 3-mercaptopyruvate sulfotransferase (MPST) activities, (2) decrease in sulfane sulfur level (S*), (3) lowering of nonprotein sulfhydryl groups (NPSH) group level, and (4) enhancement of prooxidant processes (rise in reactive oxygen species (ROS) and malondialdehyde (MDA) level). This indicates that cyanate inhibits anaerobic cysteine metabolism and shows prooxidant action in the liver. Out of the above-mentioned changes, lipoate administered with cyanate jointly was able to correct MDA, ROS and NPSH levels, and TST activity. It had no significant effect on MPST and CST activities. It indicates that lipoate can prevent prooxidant cyanate action and cyanate-induced TST inhibition. These observations can be promising for CRF patients since lipoate can play a dual role in these patients as an efficient antioxidant defense and a protection against cyanate and cyanide toxicity.

  15. Clinical grand rounds: atypical hemolytic uremic syndrome.

    PubMed

    Hodgkins, Kavita S; Bobrowski, Amy E; Lane, Jerome C; Langman, Craig B

    2012-01-01

    Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS.

  16. Lipid peroxidation in rats chronically fed ethanol.

    PubMed Central

    Teare, J P; Greenfield, S M; Watson, D; Punchard, N A; Miller, N; Rice-Evans, C A; Thompson, R P

    1994-01-01

    Chronic alcohol consumption induces cytochrome P450IIE1, enabling habitual abusers to consume far greater quantities of alcohol than normal subjects. This pathway of metabolism leads to the production of free radical species, which cause tissue damage through peroxidation of cell membranes. Groups of Wistar rats of equal male: female ratio (n = 24) were fed alcohol by gavage twice daily to achieve a dosage of 15 g/kg body weight. Mean peak blood alcohol concentrations of 186 mg% were produced in males and 156 mg% in females. The animals were allowed free access to standard laboratory chow and water. Control animals were pair-fed to the alcoholic group and fed isocaloric glucose by gavage. Groups of animals were killed between 9 and 11 am on consecutive mornings, after nocturnal feeding, since it has previously been shown that fasting rapidly depletes hepatic glutathione concentrations. Hepatic glutathione was measured by a spectrophotometric enzymatic recycling procedure. As a marker of lipid peroxidation hepatic malonaldehyde (MDA) was measured by high performance liquid chromatography. Hepatic MDA was increased in the alcoholic group (p < 0.001), as was total hepatic glutathione (p < 0.0001). Plasma concentrations of alpha-tocopherol were increased in the alcoholic group, but ascorbic acid and superoxide dismutase values were not affected. No sex differences were detected. The increased MDA production in the alcohol group is strong evidence that lipid peroxidation is a mechanism of alcoholic tissue damage. The rise in hepatic glutathione may be an adaptive response to free radical production that protects the rat against tissue damage. PMID:7828990

  17. Renal Response to Chronic Centrifugation in Rats

    NASA Technical Reports Server (NTRS)

    Ortiz, Rudy M.; Wang, T. J.; Corbin, B. J.; Wade, C. E.; Hargens, Alan R. (Technical Monitor)

    1996-01-01

    Previously reported effects of chronic centrifugation on renal function in mammals are contradictory. The present study was conducted as an effort to provide a comprehensive analysis of renal response to chronic centrifugation (12 days at +2 Gz). Sixteen male Sprague-Dawley rats (210-230 g) were used: eight centrifuged (EC) and eight off centrifuge controls (OCC). During centrifugation EC had lower body weight and food consumption. EC showed a decrease (72%) in water intake for the first two days (T1 and T2) followed by significant increases from T4-T6. EC urine output increased two-fold over the first four days, returning to baseline by T9. EC urea excretion was elevated on T3 through T5. Creatinine, Na(+), K(+), and osmolar excretion were lower than OCC over the last four days of the study. Assuming constant plasma osmolarity and creatinine levels, EC free water clearance (C(sub H2O)) was elevated significantly on T4 when the peak urine output was exhibited. EC also had a greater C(sub H2O) over the last four days, associated with a significantly lower osmolar clearance and GFR. The initial diuresis exhibited during centrifugation can be attributed to a reduced water resorption and increased urea excretion. This diuresis was mediated independent of changes in GFR over the first eight days. However, differences in excretion seen after eight days of centrifugation are probably GFR mediated which would imply animals established a new homeostatic setpoint by that time. Centrifugation elicites an acute alteration in fluid homeostasis followed by adaptation within a week.

  18. Normal and Pathologic Concentrations of Uremic Toxins

    PubMed Central

    Duranton, Flore; Cohen, Gerald; De Smet, Rita; Rodriguez, Mariano; Jankowski, Joachim; Vanholder, Raymond

    2012-01-01

    An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD. PMID:22626821

  19. Effect of Sertraline on Uremic Pruritus Improvement in ESRD Patients

    PubMed Central

    Shakiba, Mansor; Sanadgol, Hoshang; Azmoude, Hamid Reza; Mashhadi, Mohamad Ali; Sharifi, Hassan

    2012-01-01

    Background. Although uremic pruritus is a common and upsetting problem of chronic kidney disease, there is no approved treatment for it. This study was undertaken to find the efficiency of sertraline as a possible treatment for uremic pruritus. Methods. 19 ESRD patients under hemodialysis with severe chronic pruritus were randomly selected to participate in this before-after clinical trial. Before and after starting treatment with sertraline, a detailed pruritus history was obtained and pruritus graded by the 30-item inventory of pruritus that patients based on priorities grade allocated to 3 classes. Subjects were treated with sertraline 50 mg oral daily for four months, with monthly assessments of pruritus symptoms. Results. Before treatment with sertraline, the grade of pruritus in 9 (47.4%) patients was moderate and severe in 10 (52.6%) patients. After treatment, grade of pruritus in 11 (57.8%) patients was weak, 6 (31.5%) have moderate and only 2 (10.7%) patients have severe pruritus. Of 10 patients with severe pruritus, 5 (50%) patients experiencing weak pruritus, and 4 (40%) patients have moderate pruritus after treatment. Based on Wilcoxon signed-rank test, the difference between the grade of pruritus before and after treatment with sertraline was significant (P = 0.001). Conclusions. Although no definitive recommendation can be made regarding treatment of uremic pruritus, we found an increased antipruritic effect of sertraline in ESRD patients. PMID:22973512

  20. [Uremic pruritus: an unresolved challenge].

    PubMed

    Aucella, F; Gesuete, A

    2009-01-01

    Pruritus is a common and unpleasant symptom in the dialysis setting, affecting about half of all hemodialysis and peritoneal dialysis patients. It has a great impact on patients' quality of life and is also associated with increased mortality. The pathogenesis of uremic pruritus (UP) is clearly multifactorial and still poorly understood. At least four main hypotheses have been put forward: dermatological abnormalities, an immune-system derangement that results in a proinflammatory state, an imbalance of the endogenous opioidergic system, and a neuropathic mechanism. The neurophysiology of itch has been shown to be quite similar to that of pain, supporting the hypothesis that the two phenomena may be closely related in dialysis patients, who often also experience uremic neuropathy. Moreover, an array of other triggering factors may include uremic toxins, systemic inflammation, cutaneous xerosis, and common comorbidities such as diabetes mellitus, endocrinopathies and viral hepatitis. The first step in the treatment of UP focuses on some general strategies that include the optimization of the dialysis schedule using biocompatible membranes such as polymethyl methacrylate, and the control of the divalent ion metabolism. The second step may be local therapy with skin emollients and capsaicin creams. More specific treatments that appear promising but have not been proven to be definitively efficacious include UVB light, gabapentin and the novel k-opioid-agonist nalfurafine. Nephrologists, who still tend to neglect this disabling symptom, need to be aware that UP is associated with poorer patient outcomes and that a stepwise therapeutic approach is now available.

  1. Enhanced Gamma Oscillatory Activity in Rats with Chronic Inflammatory Pain

    PubMed Central

    Wang, Jing; Wang, Jing; Xing, Guo-Gang; Li, Xiaoli; Wan, You

    2016-01-01

    It has been reported that oscillatory gamma activity participates in brief acute pain and tonic ongoing pain. It is of great interest to determine whether the gamma activity is involved in chronic pain since chronic pain is a more severe pathological condition characterized by pain persistency. To investigate the oscillatory gamma activity in chronic pain, in the present study, we recorded spontaneous electrocorticogram (ECoG) signals during chronic pain development in rats with chronic inflammatory pain induced by monoarthritis. Power spectrum analysis of ECoG data showed that gamma power increased significantly at the late stage of chronic inflammatory pain. The increased gamma activity occurred mainly at electrodes over primary somatosensory cortices. In rats with chronic pain, the gamma power was positively correlated with the hyperalgesia measured by laser energy that elicited hindpaw withdrawal response. Furthermore, an increased coupling between the amplitude of gamma power and the phase of theta oscillations was observed in chronic inflammatory pain condition. These results indicate an enhanced spontaneous gamma activity in chronic pain and suggest a potential biomarker for the severity of chronic pain. PMID:27847461

  2. Sonic hedgehog expression in a rat model of chronic pancreatitis

    PubMed Central

    Wang, Luo-Wei; Lin, Han; Lu, Yi; Xia, Wei; Gao, Jun; Li, Zhao-Shen

    2014-01-01

    AIM: To analyze the activation of sonic hedgehog (SHh) signaling pathways in a rat model of chronic pancreatitis. METHODS: Forty Wistar rats were randomly divided into 2 groups: experimental group and control group (20 rats in each group). Dibutyltin dichloride was infused into the tail vein of the rats to induce chronic pancreatitis in the experimental group. The same volume of ethanol and glycerol mixture was infused in the control group. The expression of Ptch, Smo and Gli were analyzed using immunohistochemistry, and real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with the control group, significant histological changes in terms of the areas of abnormal architecture, glandular atrophy, fibrosis, pseudo tubular complexes, and edema were observed at week 4 in the experimental group. The expression of Ptch1, Smo and Gli1 in the pancreatic tissue increased significantly in the experimental group. Using RT-PCR, mRNA levels of Ptch, Smo and Gli in the experimental group increased significantly compared with the control group. CONCLUSION: The SHh signaling pathway is aberrantly activated in rats with chronic pancreatitis. The SHh signaling pathway plays an important role in the development of chronic pancreatitis. These results may be helpful in studies focusing on the relationship between chronic pancreatitis and pancreatic cancer. PMID:24782623

  3. Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure

    PubMed Central

    Gurbuz, Nilgun; Kol, Arif; Ipekci, Tumay; Ates, Erhan; Baykal, Asli; Usta, Mustafa F

    2015-01-01

    The relationship between erectile dysfunction (ED) and chronic renal failure (CRF) has been reported in several studies. This study aimed to investigate whether the chronic use of sildenafil could enhance the erectile capacity in CRF-induced rats. In addition, we assessed the effect of that treatment on certain molecules, which have been suggested to play crucial roles in erectile physiology and CRF-related ED as well. Three groups of animals were utilized: (1) age-matched control rats, (2) CRF-induced rats, (3) CRF-induced rats treated with chronic administration of sildenafil (5 mg kg−1 p.o. for 6 weeks [treatment started after 6 weeks of CRF induction]). At 3 months, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue advanced glycation end products (AGE's)/5-hydroxymethyl-2-furaldehyde, malondialdehyde (MDA), cGMP (ELISA), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Western blot) analyses were performed in all rat groups. CRF-induced rats had a significant decrease in erectile function when compared to control rats (P < 0.05). The increase in both intracavernosal pressure (ICP) and area under the curve of CRF-induced rats treated with sildenafil (Group 3) was greater than CRF-induced rats (Group 2). Additionally, sildenafil treatment decreased AGE, MDA and iNOS levels, while it preserved nNOS and cGMP contents in CRF-induced penile tissue. Decreased AGE, MDA, iNOS and increased nNOS, cGMP levels at the sildenafil-treated group increased both ICP and Total ICP to CNS, which led to improve erectile function in CRF-induced rats. The results of the present study revealed the therapeutic effect of chronic sildenafil administration on erectile function in CRF-induced rats. PMID:25652632

  4. Vascular ossification – calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis – calcific uremic arteriolopathy: the emerging role of sodium thiosulfate

    PubMed Central

    Hayden, Melvin R; Tyagi, Suresh C; Kolb, Lisa; Sowers, James R; Khanna, Ramesh

    2005-01-01

    Background Vascular calcification is associated with metabolic syndrome, diabetes, hypertension, atherosclerosis, chronic kidney disease, and end stage renal disease. Each of the above contributes to an accelerated and premature demise primarily due to cardiovascular disease. The above conditions are associated with multiple metabolic toxicities resulting in an increase in reactive oxygen species to the arterial vessel wall, which results in a response to injury wound healing (remodeling). The endothelium seems to be at the very center of these disease processes, acting as the first line of defense against these multiple metabolic toxicities and the first to encounter their damaging effects to the arterial vessel wall. Results The pathobiomolecular mechanisms of vascular calcification are presented in order to provide the clinician – researcher a database of knowledge to assist in the clinical management of these high-risk patients and examine newer therapies. Calciphylaxis is associated with medial arteriolar vascular calcification and results in ischemic subcutaneous necrosis with vulnerable skin ulcerations and high mortality. Recently, this clinical syndrome (once thought to be rare) is presenting with increasing frequency. Consequently, newer therapeutic modalities need to be explored. Intravenous sodium thiosulfate is currently used as an antidote for the treatment of cyanide poisioning and prevention of toxicities of cisplatin cancer therapies. It is used as a food and medicinal preservative and topically used as an antifungal medication. Conclusion A discussion of sodium thiosulfate's dual role as a potent antioxidant and chelator of calcium is presented in order to better understand its role as an emerging novel therapy for the clinical syndrome of calciphylaxis and its complications. PMID:15777477

  5. Chronic amantadine treatment enhances the sexual behaviour of male rats.

    PubMed

    Ferraz, Marcia Martins Dias; Fontanella, Julia Cordeiro; Damasceno, Fabio; Silva de Almeida, Olga Maria Martins; Ferraz, Marcos Rochedo

    2007-04-01

    The acute administration of amantadine (AMA), a dopaminomimetic and NMDA glutamatergic receptor antagonist also used as an anti-Parkinsonian agent, stimulates male rat sexual behaviour. However it remains unclear whether long term AMA supplementation might also provoke a similar increase in male rat sexual conduct. In the present study, male rats were administered AMA (5-50 mg/kg/day) or vehicle daily for 21 days and their sexual response was monitored weekly. Chronic treatment with AMA effectively increased the sexual response of male rats, similarly to what had been observed before with acute amantadine treatment. The main effect of chronic AMA treatment occurs in arousal and in ejaculatory response, whilst the excitatory component was not affected. The 21-day treatment with AMA did not lead to tolerance, suggesting that perhaps AMA could be used in male human patients to prevent sexual inhibition caused by anti-depressant and anti-psychotic agents.

  6. Chronic effects of mercuric chloride ingestion on rat adrenocortical function

    SciTech Connect

    Agrawal, R.; Chansouria, J.P.N. )

    1989-09-01

    Mercurial contamination of environment has increased. Mercury accumulates in various organs and adversely affects their functions. Some of the most prominent toxic effects of inorganic mercury compounds include neurotoxicity, hepatotoxicity and nephrotoxicity. Besides this, mercury has also been reported to affect various endocrine glands like pituitary, thyroid, gonadal and adrenal glands. There have been no reports on the toxic effects of chronic oral administration of varying doses of mercuric chloride on adrenocortical function in albino rats. The present work was undertaken to study the adrenocortical response to chronic oral administration of mercuric chloride of varying dose and duration in albino rats.

  7. Cromolyn sodium: a potential therapy for uremic pruritus?

    PubMed

    Rosner, Mitchell H

    2006-04-01

    Uremic pruritus occurs in up to 50% of patients undergoing chronic hemodialysis. The pathogenesis of this disabling condition is unknown but likely involves multiple pathways involving the peripheral and central nervous system as well as local chemical and inflammatory mediators. Therapy has involved modification of the dialysis procedure, topical medications such as emollients, physical treatments such as ultraviolet light, and several oral medications such as antihistamines, activated charcoal, and gabapentin. Unfortunately, most of these therapies have not been subjected to rigorous clinical trials and clinical success has been variable. Two patients with disabling uremic pruritus refractory to multiple interventions are reported, who showed significant improvement in pruritus severity as assessed by a visual analog scale when they were treated with the mast cell stabilizer cromolyn sodium. Cessation of cromolyn resulted in return of pruritus, which improved with rechallenge with the medication. Cromolyn sodium may offer an alternative therapy for patients with refractory uremic pruritus, and should be subjected to a randomized placebo-controlled trial.

  8. Sodium status influences chronic amphotericin B nephrotoxicity in rats.

    PubMed Central

    Ohnishi, A; Ohnishi, T; Stevenhead, W; Robinson, R D; Glick, A; O'Day, D M; Sabra, R; Jackson, E K; Branch, R A

    1989-01-01

    The nephrotoxic potential of amphotericin B (5 mg/kg per day intraperitoneally for 3 weeks) has been investigated in salt-depleted, normal-salt, and salt-loaded rats. In salt-depleted rats, amphotericin B decreased creatinine clearance linearly with time, with an 85% reduction by week 3. In contrast, in normal-salt rats creatinine clearance was decreased but to a lesser extent at week 2 and 3, and in salt-loaded rats creatinine clearance did not change for 2 weeks and was decreased by 43% at week 3. All rats in the sodium-depleted group had histopathological evidence of patchy tubular cytoplasmic degeneration in tubules that was not observed in any normal-salt or salt-loaded rat. Concentrations of amphotericin B in plasma were not significantly different among the three groups at any time during the study. However, at the end of 3 weeks, amphotericin B levels in the kidneys and liver were significantly higher in salt-depleted and normal-salt rats than those in salt-loaded rats, with plasma/kidney ratios of 21, 14, and 8 in salt-depleted, normal-salt, and salt-loaded rats, respectively. In conclusion, reductions in creatinine clearance and renal amphotericin B accumulation after chronic amphotericin B administration were enhanced by salt depletion and attenuated by sodium loading in rats. PMID:2802551

  9. Chronic CXCL10 Alters Neuronal Properties in Rat Hippocampal Culture

    PubMed Central

    Cho, Jungsook; Nelson, Thomas E.; Bajova, Hilda; Gruol, Donna L.

    2009-01-01

    The chemokine CXCL10 is expressed in the central nervous system (CNS) during neuroinflammatory conditions. Neurons express CXCR3, the receptor for CXCL10, and neuronal function has been shown to be altered by acute exposure to CXCL10. Little is known about the effects of chronic exposure to CXCL10 on neuronal function. Results from our studies show that chronic exposure of cultured rat hippocampal neurons to CXCL10 results in altered levels of protein for GABA and glutamate receptors and altered synaptic network activity. These effects of CXCL10 may contribute to altered CNS function that occurs in some chronic neuroinflammatory conditions. PMID:19167097

  10. [Massive hydrothorax in a ease of hemolytic uremic syndrome: conservative treatment without interruption of peritoneal dialysis].

    PubMed

    Marin, Gustavo R

    2016-12-01

    The hydrothorax is a known but rare complication of acute and chronic peritoneal dialysis. Patients with hemolytic uremic syndrome seem to be more prone to this complication. Usually discontinuation of treatment is necessary due to the lack of resolution or recurrence of hydrothorax and transfer to hemodialysis, but some patients can continue dialysis with modification of technique and with resolution of hydrothorax.

  11. [Hemolytic uremic syndrome caused by enterohaemorrhagic Escherichia coli].

    PubMed

    Ibarra, Cristina; Goldstein, Jorge; Silberstein, Claudia; Zotta, Elsa; Belardo, Marcela; Repetto, Horacio A

    2008-10-01

    Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, plaquetopenia and kidney damage. It is the leading cause of acute renal failure in pediatric age and the second for chronic renal failure. Shiga toxin-producing Escherichia coli (STEC) is the first etiologic agent of HUS being its main reservoir cattle and transmitted via contaminated food. At present, there is no specific treatment to reduce the progression of HUS. The study of the mechanisms by which STEC infects and Shiga toxin induces HUS can help to find new strategies to prevent this disease.

  12. Calcific Uremic Arteriolopathy: An Underrecognized Entity

    PubMed Central

    Kumar, Victoria Ann

    2011-01-01

    Calcific uremic arteriolopathy (CUA), or calciphylaxis, is an uncommon and underrecognized disease that often occurs in the setting of chronic kidney disease or end-stage renal disease. It is characterized by small-vessel calcification, although many times it is associated with normal serum levels of calcium, phosphorus, and parathyroid hormone. The lesions appear as necrotic eschars, ulcerations, indurated nodules, and dry gangrene and are usually very painful. Diagnosis is based on clinical judgment and recognition of characteristic skin lesions. Biopsy can be performed but may be complicated by poor wound healing. Treatment of CUA involves rigorous wound care, strict control of mineral metabolism with avoidance of calcium and vitamin D analogs, and pain control. Other treatment options include sodium thiosulfate, hyperbaric oxygen therapy, daily hemodialysis using low-calcium dialysate, and bisphosphonates. Even with treatment, CUA is associated with significant morbidity and mortality. The patient in the case reported here had characteristic skin lesions and several risk factors for CUA, but diagnosis was delayed. PMID:21841931

  13. H NMR spectroscopy-based metabolomic assessment of uremic toxicity, with toxicological outcomes, in male rats following an acute, mid-life insult from ochratoxin a.

    PubMed

    Mantle, Peter G; Nicholls, Andrew W; Shockcor, John P

    2011-06-01

    Overt response to a single 6.25 mg dose of ochratoxin A (OTA) by oral gavage to 15 months male rats was progressive loss of weight during the following four days. Lost weight was restored within one month and animals had a normal life-span without OTA-related terminal disease. Decline in plasma OTA concentration only commenced four days after dosing, while urinary excretion of OTA and ochratoxin alpha was ongoing. During a temporary period of acute polyuria, a linear relationship between urine output and creatinine concentration persisted. Elimination of other common urinary solutes relative to creatinine was generally maintained during the polyuria phase, except that phosphate excretion increased temporarily. (1)H NMR metabolomic analysis of urine revealed a progressive cyclic shift in the group principal components data cluster from before dosing, throughout the acute insult phase, and returning almost completely to normality when tested six months later. Renal insult by OTA was detected by (1)H NMR within a day of dosing, as the most sensitive early indicator. Notable biomarkers were trimethylamine N-oxide and an aromatic urinary profile dominated by phenylacetylglycine. Tolerance of such a large acute insult by OTA, assessed by rat natural lifetime outcomes, adds a new dimension to toxicology of this xenobiotic.

  14. Adsorption capacity of poly(ether imide) microparticles to uremic toxins.

    PubMed

    Tetali, Sarada D; Jankowski, Vera; Luetzow, Karola; Kratz, Karl; Lendlein, Andreas; Jankowski, Joachim

    2016-01-01

    Uremia is a phenomenon caused by retention of uremic toxins in the plasma due to functional impairment of kidneys in the elimination of urinary waste products. Uremia is presently treated by dialysis techniques like hemofiltration, dialysis or hemodiafiltration. However, these techniques in use are more favorable towards removing hydrophilic than hydrophobic uremic toxins. Hydrophobic uremic toxins, such as hydroxy hipuric acid (OH-HPA), phenylacetic acid (PAA), indoxyl sulfate (IDS) and p-cresylsulfate (pCRS), contribute substantially to the progression of chronic kidney disease (CKD) and cardiovascular disease. Therefore, objective of the present study is to test adsorption capacity of highly porous microparticles prepared from poly(ether imide) (PEI) as an alternative technique for the removal of uremic toxins. Two types of nanoporous, spherically shaped microparticles were prepared from PEI by a spraying/coagulation process.PEI particles were packed into a preparative HPLC column to which a mixture of the four types of uremic toxins was injected and eluted with ethanol. Eluted toxins were quantified by analytical HPLC. PEI particles were able to adsorb all four toxins, with the highest affinity for PAA and pCR. IDS and OH-HPA showed a partially non-reversible binding. In summary, PEI particles are interesting candidates to be explored for future application in CKD.

  15. Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction.

    PubMed

    Jourde-Chiche, Noémie; Dou, Laetitia; Cerini, Claire; Dignat-George, Françoise; Brunet, Philippe

    2011-01-01

    Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium-dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia-specific factors. Several uremic toxins, mostly protein-bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p-cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro-oxidant and pro-inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein-bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.

  16. Repeated social defeat stress induces chronic hyperthermia in rats.

    PubMed

    Hayashida, Sota; Oka, Takakazu; Mera, Takashi; Tsuji, Sadatoshi

    2010-08-04

    Psychological stressors are known to increase core body temperature (T(c)) in laboratory animals. Such single stress-induced hyperthermic responses are typically monophasic, as T(c) returns to baseline within several hours. However, studies on the effects of repeated psychological stress on T(c) are limited. Therefore, we measured T(c) changes in male Wistar rats after they were subjected to 4 social defeat periods (each period consisting of 7 daily 1h stress exposures during the light cycle followed by a stress-free day). We also assessed affective-like behavioral changes by elevated plus maze and forced swim tests. In the stressed rats, the first social defeat experience induced a robust increase in T(c) (+1.3 degrees C). However, the T(c) of these rats was not different from control animals during the subsequent dark period. In comparison, after 4 periods of social defeat, stressed rats showed a small but significantly higher (+0.2-0.3 degree C) T(c) versus control rats during both light and dark periods. Stressed rats did not show increased anxiety-like behavior versus control rats as assessed by the elevated plus maze test. However, in the forced swim test, the immobility time of stressed rats was significantly longer versus control rats, suggesting an increase in depression-like behavior. Furthermore, hyperthermia and depression-like behavior were still observed 8 days after cessation of the final social defeat session. These results suggest that repeated social defeat stress induces a chronic hyperthermia in rats that is associated with behavior resembling depression but not anxiety.

  17. An Enlarged Profile of Uremic Solutes

    PubMed Central

    Tanaka, Hisae; Sirich, Tammy L.; Plummer, Natalie S.; Weaver, Daniel S.; Meyer, Timothy W.

    2015-01-01

    Better knowledge of the uremic solutes that accumulate when the kidneys fail could lead to improved renal replacement therapy. This study employed the largest widely available metabolomic platform to identify such solutes. Plasma and plasma ultrafiltrate from 6 maintenance hemodialysis (HD) patients and 6 normal controls were first compared using a platform combining gas and liquid chromatography with mass spectrometry. Further studies compared plasma from 6 HD patients who had undergone total colectomy and 9 with intact colons. We identified 120 solutes as uremic including 48 that had not been previously reported to accumulate in renal failure. Combination of the 48 newly identified solutes with those identified in previous reports yielded an extended list of more than 270 uremic solutes. Among the solutes identified as uremic in the current study, 9 were shown to be colon-derived, including 6 not previously identified as such. Literature search revealed that many uremic phenyl and indole solutes, including most of those shown to be colon-derived, come from plant foods. Some of these compounds can be absorbed directly from plant foods and others are produced by colon microbial metabolism of plant polyphenols that escape digestion in the small intestine. A limitation of the metabolomic method was that it underestimated the elevation in concentration of uremic solutes which were measured using more quantitative assays. PMID:26317986

  18. Chronic administration of quercetin prevent spatial learning and memory deficits provoked by chronic stress in rats.

    PubMed

    Mohammadi, Hadis Said; Goudarzi, Iran; Lashkarbolouki, Taghi; Abrari, Kataneh; Elahdadi Salmani, Mahmoud

    2014-08-15

    There are several reports that cognitive impairment is observed in stress related disorders and chronic stress impairs learning and memory. However, very few studies have looked into the possible ways of preventing this stress-induced deficit. This research study was conducted to evaluate the effects of quercetin, a natural flavonoid, with strong antioxidant and free radical scavenger properties, on chronic stress induced learning and memory deficits and oxidative stress in hippocampus. For chronic stress, rats were restrained daily for 6h/day (from 9:00 to 15:00) for 21 days in well-ventilated plexiglass tubes without access to food and water. The animals were injected with quercetin or vehicle 60 min before restraint stress over a period of 21 days. Then, rats trained with six trials per day for 6 consecutive days in the water maze. On day 28, a probe test was done to measure memory retention. In addition, oxidative stress markers in the hippocampus were evaluated. Results of this study demonstrated that chronic stress exposure rats exhibited higher escape latency during training trials and reduced time spent in target quadrant, higher escape location latency and average proximity in probe trial test. Quercetin (50mg/kg) treatment during restraint stress (21 days) markedly decreased escape latency and increased time spent in target quadrant during Morris water maze task. In comparison to vehicle treated group, chronic-stress group had significantly higher malondialdehyde (MDA) levels, significantly higher superoxide dismutase (SOD) activity and significantly lower glutathione peroxidase (GPx) activity in the hippocampus. Quercetin treatment caused a significant decrease in the hippocampus MDA levels and improves SOD and GPx activities in stressed animals. Finally, quercetin significantly decreased plasma corticosterone levels in stressed animals. Based on results of this study, chronic stress has detrimental effects on learning and memory and quercetin treatment

  19. Chronic alcoholism-mediated metabolic disorders in albino rat testes

    PubMed Central

    Bondarenko, Larysa B.; Matvienko, Anatoliy V.; Kovalenko, Valentina M.

    2014-01-01

    There is good evidence for impairment of spermatogenesis and reductions in sperm counts and testosterone levels in chronic alcoholics. The mechanisms for these effects have not yet been studied in detail. The consequences of chronic alcohol consumption on the structure and/or metabolism of testis cell macromolecules require to be intensively investigated. The present work reports the effects of chronic alcoholism on contents of free amino acids, levels of cytochrome P450 3A2 (CYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and protein thiol groups in rat testes. Wistar albino male rats were divided into two groups: I – control (intact animals), II – chronic alcoholism (15% ethanol self-administration during 150 days). Following 150 days of alcohol consumption, testicular free amino acid content was found to be significantly changed as compared with control. The most profound changes were registered for contents of lysine (–53%) and methionine (+133%). The intensity of DNA fragmentation in alcohol-treated rat testes was considerably increased, on the contrary CYP3A2 mRNA expression in testis cells was inhibited, testicular contents of total and etherified cholesterol increased by 25% and 45% respectively, and protein SH-groups decreased by 13%. Multidirectional changes of the activities of testicular dehydrogenases were detected. We thus obtained complex assessment of chronic alcoholism effects in male gonads, affecting especially amino acid, protein, ATP and NADPH metabolism. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed metabolic disorders can have negative implication on cellular regulation of spermatogenesis under long-term ethanol exposure. PMID:26109895

  20. Regulation of body mass in rats exposed to chronic acceleration

    NASA Technical Reports Server (NTRS)

    Pitts, G. C.; Bull, L. S.; Oyama, J.

    1975-01-01

    Female rats approximately 6 mo old were chronically centrifuged for up to 30 days at 2.76 G or 3.18 G and sacrificed at intervals for body-composition study. Both fat and the fat-free body mass (FFBM) were reduced during the 1st wk of centrifugation, with the fat showing considerably more variation both within and between groups. The FFBM was reduced below control level to the same extent in rats fed commercial chow, a high-fat diet, or a high-protein diet or in rats prefasted to produce a body-mass deficit at the start of centrifugation. There were no centrifugation-associated changes in body water content. It was concluded that body fat showed no evidence of regulation, FFBM is regulated at any constant level of acceleration between 1 and 4.15 G, and the change in FFBM induced by a change in acceleration is probably not regulated.

  1. Effects of chronic amiodarone treatment on rat testis.

    PubMed

    Özkaya, Ahmet Kağan; Dilber, Embiya; Gürgen, Seren Gülşen; Kutlu, Ömer; Cansu, Ali; Gedik, Yusuf

    2016-04-01

    Amiodarone is a potent agent used to treat tachyarrhythmias, which are especially refractory to other medications, in both adults and children. Although widely used as an antiarrhythmic drug, amiodarone causes many serious adverse effects that limit its use. This study investigated the possible morphological and apoptotic effects of amiodarone on rat testes. Amiodarone was administered to male Sprague-Dawley rats at doses of 20 or 200mg/kg/day for 14 days. A histopathological examination of testicular tissue revealed the presence of inflammatory cells in the seminiferous tubule lumen together with swelling and vacuolization in the cytoplasm of some spermatogonia; these effects occured in a dose-dependent manner. Immunohistochemical staining showed evidence of apoptosis, including caspase-3, caspase-9, Bax and increased DNA fragmentation was detected via a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. In conclusion, the results show that chronic amiodarone treatment causes dose-dependent degenerative and apoptotic effects on rat testes.

  2. Chronic cobalt treatment decreases hyperglycemia in streptozotocin-diabetic rats.

    PubMed

    Vasudevan, Harish; McNeill, John H

    2007-04-01

    Diabetes is a metabolic disorder characterized by elevated blood glucose levels. Although conventional treatments such as insulin and other drugs reduce blood glucose, there is still a therapeutic need for effective orally administered drugs. Trace elements like vanadium and tungstate have been successfully demonstrated to reduce blood glucose in experimental diabetes with minimal chronic complications. We investigated the anti-hyperglycemic effects of cobalt in streptozotocin-diabetic rats. Normal and diabetic rats were provided with drinking water containing 3.5 mM cobalt chloride for three weeks followed by 4 mM for four weeks. Body weights and fluid consumption were monitored on a daily basis, while food intake was recorded twice every week. Prior to termination, an oral glucose tolerance test was performed on the animals. Diabetic rats lost significant body weight (357 +/- 2 gm) compared to controls (482 +/- 3 gm). Body weight was further reduced by cobalt treatment (290 +/- 2 gm). Although it was difficult to establish a dosing regimen without weight loss, food and fluid consumption in cobalt-treated diabetic rats improved significantly compared to untreated diabetics. Plasma glucose levels were significantly reduced with reference to diabetic controls (29.3 +/- 0.9 mM) by the fourth week to a lower but still hyperglycemic level (13.6 +/- 3.4 mM). Cobalt-treated diabetic rats demonstrated an enhanced ability to clear a glucose load compared to untreated diabetics. Cobalt treatment neither affected the feeding and drinking patterns nor plasma glucose in normoglycemic animals although body weights decreased compared to untreated controls. We conclude that chronic cobalt treatment decreases plasma glucose levels in STZ-diabetic rats and improves tolerance to glucose.

  3. Bile secretion in albino rat following chronic honey intake.

    PubMed

    Alagwu, E A; Nneli, R O; Okwari, O O; Osim, E E

    2009-12-01

    This study was carried out to evaluate the effect of honey intake on bile secretion, bile electrolytes, bilirubin and cholesterol levels including plasma cholesterol in albino rats. 20 male albino rats (200-210 g) were used in the study. The rats were assigned randomly into 2 groups (control and honey-fed groups), each group containing 10 rats. The control was fed on normal rat feed and water while the test group was fed on normal rat feed with honey added to its drinking water (1 ml of honey to every initial 10 ml of water) for 22 weeks. After 22 weeks the animals were starved for 12 hrs before the experiment, weighed and anaesthetized with sodium thiopentone (6 mg/100 mg body weight) intraperitoneally. The common bile duct was cannulated and bile collected for 3 hrs. The rate of bile flow was noted, the concentrations of bile electrolytes and bilirubin, bile and plasma cholesterol levels were determined in the control and test groups. The results obtained showed a significant [P<0.05] decrease in the rate of bile flow in the test (0.30+/-0.03 ml/hr) compared with the control groups (0.45+/-0.04 ml/hr). There were no significant differences in the concentration of bile electrolytes and bilirubin in the two groups. However, there was a significant [P<0.05] increase in the bile cholesterol and decrease in plasma cholesterol levels in the test rats compared with the control. It is therefore concluded that chronic consumption of unprocessed Nigerian honey resulted in decrease bile flow, increase bile cholesterol and decrease plasma cholesterol in albino rats.

  4. Enhancement of erythroid colony growth by triiodothyronine in cell cultures from bone marrow of normal and anemic rats with chronic renal failure.

    PubMed

    Malgor, L A; Valsecia, M E; Verges, E G; de Markowsky, E E

    1995-01-01

    In order to make a contribution in clarifying the role of thyroid hormones on modulation of erythropoiesis and to gain a further insight on the effects of these hormones in the anemia of chronic renal failure (CRF), we studied the action of triiodo-1-thyronine (LT3) and DT3, a dextrorotary non-calorigenic isomer of T3 on late (CFU-E) and early (BFU-E) committed erythroid precursor cells from bone marrow of normal and anemic uremic rats. Cultures were prepared using the methylcellulose technique containing a standard dose (182 mU/ml) of erythropoietin (Ep), LT3 and DT3 in doses of 0.5 and 1.5 micrograms/ml. Thyroid hormones were added to cultures in the absence of Ep. Our results demonstrated that LT3 and DT3 produced a direct and significant stimulation of CFU-E formation and a moderate increase of BFU-E. A dose-correlation was apparent in cultures containing thyroid hormones. DT3 was somewhat less active than LT3. As expected, Ep also produced a significant increase in erythroid colony formation, mainly CFU-E. It is notheworthy that the effects of LT3, DT3 and Ep on erythroid colony growth were significantly higher in marrow cultures from anemic rats with CRF, indicating an increased proliferative cell kinetics of committed erythroid cells in response to these drugs.

  5. Impact of Iodinated Contrast on Renal Function and Hemodynamics in Rats with Chronic Hyperglycemia and Chronic Kidney Disease.

    PubMed

    Fernandes, Sheila Marques; Martins, Daniel Malisani; da Fonseca, Cassiane Dezoti; Watanabe, Mirian; Vattimo, Maria de Fátima Fernandes

    2016-01-01

    Iodinated contrast (IC) is clinically used in diagnostic and interventional procedures, but its use can result in contrast-induced acute kidney injury (CI-AKI). Chronic kidney disease (CKD) and chronic hyperglycemia (CH) are important predisposing factors to CI-AKI. The aim of this study was to investigate the impact of iodinated contrast on the renal function and hemodynamics in rats with chronic hyperglycemia and chronic kidney disease. A total of 30 rats were divided into six groups; Sham: control of chronic renal disease; Citrate: control of chronic hyperglycemia (CH); Nx5/6: rats with 5/6 nephrectomy; Chronic Hyperglycemia: rats receiving Streptozotocin 65 mg/kg; Nx5/6 + IC: rats Nx5/6 received 6 mL/kg of IC; CH + IC: Chronic hyperglycemia rats receiving 6 mL/kg of IC. Renal function (inulin clearance; urinary neutrophil gelatinase-associated lipocalin, NGAL) and hemodynamics (arterial blood pressure; renal blood flow; renal vascular resistance) were evaluated. Iodinated contrast significantly increased urinary NGAL and reduced inulin clearance, while the hemodynamics parameters showed changes in arterial blood pressure, renal blood flow, and renal vascular resistance in both CKD and CH groups. The results suggest that the iodinated contrast in risk factors models has important impact on renal function and hemodynamics. NGAL was confirmed to play a role of highlight in diagnosis of CI-AKI.

  6. Femoral development in chronically centrifuged rats

    NASA Technical Reports Server (NTRS)

    Smith, S. D.

    1977-01-01

    Groups of 30-d-old male and female rats were centrifuged at 2.00 G (RE, Rotation Experimental), 1.05 G (RC, Rotation Control) or exposed to the noise and wind of the centrifuge at 1.00 G (EC, Earth Control) for periods of 1, 2, 4, 8, and 16 weeks. Measurements of their femurs indicated that exposure to centrifugation a) decreased femoral length in RE animals, b) increased femoral length in RC animals, c) reduced femoral diameter in RE and RC animals, d) increased L/D ratios in RC animals, e) decreased L/D ratios in RE animals, f) increased femur length/body weight in RE animals, g) decreased cortical thickness (CT) in RE animals, h) increased relative CT in RE animals, and decreased it in RC animals, i) accelerated ossification in RC femoral heads, j) thinned and distorted RE epiphyseal plates, and k) thickened condylar cartilage in RE females. The effects tended to be strongly sexually dimorphic, with females more severely affected by the stress than males.

  7. Chronic Methamphetamine Effects on Brain Structure and Function in Rats

    PubMed Central

    Thanos, Panayotis K.; Kim, Ronald; Delis, Foteini; Ananth, Mala; Chachati, George; Rocco, Mark J.; Masad, Ihssan; Muniz, Jose A.; Grant, Samuel C.; Gold, Mark S.; Cadet, Jean Lud; Volkow, Nora D.

    2016-01-01

    Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [18F] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [3H]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [3H]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA

  8. Chronic Methamphetamine Effects on Brain Structure and Function in Rats.

    PubMed

    Thanos, Panayotis K; Kim, Ronald; Delis, Foteini; Ananth, Mala; Chachati, George; Rocco, Mark J; Masad, Ihssan; Muniz, Jose A; Grant, Samuel C; Gold, Mark S; Cadet, Jean Lud; Volkow, Nora D

    2016-01-01

    Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [18F] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [3H]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [3H]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA

  9. Compensatory effects of chronic electrostimulation on unweighted rat soleus muscle.

    PubMed

    Leterme, D; Falempin, M

    1994-01-01

    The purpose of this study was to investigate the effects of electrostimulation in counteracting the transformation of the unweighted rat soleus muscle. The stimulation resembled the firing patterns of normal slow motor units and was imposed during hindlimb suspension. For the 10-day hindlimb suspended rats, the transformation of the slow soleus muscle towards a faster type was characterized by a decrease in the time to peak tension and the half-relaxation time of the twitch, a reduction in the P20/P0 index, i.e. the ratio of the subtetanic tension at 20 Hz relative to the tetanic tension, and a decrease in the percentage distributions of type I fibres accompanied by an increase of type IIa and IIc fibres. These changes were prevented by electrostimulation since, for the parameters mentioned above, no significant difference was observed in the soleus of the suspended rats that received electrostimulation when compared with the control rats. Nevertheless, neither the loss of mass nor the decrease in force output in the suspended rats were prevented by electrostimulation. The present results suggest a positive compensation of the suspension-induced alterations in the contractile and histochemical properties of the soleus muscle by means of chronic electrostimulation, which, however, do not prevent atrophy or the loss of contractile force.

  10. FGF23 fails to inhibit uremic parathyroid glands.

    PubMed

    Canalejo, Rocío; Canalejo, Antonio; Martinez-Moreno, Julio Manuel; Rodriguez-Ortiz, M Encarnacion; Estepa, Jose C; Mendoza, Francisco Javier; Munoz-Castaneda, Juan Rafael; Shalhoub, Victoria; Almaden, Yolanda; Rodriguez, Mariano

    2010-07-01

    Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D(3). FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal-regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal-regulated kinase 1/2-mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition.

  11. Effects of intraperitoneal thymoquinone on chronic neuropathic pain in rats.

    PubMed

    Amin, Bahareh; Taheri, Mohammad Mehdi Heravi; Hosseinzadeh, Hossein

    2014-10-01

    In this study, we evaluated the protective effects of thymoquinone, the major constituent of Nigella sativa seeds on the neuropathic pain of rats with chronic constrictive injury of the sciatic nerve. Rats received repeated administration of thymoquinone (1.25, 2.5, and 5 mg/kg, i. p.) once a day for 14 days, beginning immediately after the nerve injury. Mechanical allodynia, cold allodynia, and thermal hyperalgesia were assessed with the von Frey filament, acetone drop, or radiant heat stimulus, respectively. Recent evidence points towards a role of oxidative stress, spinal glia activation, and cell death in the pathogenesis of neuropathic pain. Ionized calcium-binding adapter molecule 1 (a marker of microglia), glial fibrillary acidic protein (a marker of astroglia), Bcl2-associated X protein (a proapoptotic protein), and B-cell lymphoma protein 2 (an antiapoptotic protein) were measured using Western blot on days 3, 7, and 14 post chronic constrictive injury. The changes in the protein levels of malondialdehyde and glutathione, biomarkers of oxidative stress, were assessed by spectrophotometric assay on day 14 post chronic constrictive injury. Repeated treatment with thymoquinone (2.5 and 5 mg/kg) significantly alleviated behavioral signs of neuropathic pain. In the lumbar spinal cord of neuropathic rats, ionized calcium-binding adapter molecule 1 and Bcl2-associated X protein increased on day 3 post chronic constrictive injury, whereas B-cell lymphoma protein 2 did not significantly change. After repeated thymoquinone administration, the elevated Bcl2-associated X protein and ionized calcium-binding adapter molecule reduced on day 3, while the level of B-cell lymphoma protein 2 was even stimulated. Ionized calcium-binding adapter molecule and Bcl2-associated X protein/B-cell lymphoma protein 2 ratio declined by days 7 and 14; consequently, there were no significant differences among groups. No or little change was observed in the glial fibrillary acidic

  12. An update on protein-bound uremic retention solutes.

    PubMed

    Vanholder, Raymond; Schepers, Eva; Pletinck, Anneleen; Neirynck, Nathalie; Glorieux, Griet

    2012-01-01

    Although protein-bound uremic retention solutes are recognized as 1 of the 3 main categories of uremic retention solutes, they only recently have been submitted to thorough analysis. In vitro and ex vivo data link both p-cresyl sulfate and indoxyl sulfate, two of the main compounds of this solute group, to negative impact on the cardiovascular system and progression of kidney failure. Recent in vivo observational data also relate concentration of these compounds to survival outcome, inflammation, and vascular disease in different, even moderate, stages of chronic kidney disease. Removal by different dialysis strategies, even high-flux hemodialysis, is difficult, and only by applying convection, some improvement of removal has been obtained. The other strategy with the potential to decrease concentration is by influencing intestinal generation and/or absorption. The sorbent Kremezin (AST-120) has been shown in controlled studies to decrease protein-bound solute concentration. In pilot controlled studies, AST-120 has been shown to be superior on outcome parameters to placebo. Results from large randomized trials are awaited, before these data can be considered as solid enough to warrant the recommendation to use these compounds for overall therapeutic purposes.

  13. Sub-chronic toxicity of methyl benzimidazole carbamate in rats

    SciTech Connect

    Janardhan, A.; Rao, A.B.; Sisodia, P.

    1987-05-01

    Methyl benzimidazole carbamate (MBC) is a broad spectrum systemic fungicide effectively used against a wide variety of pests of vegetable crops and fruit orchards. On seed treatment MBC was found to be actively absorbed by the seedlings and transported to aerial parts. The residual activity of the chemical on various parts of vegetable and food crops was reported to vary from 3.5 to 6.3 ppm persisting from 15 days to 45 days in different parts of the plant. However, WHO has recommended the desirability of conducting short-term and long-term toxicity studies of this fungicide in mammals. Subsequent studies revealed its embryotoxic potential in rats and rabbits. This paper gives the results of sub-chronic administration of MBC in rats designed to assay the possible toxicity to vital organs like the haemopoetic system, liver and kidneys.

  14. Norepinephrine-induced diuresis in chronically ethanol-treated rats

    SciTech Connect

    Pohorecky, L.A. )

    1989-01-01

    Previous research from this laboratory indicated that noradrenergic mechanisms might mediate ethanol diuresis. Experiments described here examined changes in sensitivity of noradrenergic mechanisms in animals chronically treated with ethanol. Norepinephrine hydrochloride (0-12 ug intracerebroventricularly) produced dose-dependent diuresis in control and ethanol treated rats on the first day of treatment. Tolerance to ethanol diuresis was present after 10 day of ethanol treatment. Lack of responsiveness to norepinephrine-induced diuresis was evident only on the 20th day of treatment in both the ethanol and dextrin-maltose groups of rats. These results indicate a temporal dissociation between the tolerance to ethanol-induced and norepinephrine-induced diuresis and suggest that norepinephrine may not play a primary role in the development of tolerance to the diuretic action of ethanol.

  15. Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs* **

    PubMed Central

    Torres, Ronaldo Lopes; Torres, Iraci Lucena da Silva; Laste, Gabriela; Ferreira, Maria Beatriz Cardoso; Cardoso, Paulo Francisco Guerreiro; Belló-Klein, Adriane

    2014-01-01

    Objective: To determine the effects of acute and chronic administration of methylprednisolone on oxidative stress, as quantified by measuring lipid peroxidation (LPO) and total reactive antioxidant potential (TRAP), in rat lungs. Methods: Forty Wistar rats were divided into four groups: acute treatment, comprising rats receiving a single injection of methylprednisolone (50 mg/kg i.p.); acute control, comprising rats i.p. injected with saline; chronic treatment, comprising rats receiving methylprednisolone in drinking water (6 mg/kg per day for 30 days); and chronic control, comprising rats receiving normal drinking water. Results: The levels of TRAP were significantly higher in the acute treatment group rats than in the acute control rats, suggesting an improvement in the pulmonary defenses of the former. The levels of lung LPO were significantly higher in the chronic treatment group rats than in the chronic control rats, indicating oxidative damage in the lung tissue of the former. Conclusions: Our results suggest that the acute use of corticosteroids is beneficial to lung tissue, whereas their chronic use is not. The chronic use of methylprednisolone appears to increase lung LPO levels. PMID:25029646

  16. Hemodynamic alterations in chronically conscious unrestrained diabetic rats.

    PubMed

    Carbonell, L F; Salom, M G; Garcia-Estañ, J; Salazar, F J; Ubeda, M; Quesada, T

    1987-05-01

    Important cardiovascular dysfunctions have been described in streptozotocin (STZ)-diabetic rats. To determine the influence of these changes on the hemodynamic state and whether insulin treatment can avoid them, different hemodynamic parameters, obtained by the thermodilution method, were studied in STZ-induced (65 mg/kg) diabetic male Wistar rats, as well as in age-control, weight-control, and insulin-treated diabetic ones. All rats were examined in the conscious, unrestrained state 12 wk after induction of diabetes or acidified saline (pH 4.5) injection. At 12 wk of diabetic state most important findings were normotension, high blood volume, bradycardia, increase in stroke volume, cardiac output, and cardiosomatic ratio, and decrease in total peripheral resistance and cardiac contractility and relaxation (dP/dtmax and dP/dtmin of left ventricular pressure curves). The insulin-treated diabetic rats did not show any hemodynamic differences when compared with the control animals. These results suggest that important hemodynamic alterations are present in the chronic diabetic state, possibly conditioning congestive heart failure. These alterations can be prevented by insulin treatment.

  17. Effect of chronic centrifugation on body composition in the rat.

    NASA Technical Reports Server (NTRS)

    Pitts, G. C.; Bull, L. S.; Oyama, J.

    1972-01-01

    Two groups of adult female rats were chronically centrifuged for 60 days (2.76 G, 4.15 G, controls at 1.00 G). Live weights of centrifugal rats decreased about 20 g (6%) per Delta 1 G above control. This weight loss comprised reductions in both body fat and fat-free body weight (FFBW) as determined by body-composition studies on eight rats per group killed at the end of centrifugation. Of nine components constituting the FFBW, only skeletal muscle, liver, and heart changed significantly in weight. Chemical composition showed reductions (compared with controls) in the fat fraction of most components and increases in the water fraction of liver and gut. Identical measurements were made on the remaining eight rats per group killed 43 days after return to 1 G. Neither centrifuged group had reached the control body-weight level at this time. No statistically significant effect of previous G level was found in any of the body-composition parameters. The possible involvment of physiological regulation was considered.

  18. Chronic Stress Decreases Cerebrovascular Responses During Rat Hindlimb Electrical Stimulation

    PubMed Central

    Lee, Sohee; Kang, Bok-Man; Shin, Min-Kyoo; Min, Jiwoong; Heo, Chaejeong; Lee, Yubu; Baeg, Eunha; Suh, Minah

    2015-01-01

    Repeated stress is one of the major risk factors for cerebrovascular disease, including stroke, and vascular dementia. However, the functional alterations in the cerebral hemodynamic response induced by chronic stress have not been clarified. Here, we investigated the in vivo cerebral hemodynamic changes and accompanying cellular and molecular changes in chronically stressed rats. After 3 weeks of restraint stress, the elicitation of stress was verified by behavioral despair in the forced swimming test and by physical indicators of stress. The evoked changes in the cerebral blood volume and pial artery responses following hindpaw electrical stimulation were measured using optical intrinsic signal imaging. We observed that, compared to the control group, animals under chronic restraint stress exhibited a decreased hemodynamic response, with a smaller pial arterial dilation in the somatosensory cortex during hindpaw electrical stimulation. The effect of chronic restraint stress on vasomodulator enzymes, including neuronal nitric oxide synthase (nNOS) and heme oxygenase-2 (HO-2), was assessed in the somatosensory cortex. Chronic restraint stress downregulated nNOS and HO-2 compared to the control group. In addition, we examined the subtypes of cells that can explain the environmental changes due to the decreased vasomodulators. The expression of parvalbumin in GABAergic interneurons and glutamate receptor-1 in neurons were decreased, whereas the microglial activation was increased. Our results suggest that the chronic stress-induced alterations in cerebral vascular function and the modulations of the cellular expression in the neuro-vasomodulatory system may be crucial contributing factors in the development of various vascular-induced conditions in the brain. PMID:26778944

  19. Cerebro-renal interactions: impact of uremic toxins on cognitive function.

    PubMed

    Watanabe, Kimio; Watanabe, Tsuyoshi; Nakayama, Masaaki

    2014-09-01

    Cognitive impairment (CI) associated with chronic kidney disease (CKD) has received attention as an important problem in recent years. Causes of CI with CKD are multifactorial, and include cerebrovascular disease, renal anemia, secondary hyperparathyroidism, dialysis disequilibrium, and uremic toxins (UTs). Among these causes, little is known about the role of UTs. We therefore selected 21 uremic compounds, and summarized reports of cerebro-renal interactions associated with UTs. Among the compounds, uric acid, indoxyl sulfate, p-cresyl sulfate, interleukin 1-β, interleukin 6, TNF-α, and PTH were most likely to affect the cerebro-renal interaction dysfunction; however, sufficient data have not been obtained for other UTs. Notably, most of the data were not obtained under uremic conditions; therefore, the impact and mechanism of each UT on cognition and central nervous system in uremic state remains unknown. At present, impacts and mechanisms of UT effects on cognition are poorly understood. Clarifying the mechanisms and establishing novel therapeutic strategies for cerebro-renal interaction dysfunction is expected to be subject of future research.

  20. Pulmonary blood volume (PRV) in rats with chronic mountain sickness

    SciTech Connect

    Ou, L.C.; Sardella, G.L.; Hill, N.S.; Tenney, S.M.

    1986-03-05

    Upon chronic exposure to severe hypoxia, Hilltop (H) strain of Sprague-Dawley rats develops excessive polycythemia, severe hypervolemia and marked elevation in pulmonary arterial pressure (PAP), whereas Madison (M) strain develops only moderate responses. Hypervolemia is expected to increase the PBV which might contribute to the development of severe pulmonary hypertension. Two groups of 6 animals each of the H and M strains were exposed to sea level (SL) and a simulated altitude of 18,000 ft for 14 days. At the end of exposure each animal was measured for RBC volume (RBCV), total blood volume (TBV), PBV and PAP under normoxia for control and under hypoxia (10% O/sub 2/) for the hypoxic groups. RBCV was determined by /sup 51/Cr-RBC dilution and PBV was trapped by tightening an implanted loose ligature around the ascending aorta and PA. There were not strain differences in all parameters studied at SL. RBCV, TBV and PAP increased with hypoxia in both strains but significantly more so in H than M. PBV per g lung WT decreased in both strains despite elevated TBV and PAP, but more so in M than H. There were good correlations between the PBV and TBV, and between PAP and PBV in the hypoxic H and M rats. The data suggest that chronic hypoxia reduced the distensibility and perhaps the vascular capacity of the lungs such that small relative increase in PBV could significantly contribute to the rise in PAP.

  1. Uremic Serum and Solutes Increase Post–Vascular Interventional Thrombotic Risk Through Altered Stability of Smooth Muscle Cell Tissue Factor

    PubMed Central

    Chitalia, Vipul C.; Shivanna, Sowmya; Martorell, Jordi; Balcells, Mercedes; Bosch, Irene; Kolandaivelu, Kumaran; Edelman, Elazer R.

    2013-01-01

    Background Stent thrombosis (ST), a postinterventional complication with a mortality rate of 50%, has an incidence that rises precipitously in patients at risk. Chronic renal failure and end-stage renal disease have emerged as particularly strong ST risk factors, yet the mechanism remains elusive. Tissue factor (TF) is a crucial mediator of injury-related thrombosis and has been implicated for ST. We posit that uremia modulates TF in the local vessel wall to induce postinterventional thrombosis in patients with end-stage renal disease. Methods and Results As a model of the de-endothelialized, postinterventional state, we exposed primary human vascular smooth muscle cells (vSMCs) pretreated with uremic serum (obtained from ESRD patients on hemodialysis) to coronary-like blood flow. vSMC TF expression, activity, stability, and posttranslational modification were examined after vSMCs were treated with uremic serum or solutes. We found significantly greater clot formation after uremic serum exposure, which was substantially reduced with the prior treatment with anti-TF neutralizing antibody. Uremic sera induced 2- to 3-fold higher TF expression and activity in vSMCs independent of diabetes mellitus. Relevant concentrations of isolated uremic solutes such as indole-3-acetic acid (3.5 μg/mL), indoxyl sulfate (25 μg/mL), and uric acid (80 μg/mL) recapitulated these effects in cell culture and the flow loop model. We show further that TF undergoes ubiquitination at baseline and that uremic serum, indole-3-acetic acid, and indoxyl sulfate significantly prolong TF half-life by inhibiting its ubiquitination. Conclusions The uremic milieu is profoundly thrombogenic and upregulates vSMC TF levels by increasing TF stability and decreasing its ubiquitination. Together, these data demonstrate for the first time that the posttranslational regulation of TF in uremia may have a causative role in the increased ST risk observed in uremic patients. These data suggest that

  2. Biochemical, metabolic, and behavioral characteristics of immature chronic hyperphenylalanemic rats

    PubMed Central

    Dienel, Gerald A.; Cruz, Nancy F.

    2015-01-01

    Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25–27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least three weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired. PMID:26224289

  3. Chronic spinal infusion of loperamide alleviates postsurgical pain in rats.

    PubMed

    Kumar, Rakesh; Reeta, K H; Ray, Subrata Basu

    2014-04-01

    Plantar incision in rat generates spontaneous pain behaviour. The opioid drug, morphine used to treat postsurgical pain produces tolerance after long-term administration. Loperamide, a potent mu-opioid agonist, has documented analgesic action in various pain conditions. However, loperamide analgesia and associated tolerance following continuous spinal administration in postsurgical pain has not been reported. Chronic spinal infusion of drugs was achieved using intrathecal catheters connected to osmotic minipump. Coinciding with the onset of spinal infusion of loperamide or morphine, rats were subjected to plantar incision. Pain-related behaviour was assessed by Hargreaves apparatus (thermal hyperalgesia) and von Frey filaments (mechanical allodynia). Morphine and loperamide (0.5, 1 and 2 microL/h) induced analgesia was observed until 7th day post-plantar incision in Sprague-Dawley rats. Morphine and loperamide produced dose-dependent analgesia. Loperamide, in the highest dose, produced analgesia till 7th day. However, the highest dose of morphine produced inhibition of thermal hyperalgesia till 5th day and mechanical allodynia only till 3rd day post-plantar incision. Morphine and loperamide produced analgesia in postsurgical pain, which may be mediated through different mechanisms. Longer duration of analgesia with loperamide could probably be due sustained blockade of calcium channels.

  4. Corticofugal outputs facilitate acute, but inhibit chronic pain in rats.

    PubMed

    Wang, Ning; Wang, Jin-Yan; Luo, Fei

    2009-03-01

    It has been widely accepted that the primary somatosensory cortex (SI) plays an essential role in the sensory-discriminative aspect of pain perception. However, it remains unclear whether the SI has a role in the descending modulation of pain. Although there are abundant fibers projecting back from sensory cortex to thalamic nuclei, and the influence of cortical modulation from SI on the thalamic nociceptive relay neurons has been addressed, little is known about how the cortical outputs modulate the nociceptive behaviors resulting from tissue injury or evoked by painful stimulation. The present study was designed to test whether the cortical outputs influenced the nociceptive behaviors using rat models of noxious thermal-induced acute pain, formalin-induced acute and CFA-evoked chronic inflammatory pain. The results showed that intracortical microinjection of GABAA agonist muscimol significantly reduced the first and second phase behaviors in formalin tests and elevated the nociceptive thresholds in the thermal stimulus-elicited acute pain, suggesting a facilitatory influence of SI on the acute pain sensation. By contrast, microinjection of GABAA antagonist bicuculline remarkably reduced the thermal hyperalgesia of the CFA-inflamed hindpaws, indicating an inhibitory effect of SI output in the chronic pain state. The opposite modulatory effects in acute and chronic pain states suggest that there exists a functional switch for the SI cortex at different stages of pain disease, which is of great significance for the biological adaptation.

  5. Taste modulation of nociception differently affects chronically stressed rats.

    PubMed

    Fontella, Fernanda Urruth; Nunes, Marcele Leon; Crema, Leonardo M; Balk, Rodrigo S; Dalmaz, Carla; Netto, Carlos Alexandre

    2004-01-01

    Stress responses cover a wide range of physiological changes, including alterations in the perception of and response to pain. Animals submitted to repeated stress present altered nociception and this effect is part of this process of adaptation; in addition pleasant and unpleasant experiences with tastes and odors have been shown to affect distinct behavioral aspects, such as pain perception. The aim of the present study is to verify the responses of repeatedly stressed rats (1 h of daily immobilization during 40 days) to pleasant and unpleasant tastes on nociception, when compared to control animals. An increase in the tail-flick latency (TFL) was observed 5 min after exposure to a sweet taste in the control group, whereas no effect was observed in chronically stressed animals. When submitted to an unpleasant taste (5% acetic acid), the chronically stressed group presented an increase in TFL, whereas no effect was observed in the control group. In conclusion, chronically stressed animals present different nociceptive responses to sweet and acid tastes; although control animals suitably respond to a sweet stimulus, stressed animals seem to be more apt to react to the unpleasant stimulus.

  6. Speckle tracking echocardiography detects uremic cardiomyopathy early and predicts cardiovascular mortality in ESRD.

    PubMed

    Kramann, Rafael; Erpenbeck, Johanna; Schneider, Rebekka K; Röhl, Anna B; Hein, Marc; Brandenburg, Vincent M; van Diepen, Merel; Dekker, Friedo; Marx, Nicolaus; Floege, Jürgen; Becker, Michael; Schlieper, Georg

    2014-10-01

    Cardiovascular mortality is high in ESRD, partly driven by sudden cardiac death and recurrent heart failure due to uremic cardiomyopathy. We investigated whether speckle-tracking echocardiography is superior to routine echocardiography in early detection of uremic cardiomyopathy in animal models and whether it predicts cardiovascular mortality in patients undergoing dialysis. Using speckle-tracking echocardiography in two rat models of uremic cardiomyopathy soon (4-6 weeks) after induction of kidney disease, we observed that global radial and circumferential strain parameters decreased significantly in both models compared with controls, whereas standard echocardiographic readouts, including fractional shortening and cardiac output, remained unchanged. Furthermore, strain parameters showed better correlations with histologic hallmarks of uremic cardiomyopathy. We then assessed echocardiographic and clinical characteristics in 171 dialysis patients. During the 2.5-year follow-up period, ejection fraction and various strain parameters were significant risk factors for cardiovascular mortality (primary end point) in a multivariate Cox model (ejection fraction hazard ratio [HR], 0.97 [95% confidence interval (95% CI), 0.95 to 0.99; P=0.012]; peak global longitudinal strain HR, 1.17 [95% CI, 1.07 to 1.28; P<0.001]; peak systolic and late diastolic longitudinal strain rates HRs, 4.7 [95% CI, 1.23 to 17.64; P=0.023] and 0.25 [95% CI, 0.08 to 0.79; P=0.02], respectively). Multivariate Cox regression analysis revealed circumferential early diastolic strain rate, among others, as an independent risk factor for all-cause mortality (secondary end point; HR, 0.43; 95% CI, 0.25 to 0.74; P=0.002). Together, these data support speckle tracking as a postprocessing echocardiographic technique to detect uremic cardiomyopathy and predict cardiovascular mortality in ESRD.

  7. The uremic toxin indoxyl sulfate acts as a pro- or antioxidant on LDL oxidation.

    PubMed

    Praschberger, M; Hermann, M; Wanner, J; Jirovetz, L; Exner, M; Kapiotis, S; Gmeiner, B M K; Laggner, H

    2014-06-01

    Uremic toxins have been shown to play a role in chronic kidney disease (CKD) associated oxidative stress. Oxidative stress and inflammation have been associated with increased risk of cardiovascular disease in uraemia. The oxidative modification of LDL may play a role in early atherogenesis. Enhanced LDL oxidation has been found in uremic patients which may account for accelerated atherosclerosis observed in CKD. The uremic toxin indoxyl sulfate (IS) has been reported to exert oxidative and antioxidative activity. Thus, in the present study we have investigated the influence of IS on the atherogenic modifications of LDL exposed in vitro to different oxidising systems. The transition metal ion (Cu(2+)) and hemin/H2O2 induced lipid oxidation reactions monitored by conjugated diene formation, were inhibited by the presence of IS, which points to possible antioxidant effects by this uremic toxin. A protective effect of IS on LDL apoprotein modification by the exposure to the product of the myeloperoxidase/H2O2/Cl(-) system HOCl, was also observed as estimated by protein carbonyl formation. In contrast, a marked increase in conjugated dienes and lipid hydroperoxides was observed when lipid oxidation was initiated by the free radical generator AAPH in presence of IS. The GC-MS analysis revealed the formation of indole-2,3-dione and 6,12-dihydro-6,12-dioxo-indolo[2,1-b]quinazoline (tryptanthrin) in IS/AAPH reaction. A scheme for the generation of tryptanthrin from IS via indoxyl radicals is proposed, which may facilitate LDL lipid oxidation. Our observations add further insight in the Janus-faced properties of this important uremic toxin.

  8. Pharmacological attenuation of chronic alcoholic pancreatitis induced hypersensitivity in rats

    PubMed Central

    McIlwrath, Sabrina L; Westlund, Karin N

    2015-01-01

    AIM: To characterize an alcohol and high fat diet induced chronic pancreatitis rat model that mimics poor human dietary choices. METHODS: Experimental rats were fed a modified Lieber-DeCarli alcohol (6%) and high-fat (65%) diet (AHF) for 10 wk while control animals received a regular rodent chow diet. Weekly behavioral tests determined mechanical and heat sensitivity. In week 10 a fasting glucose tolerance test was performed, measuring blood glucose levels before and after a 2 g/kg bodyweight intraperitoneal (i.p.) injection of glucose. Post mortem histological analysis was performed by staining pancreas and liver tissue sections with hematoxylin and eosin. Pancreas sections were also stained with Sirius red and fast green to quantify collagen content. Insulin-expressing cells were identified immunohistochemically in separate sections. Tissue staining density was quantified using Image J software. After mechanical and heat sensitivity became stable (weeks 6-10) in the AHF-fed animals, three different drugs were tested for their efficacy in attenuating pancreatitis associated hypersensitivity: a Group II metabotropic glutamate receptor specific agonist (2R,4R)-4-Aminopyrrolidine-2,4-dicarboxylate (APDC, 3 mg/kg, ip; Tocris, Bristol, United Kingdom), nociceptin (20, 60, 200 nmol/kg, ip; Tocris), and morphine sulfate (3 mg/kg, μ-opioid receptor agonist; Baxter Healthcare, Deerfield, IL, United States). RESULTS: Histological analysis of pancreas and liver determined that unlike control rats, AHF fed animals had pancreatic fibrosis, acinar and beta cell atrophy, with steatosis in both organs. Fat vacuolization was significantly increased in AHF fed rats (6.4% ± 1.1% in controls vs 23.8% ± 4.2%, P < 0.05). Rats fed the AHF diet had reduced fasting glucose tolerance in week 10 when peak blood glucose levels reached significantly higher concentrations than controls (127.4 ± 9.2 mg/dL in controls vs 161.0 ± 8.6 mg/dL, P < 0.05). This concurred with a 3.5 fold higher

  9. Functional Genomic Analysis Identifies Indoxyl Sulfate as a Major, Poorly Dialyzable Uremic Toxin in End-Stage Renal Disease

    PubMed Central

    Jhawar, Sachin; Singh, Prabhjot; Torres, Daniel; Ramirez-Valle, Francisco; Kassem, Hania; Banerjee, Trina; Dolgalev, Igor; Heguy, Adriana; Zavadil, Jiri; Lowenstein, Jerome

    2015-01-01

    Background Chronic renal failure is characterized by progressive renal scarring and accelerated arteriosclerotic cardiovascular disease despite what is considered to be adequate hemodialysis or peritoneal dialysis. In rodents with reduced renal mass, renal scarring has been attributed to poorly filtered, small protein-bound molecules. The best studied of these is indoxyl sulfate (IS). Methods We have attempted to establish whether there are uremic toxins that are not effectively removed by hemodialysis. We examined plasma from patients undergoing hemodialysis, employing global gene expression in normal human renal cortical cells incubated in pre- and post- dialysis plasma as a reporter system. Responses in cells incubated with pre- and post-dialysis uremic plasma (n = 10) were compared with responses elicited by plasma from control subjects (n = 5). The effects of adding IS to control plasma and of adding probenecid to uremic plasma were examined. Plasma concentrations of IS were measured by HPLC (high pressure liquid chromatography). Results Gene expression in our reporter system revealed dysregulation of 1912 genes in cells incubated with pre-dialysis uremic plasma. In cells incubated in post-dialysis plasma, the expression of 537 of those genes returned to baseline but the majority of them (1375) remained dysregulated. IS concentration was markedly elevated in pre- and post-dialysis plasma. Addition of IS to control plasma simulated more than 80% of the effects of uremic plasma on gene expression; the addition of probenecid, an organic anion transport (OAT) inhibitor, to uremic plasma reversed the changes in gene expression. Conclusion These findings provide evidence that hemodialysis fails to effectively clear one or more solutes that effect gene expression, in our reporter system, from the plasma of patients with uremia. The finding that gene dysregulation was simulated by the addition of IS to control plasma and inhibited by addition of an OAT inhibitor to

  10. Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats.

    PubMed

    Robbins, M T; DeBerry, J; Ness, T J

    2007-08-15

    This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).

  11. Rat models of asthma and chronic obstructive lung disease.

    PubMed

    Martin, James G; Tamaoka, Meiyo

    2006-01-01

    The rat has been extensively used to model asthma and somewhat less extensively to model chronic obstructive pulmonary disease (COPD). The features of asthma that have been successfully modeled include allergen-induced airway constriction, eosinophilic inflammation and allergen-induced airway hyperresponsiveness. T-cell involvement has been directly demonstrated using adoptive transfer techniques. Both CD4+ and CD8+ T cells are activated in response to allergen challenge in the sensitized rat and express Thelper2 cytokines (IL-4, IL-5 and IL-13). Repeated allergen exposure causes airway remodeling. Dry gas hyperpnea challenge also evokes increases in lung resistance, allowing exercise-induced asthma to be modeled. COPD is modeled using elastase-induced parenchymal injury to mimic emphysema. Cigarette smoke-induced airspace enlargement occurs but requires months of cigarette exposure. Inflammation and fibrosis of peripheral airways is an important aspect of COPD that is less well modeled. Novel approaches to the treatment of COPD have been reported including treatments aimed at parenchymal regeneration.

  12. Chronic caffeine exposure potentiates nicotine self-administration in rats.

    PubMed

    Shoaib, M; Swanner, L S; Yasar, S; Goldberg, S R

    1999-03-01

    The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the euphoric effects of nicotine. The aim of the present experiment was to examine effects of chronic exposure to caffeine on responding maintained by nicotine. Sprague-Dawley rats consuming caffeine (approximately 150-180 mg/kg per day) in their drinking water for 7 days prior to the beginning and throughout behavioural testing acquired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. In a cross-over design, exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine to the drinking water of control rats increased responding maintained by nicotine over 90%. These findings strongly suggest that caffeine can potentiate the reinforcing properties of nicotine, thus highlighting the importance of environmental factors in shaping and maintaining tobacco smoking.

  13. Electrical needle therapy of uremic pruritus.

    PubMed

    Duo, L J

    1987-01-01

    Six patients with intractable uremic pruritus were treated with a modified acupuncture technique, the electrical needle stimulation (ENS). Results were followed with a pruritic score scale based on severity, frequency and distribution of itching, together with sleeping hours and waking up at night. The results were encouraging: pruritus was drastically improved during or after ENS in several patients. A control treatment with superficial electrical stimulation was ineffective.

  14. Pathological role of aminolevulinate in uremic patients.

    PubMed

    Hasuike, Yukiko; Nonoguchi, Hiroshi; Tokuyama, Masanori; Hata, Reiko; Kitamura, Rie; Hori, Kahori; Nanami, Masayoshi; Otaki, Yoshinaga; Kuragano, Takahiro; Nakanishi, Takeshi

    2011-02-01

    Previous reports have demonstrated that δ-aminolevulinate (ALA) can promote iron release from horse spleen ferritin under conditions of high serum ALA levels in uremia; therefore, we speculated that the accumulated ALA in uremic patients would stimulate iron release from ferritin, resulting in accelerated oxidative stress and uremic complications. We measured the plasma ALA of uremic patients and examined the ALA-induced iron release from human ferritin. The participants consisted of 30 hemodialysis patients and 14 healthy subjects. Plasma malondialdehyde was measured as a surrogate marker of lipid peroxidation. The plasma exchange effluent from two patients who had undergone plasma exchange (for the treatment of systemic lupus erythematosus and acute myeloblastic leukemia) was collected and treated to obtain the human ferritin-rich fraction. Iron release from ferritin was examined using bathophenanthroline sulfate. The influence of antioxidants and different pH levels on iron release were investigated. Plasma ALA and malondialdehyde concentration in the hemodialysis patient was significantly higher than that in healthy subjects. ALA was positively correlated with malondialdehyde. The abundance of iron release was dependent on the ALA concentration and incubation time. Iron release at the high pH of 7.6 was decreased compared with that at pH 7.4. Citrate increased iron release at pH 7.4, but citrate-stimulated iron release was totally abolished at pH 7.6. Our study suggests that ALA accumulation may have a role to play in certain complications in uremic patients, such as oxidative stress, by releasing iron from ferritin.

  15. Bioengineered kidney tubules efficiently excrete uremic toxins

    PubMed Central

    Jansen, J.; Fedecostante, M.; Wilmer, M. J.; Peters, J. G.; Kreuser, U. M.; van den Broek, P. H.; Mensink, R. A.; Boltje, T. J.; Stamatialis, D.; Wetzels, J. F.; van den Heuvel, L. P.; Hoenderop, J. G.; Masereeuw, R.

    2016-01-01

    The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three-dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs. PMID:27242131

  16. Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats.

    PubMed

    Uzbay, Tayfun; Kayir, Hakan; Celik, Turgay; Yüksel, Nevzat

    2006-05-01

    Effects of acute and chronic tianeptine treatments on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Acute or chronic (twice daily) tianeptine (5, 10 and 20 mg/kg) and saline were administered to rats intraperitoneally. Acute and last chronic tianeptine injections and saline were done 30 min before ethanol withdrawal testing. After 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, tremor, wet dog shakes, stereotyped behavior and audiogenic seizures were recorded or rated. Locomotor activity in naive (no ethanol-dependent rats) was also tested after acute tianeptine treatments. Acute but not chronic tianeptine treatment attenuated locomotor hyperactivity and agitation in ethanol-dependent rats. Both acute and chronic tianeptine treatment produced some significant inhibitory effects on tremor, wet dog shakes, stereotyped behaviors and audiogenic seizures during the ethanol withdrawal. Our results suggest that acute or chronic tianeptine treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

  17. Chronic ethanol consumption depresses hypothalamic-pituitary-adrenal function in aged rats

    SciTech Connect

    Nolan, C.J.; Bestervelt, L.L.; Mousigian, C.A.; Maimansomsuk, P.; Yong Cai; Piper, W.N. )

    1991-01-01

    In separate experiments, nine (n=20) and fifteen (n=12) month old rats were treated with either 6% ethanol or 12% sucrose in the drinking water to examine the effect of chronic ethanol consumption on the hypothalamic-pituitary-adrenal axis of aged rats. Blood was collected and plasma concentrations of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay. Adrenal glands were cleaned, quartered and used to test in vitro responsiveness to ACTH. Anterior pituitary glands from all 15 month old rats and one half of the nine month old rats were collected, frozen and extracted for measurement of tissue ACTH concentration. The remaining anterior pituitary glands from the nine month old rats were challenged with corticotropin releasing hormone (CRH) to test in vitro responsiveness. In nine month old rats, chronic ethanol consumption decreased plasma ACTH and corticosterone. Pituitary ACTH concentrations were unchanged in treated nine month old rats, but the amount of pituitary ACTH released in response to CRH was decreased in rats consuming ethanol. In vitro responsiveness of the adrenal gland to ACTH in nine month old rats consuming ethanol was unchanged. Plasma ACTH and corticosterone concentrations were also decreased in 15 month old rats chronically consuming ethanol. No differences were noted in responsiveness of the adrenal gland or in the amount of pituitary ACTH due to ethanol consumptions in 15 month old rats.

  18. Glial cell line-derived neurotrophic factor gene therapy ameliorates chronic hyperprolactinemia in senile rats.

    PubMed

    Morel, G R; Sosa, Y E; Bellini, M J; Carri, N G; Rodriguez, S S; Bohn, M C; Goya, R G

    2010-05-19

    Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (10(10) pfu) of either an adenoviral vector expressing the gene for beta-galactosidase; (Y-betagal and S-betagal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF, respectively). Transgenic GDNF levels in supernatants of GDNF adenovector-transduced N2a neuronal cell cultures were 25+/-4 ng/ml, as determined by bioassay. In the rats, serum prolactin (PRL) was measured at regular intervals. On day 17 animals were sacrificed and neuronal nuclear antigen (NeuN) and tyrosine hydroxylase (TH) immunoreactive cells counted in the arcuate-periventricular hypothalamic region. The S-GDNF but not the S-betagal rats, showed a significant reduction in body weight. The chronic hyperprolactinemia of the senile females was significantly ameliorated in the S-GDNF rats (P<0.05) but not in the S-betagal rats. Neither age nor GDNF induced significant changes in the number of NeuN and TH neurons. We conclude that transgenic GDNF ameliorates chronic hyperprolactinemia in aging female rats, probably by restoring TIDA neuron function.

  19. Reboxetine Improves Auditory Attention and Increases Norepinephrine Levels in the Auditory Cortex of Chronically Stressed Rats

    PubMed Central

    Pérez-Valenzuela, Catherine; Gárate-Pérez, Macarena F.; Sotomayor-Zárate, Ramón; Delano, Paul H.; Dagnino-Subiabre, Alexies

    2016-01-01

    Chronic stress impairs auditory attention in rats and monoamines regulate neurotransmission in the primary auditory cortex (A1), a brain area that modulates auditory attention. In this context, we hypothesized that norepinephrine (NE) levels in A1 correlate with the auditory attention performance of chronically stressed rats. The first objective of this research was to evaluate whether chronic stress affects monoamines levels in A1. Male Sprague–Dawley rats were subjected to chronic stress (restraint stress) and monoamines levels were measured by high performance liquid chromatographer (HPLC)-electrochemical detection. Chronically stressed rats had lower levels of NE in A1 than did controls, while chronic stress did not affect serotonin (5-HT) and dopamine (DA) levels. The second aim was to determine the effects of reboxetine (a selective inhibitor of NE reuptake) on auditory attention and NE levels in A1. Rats were trained to discriminate between two tones of different frequencies in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance of ≥80% correct trials in the 2-ACT were randomly assigned to control and stress experimental groups. To analyze the effects of chronic stress on the auditory task, trained rats of both groups were subjected to 50 2-ACT trials 1 day before and 1 day after of the chronic stress period. A difference score (DS) was determined by subtracting the number of correct trials after the chronic stress protocol from those before. An unexpected result was that vehicle-treated control rats and vehicle-treated chronically stressed rats had similar performances in the attentional task, suggesting that repeated injections with vehicle were stressful for control animals and deteriorated their auditory attention. In this regard, both auditory attention and NE levels in A1 were higher in chronically stressed rats treated with reboxetine than in vehicle

  20. Pulmonary sensitivity to ozone exposure in sedentary versus chronically trained, female rats

    EPA Pesticide Factsheets

    Pulmonary effects to ozone with rats that have chronically exercised or have been continuously sedentary. Also includes body composition of both groups throughout experimentation.This dataset is associated with the following publication:Gordon , C., P. Phillips , T. Beasley , A. Ledbetter , A. Cenk, U. Kodavanti , and A. Johnstone. Pulmonary Sensitivity to Ozone Exposure in Sedentary Versus Chronically Trained, Female Rats. INHALATION TOXICOLOGY. Informa Healthcare USA, New York, NY, USA, 293-302, (2016).

  1. Damage to rat spermatozoal DNA after chronic cyclophosphamide exposure.

    PubMed

    Qiu, J; Hales, B F; Robaire, B

    1995-12-01

    Treatment of male rats with low dosages of cyclophosphamide causes a dramatic increase in early embryo death among their progeny without significantly affecting the general health of the male. It is hypothesized that cyclophosphamide exerts its effects by targeting specific components of spermatozoal nuclei. The purpose of the present studies was to investigate the effects of chronic cyclophosphamide treatment on spermatozoal DNA. Two approaches were pursued. The first was to determine total DNA damage by using the alkaline elution method. The second was to study spermatozoal DNA template function by using an in vitro DNA synthesis system. Adult male rats were treated with saline or cyclophosphamide (6.1 mg/kg/day) daily for 1 or 6 wk. Cauda epididymal spermatozoa were collected and subjected to alkaline elution using DNA-DNA dot hybridization to quantify the fractionated DNA. One week of treatment with cyclophosphamide caused DNA single strand breaks that could be detected only in the presence of proteinase K in the lysis solution; no DNA cross-links were observed in the animals that received 1-wk drug treatment. In contrast, 6 wk of treatment with cyclophosphamide induced a significant increase in both DNA single strand breaks and cross-links in spermatozoal nuclei; the cross-links were attributable primarily to DNA-DNA linkages. The availability of spermatozoal DNA for template function was not affected by 1 wk of treatment with cyclophosphamide but was markedly affected after 6 wk of treatment with this drug. It is proposed that during chromatin transition processes the male genome may be in an open dynamic state with many exposed sites that are vulnerable to alkylating agents. Since there is no DNA repair during spermiogenesis, damage to the genome by alkylation at this stage may be cumulative, resulting in the production of dysfunctional germ cells.

  2. Salivary Alterations in Rats with Experimental Chronic Kidney Disease

    PubMed Central

    Romero, Ana Carolina; Bergamaschi, Cassia Toledo; de Souza, Douglas Nesadal; Nogueira, Fernando Neves

    2016-01-01

    Objective This study aimed to analyze changes in saliva composition and salivary secretion process of rats with chronic kidney disease induced by 5/6 nephrectomy to set the foundation for salivary studies related to CKD. Methods CKD was induced in Wistar rats via 5/6 nephrectomy. Blood and saliva samples were collected from Control, Sham and CKD groups at 8 and 12 weeks after the surgery. Salivation was stimulated via intraperitoneal injections of pilocarpine (1.0 mg/Kg body weight) or isoproterenol (5.0 mg/Kg body weight). Saliva was collected and immediately stored at -80°C until analysis. The salivary flow rate, total protein, amylase and peroxidase activities, and urea concentrations were measured. The blood urea nitrogen (BUN) and serum creatinine concentrations were also evaluated. Results Increases in BUN and serum creatinine concentrations were observed in the CKD groups. Amylase activity was significantly reduced in response to both stimuli in the CKD groups at 8 weeks and increased in the CKD groups at 12 weeks in response to isoproterenol stimulus. The peroxidase activities of the CKD groups were significantly reduced in response to isoproterenol stimulation and were increased at 12 weeks in response to pilocarpine stimulation. Salivary urea was significantly increased in the CKD groups at 8 weeks in response to the isoproterenol stimuli and at 12 weeks in response to both salivary agonists. Conclusions The pattern of alterations observed in this experimental model is similar to those observed in patients and clearly demonstrates the viability of 5/6 nephrectomy as an experimental model in future studies to understand the alterations in salivary compositions and in salivary glands that are elicited by CKD. PMID:26859883

  3. Green tea polyphenols attenuate deterioration of bone microarchitecture in female rats with systemic chronic inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: Our previous study demonstrated that green tea polyphenols (GTP) benefit bone health in female rats with chronic inflammation, because of GTP’s antioxidant capacity. The current study further evaluates whether GTP can restore bone microstructure along with related mechanism in rats wit...

  4. Effect of atracylodes rhizome polysaccharide in rats with adenine-induced chronic renal failure.

    PubMed

    Yang, C; Liu, C; Zhou, Q; Xie, Y C; Qiu, X M; Feng, X

    2015-01-01

    The aim of the study was to elucidate the therapeutic effects of Atracylodes rhizome polysaccharide on adenine-induced chronic renal failure in rats. Fifty male Sprague Dawley rats were selected and randomly divided in to 5 groups (n=10 rats per group): The normal control group, the chronic renal failure pathological control group, the dexamethasone treatment group and two Atracylodes rhizome polysaccharide treatment groups, treated with two different concentrations of the polysaccharide, the Atracylodes rhizome polysaccharide high group and the Atracylodes rhizome polysaccharide low group. All the rats, except those in the normal control group were fed adenine-enriched diets, containing 10 g adenine per kg food for 3 weeks. After being fed with adenine, the dexamethasone treatment group, Atracylodes rhizome polysaccharide high group and Atracylodes rhizome polysaccharide low group rats were administered the drug orally for 2 weeks. On day 35, the kidney coefficient of the rats and the serum levels of creatinine, blood urea nitrogen, total protein and hemalbumin were determined. Subsequent to experimentation on a model of chronic renal failure in rats, the preparation was proven to be able to reduce serum levels of creatinine, blood urea nitrogen and hemalbumin levels (P<0.05) and improve renal function. Atracylodes rhizome polysaccharide had reversed the majority of the indices of chronic renal failure in rats.

  5. Osteoprotective Effect of Alfacalcidol in Female Rats with Systemic Chronic Inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies have shown that alfacalcidol (a hydroxylated form of vitamin D) mitigates glucocorticoid-induced bone loss. This study was undertaken to explore the mechanism and bone microarchitecture of alfacalcidol in rats with systemic chronic inflammation. Thirty female rats (3-month-old) assigned to ...

  6. Green tea polyphenols avert chronic inflammation-induced myocardial fibrosis of female rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: Green tea proposes anti-inflammatory properties which may attenuate chronic inflammation-induced fibrosis of vessels. This study evaluated whether green tea polyphenols (GTP) can avert fibrosis or vascular disruption along with mechanisms in rats with chronic inflammation. Treatments: Fo...

  7. Molecular mechanisms for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.

    PubMed

    Watanabe, Hiroshi

    2013-01-01

    Chronic kidney disease (CKD), marked by a progressive loss in renal function, is a leading cause of hemodialysis initiation and cardiovascular disease (CVD). There are currently 13.3 million patients with CKD and 300 thousand patients are currently undergoing hemodialysis in Japan. Therefore, preventing the initiation of dialysis and reducing the risk of cardiovascular death are high-priority issues from the viewpoint of public health and economic implications. Understanding the molecular mechanism responsible for the progression of CKD and cardiovascular damage regarding crosstalk between the kidney and cardiovascular system is an important issue in controlling the pathogenesis of CKD-CVD. However, the mechanisms involved in CKD-CVD are not well understood. This hinders the development of new treatment strategies. We have been investigating the role of protein bound uremic toxins, that are difficult to remove by hemodialysis, on the onset and progression of CKD and CVD. The relationship between their redox properties and the pathogenesis of CKD-CVD was examined. In this review, we focus on two sulfate conjugated uremic toxins, namely, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and summarize recent studies that provide new insights on the molecular mechanisms responsible for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.

  8. Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

    PubMed

    Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

    2016-04-01

    There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats.

  9. Chronic stress induces ageing-associated degeneration in rat Leydig cells

    PubMed Central

    Wang, Fei-Fei; Wang, Qian; Chen, Yong; Lin, Qiang; Gao, Hui-Bao; Zhang, Ping

    2012-01-01

    Several studies have suggested that stress and ageing exert inhibitory effects on rat Leydig cells. In a pattern similar to the normal process of Leydig cell ageing, stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression that then results in decreased testosterone secretion. We hypothesized that chronic stress accelerates the degenerative changes associated with ageing in Leydig cells. To test this hypothesis, we established a model of chronic stress to evaluate stress-induced morphological and functional alterations in Brown Norway rat Leydig cells; additionally, intracellular lipofuscin levels, reactive oxygen species (ROS) levels and DNA damage were assessed. The results showed that chronic stress accelerated ageing-related changes: ultrastructural alterations associated with ageing, cellular lipofuscin accumulation, increased ROS levels and more extensive DNA damage were observed. Additionally, testosterone levels were decreased. This study sheds new light on the idea that chronic stress contributes to the degenerative changes associated with ageing in rat Leydig cells in vivo. PMID:22609820

  10. A Brain Signature to Differentiate Acute and Chronic Pain in Rats

    PubMed Central

    Guo, Yifei; Wang, Yuzheng; Sun, Yabin; Wang, Jin-Yan

    2016-01-01

    The transition from acute pain to chronic pain entails considerable changes of patients at multiple levels of the nervous system and in psychological states. An accurate differentiation between acute and chronic pain is essential in pain management as it may help optimize analgesic treatments according to the pain state of patients. Given that acute and chronic pain could modulate brain states in different ways and that brain states could greatly shape the neural processing of external inputs, we hypothesized that acute and chronic pain would show differential effects on cortical responses to non-nociceptive sensory information. Here by analyzing auditory-evoked potentials (AEPs) to pure tones in rats with acute or chronic pain, we found opposite influences of acute and chronic pain on cortical responses to auditory inputs. In particular, compared to no-pain controls, the N100 wave of rat AEPs was significantly enhanced in rats with acute pain but significantly reduced in rats with chronic pain, indicating that acute pain facilitated cortical processing of auditory information while chronic pain exerted an inhibitory effect. These findings could be justified by the fact that individuals suffering from acute or chronic pain would have different vigilance states, i.e., the vigilance level to external sensory stimuli would be increased with acute pain, but decreased with chronic pain. Therefore, this auditory response holds promise of being a brain signature to differentiate acute and chronic pain. Instead of investigating the pain system per se, the study of pain-induced influences on cortical processing of non-nocicpetive sensory information might represent a potential strategy to monitor the progress of pain chronification in clinical applications. PMID:27199727

  11. Zeta Inhibitory Peptide as a Novel Therapy to Control Chronic Visceral Hypersensitivity in a Rat Model

    PubMed Central

    Chen, Yu; Guo, Lixia; Dai, Hengfen; Huang, Yang; Chen, Qianqian; Lin, Chun

    2016-01-01

    Background The pathogenesis of multiple chronic visceral pain syndromes, such as irritable bowel syndrome (IBS), is not well known, and as a result current therapies are ineffective. The objective of this study was to investigate the effect of spinal protein kinase M zeta (PKMζ) on visceral pain sensitivity in rats with IBS to better understand the pathogenesis and investigate the effect of zeta inhibitory peptide (ZIP) as a therapy for chronic visceral pain. Methods Visceral hypersensitivity rats were produced by neonatal maternal separation (NMS). Visceral pain sensitivity was assessed by electromyographic (EMG) responses of abdominal muscles to colorectal distention (CRD). Spinal PKMζ and phosphorylated PKMζ (p-PKMζ) were detected by western blot. Varying doses of ZIP were intrathecally administered to investigate the role of spinal PKMζ in chronic visceral hypersensitivity. The open field test was used to determine if ZIP therapy causes spontaneous motor activity side effects. Results Graded CRD pressure significantly increased EMG responses in NMS rats compared to control rats (p < 0.05). p-PKMζ expression increased in the thoracolumbar and lumbosacral spinal cord in the IBS-like rats with notable concomitant chronic visceral pain compared to control rats (p < 0.05). EMG data revealed that intrathecal ZIP injection (1, 5, and 10 μg) dose-dependently attenuated visceral pain hypersensitivity in IBS-like rats. Conclusions Phosphorylated PKMζ may be involved in the spinal central sensitization of chronic visceral hypersensitivity in IBS, and administration of ZIP could effectively treat chronic visceral pain with good outcomes in rat models. PMID:27776136

  12. Induction of central leptin resistance in hyperphagic pseudopregnant rats by chronic prolactin infusion.

    PubMed

    Augustine, Rachael A; Grattan, David R

    2008-03-01

    Pregnancy in rats is associated with hyperphagia, increased fat deposition, and elevated plasma leptin concentrations. Elevated leptin would be expected to inhibit food intake, but hypothalamic leptin resistance develops around midpregnancy, allowing hyperphagia to be maintained and excess energy to be stored as fat in preparation for future metabolic demands of lactation. To investigate the hormonal mechanisms inducing leptin resistance during pregnancy, the anorectic response to leptin was examined during pseudopregnancy. Pseudopregnant rats have identical hormonal profiles to early pregnancy, but no placenta formation, allowing differentiation of maternal and placental hormone effects on appetite. To investigate the effect of leptin on food intake, d-9 pseudopregnant rats were injected with leptin (4 microg) via an intracerebroventricular (icv) cannula, and then food intake was measured 24 h later. Pseudopregnant rats were hyperphagic but had normal anorectic responses to leptin. We therefore hypothesized that a longer exposure time to high concentrations of progesterone might be required to mimic the leptin resistance that occurs on d 14 of pregnancy. Pseudopregnant rats were given progesterone to prolong pseudopregnancy beyond the time that leptin resistance develops during pregnancy. However, rats remained responsive to icv leptin. To model the placental lactogen secretion that occurs during pregnancy, pseudopregnant rats were given progesterone and chronic icv ovine prolactin infusion. Central icv injection of leptin had no effect on food intake in pseudopregnant rats receiving chronic ovine prolactin. These results suggest that chronically high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance.

  13. Effects of chronic electroacupuncture on depression- and anxiety-like behaviors in rats with chronic neuropathic pain.

    PubMed

    Li, Qian; Yue, Na; Liu, Shen-Bin; Wang, Zhi-Fu; Mi, Wen-Li; Jiang, Jian-Wei; Wu, Gen-Cheng; Yu, Jin; Wang, Yan-Qing

    2014-01-01

    Growing evidence indicates that chronic neuropathic pain is frequently accompanied by an array of psychiatric diseases, such as depression and anxiety. Electroacupuncture (EA), as one therapy of traditional Chinese medicine, has displayed potent antidepressant-like effects in numerous clinical studies. The present study was designed to examine the possible effects of EA on the depressive and anxiety disorders induced by neuropathic pain. A classic rat model of neuropathic pain was produced by chronic constriction injury (CCI) of the sciatic nerve. EA was performed on acupoints "Bai-Hui" (GV20) and unilateral "Yang-Ling-Quan" (GB34). The antidepressive and anxiolytic effects of EA treatment were analyzed using the forced swimming test (FST) and the elevated plus maze (EPM) test, respectively. CCI resulted in remarkable depression- and anxiety-like behaviors, whereas the chronic EA treatment significantly improved the behavioral deficits of CCI rats. Moreover, the phosphorylation level of the NMDA receptor type 1 (NR1) subunit was decreased in the hippocampus of CCI rats. Intriguingly, continuous EA treatment effectively blocked this decrease in the levels of pNR1. These results suggested that EA has antidepressive and anxiolytic effects on rats with neuropathic pain and that this might be associated with restoring the phosphorylation of NR1 in the hippocampus.

  14. Effects of Chronic Electroacupuncture on Depression- and Anxiety-Like Behaviors in Rats with Chronic Neuropathic Pain

    PubMed Central

    Li, Qian; Yue, Na; Liu, Shen-Bin; Wang, Zhi-Fu; Mi, Wen-Li; Jiang, Jian-Wei; Wu, Gen-Cheng; Yu, Jin; Wang, Yan-Qing

    2014-01-01

    Growing evidence indicates that chronic neuropathic pain is frequently accompanied by an array of psychiatric diseases, such as depression and anxiety. Electroacupuncture (EA), as one therapy of traditional Chinese medicine, has displayed potent antidepressant-like effects in numerous clinical studies. The present study was designed to examine the possible effects of EA on the depressive and anxiety disorders induced by neuropathic pain. A classic rat model of neuropathic pain was produced by chronic constriction injury (CCI) of the sciatic nerve. EA was performed on acupoints “Bai-Hui” (GV20) and unilateral “Yang-Ling-Quan” (GB34). The antidepressive and anxiolytic effects of EA treatment were analyzed using the forced swimming test (FST) and the elevated plus maze (EPM) test, respectively. CCI resulted in remarkable depression- and anxiety-like behaviors, whereas the chronic EA treatment significantly improved the behavioral deficits of CCI rats. Moreover, the phosphorylation level of the NMDA receptor type 1 (NR1) subunit was decreased in the hippocampus of CCI rats. Intriguingly, continuous EA treatment effectively blocked this decrease in the levels of pNR1. These results suggested that EA has antidepressive and anxiolytic effects on rats with neuropathic pain and that this might be associated with restoring the phosphorylation of NR1 in the hippocampus. PMID:24795763

  15. Middle cerebral artery alterations in a rat chronic hypoperfusion model

    PubMed Central

    Márquez-Martín, Ana; Jiménez-Altayó, Francesc; Dantas, Ana P.; Caracuel, Laura; Planas, Anna M.

    2012-01-01

    Chronic cerebral hypoperfusion (CHP) induces microvascular changes that could contribute to the progression of vascular cognitive impairment and dementia in the aging brain. This study aimed to analyze the effects of CHP on structural, mechanical, and myogenic properties of the middle cerebral artery (MCA) after bilateral common carotid artery occlusion (BCCAO) in adult male Wistar rats. Sham animals underwent a similar surgical procedure without carotid artery (CA) ligation. After 15 days of occlusion, MCA and CA were dissected and MCA structural, mechanical, and myogenic properties were assessed by pressure myography. Collagen I/III expression was determined by immunofluorescence in MCA and CA and by Western blot in CA. mRNA levels for 1A1, 1A2, and 3A1 collagen subunits were quantified by quantitative real-time PCR in CA. Matrix metalloproteinase (MMP-1, MMP-2, MMP-9, and MMP-13) and hypoxia-inducible factor-1α (HIF-1α) protein expression were determined in CA by Western blot. BCCAO diminished cross-sectional area, wall thickness, and wall-to-lumen ratio. Nevertheless, whereas wall stress was increased, stiffness was not modified and myogenic response was diminished. Hypoperfusion triggered HIF-1α expression. Collagen I/III protein expression diminished in MCA and CA after BCCAO, despite increased mRNA levels for 1A1 and 3A1 collagen subunits. Therefore, the reduced collagen expression might be due to proteolytic degradation, since the expression of MMP-1 and MMP-9 increased in the CA. These data suggest that BCCAO induces hypotrophic remodeling by a mechanism that involves a reduction of collagen I/III in association with increased MMP-1 and MMP-9 and that decreases myogenic tone in major arteries supplying the brain. PMID:22096118

  16. In vivo characterization of developing chronic pancreatitis in rats.

    PubMed

    Glawe, Claudia; Emmrich, Jörg; Sparmann, Gisela; Vollmar, Brigitte

    2005-02-01

    Despite numerous experimental and clinical investigations, there is no unifying concept on pathophysiology and pathogenesis of chronic pancreatitis. Defining the interplay between pancreatic microcirculation and parenchymal tissue, we will provide a basis for the better understanding of pancreatic fibrogenesis using in vivo high-resolution multifluorescence microscopy in dibutyltin chloride (DBTC)-exposed rats. Pancreatic microcirculation at days 3 and 7 after DBTC revealed leukocyte activation with a two-fold higher fraction of rolling cells and a nine- to 10-fold increase of cells firmly adherent to the endothelial lining, followed by subsequent transendothelial migration into tissue, as given by chloracetate esterase histology. In vivo staining of acinar tissue with bisbenzimide presented single cells exhibiting nuclear chromatin condensation and fragmentation. Apoptotic cell death was confirmed by immunohistochemical staining for active caspase-3 as well as by TUNEL analysis. Necrotic cells were found dispersed throughout the exocrine tissue under observation. Both modes of cell death were found highest in extent at days 3 and 7 with 15-20 cells/mm2, but progressively decreased below 10 cells/mm2 up to 28 days after DBTC. By means of in vivo microscopy yellow-green autofluorescent collagen deposits were found at day 7 and progressively increased up to approximately 12% at day 28 after DBTC. Concomitantly, density of capillaries progressively decreased and capillaries failing to conduct blood flow became apparent. Present on-line analysis indicates an early inflammatory response with acinar cell death, most probably triggering progression of disease with collagen deposition, capillary rarefication and manifestation of perfusion failure. These temporal and spatial multiparameter measurements of the in vivo microenvironment provide new insights into the pathological processes of pancreatic fibrogenesis.

  17. Chronic Intake of Green Propolis Negatively Affecting the Rat Testis

    PubMed Central

    Severi-Aguiar, Grasiela Dias de Campos; Pinto, Suellen Josine; Capucho, Cristina; Oliveira, Camila Andrea; Diamante, Maria Aparecida; Barbieri, Renata; Predes, Fabrícia Souza; Dolder, Heidi

    2017-01-01

    Background: Human and animal evidence suggests that environmental toxicants may have an adverse impact on male reproductive health, reducing the population's reproductive output. Owing to the renewed attraction for natural products, some of them constitute effective alternatives to mitigate these effects. Propolis is a candidate for this use because of its intrinsic properties. In many situations, it improved the testicular damage and alleviated the toxic effects induced by environmental contaminant exposure. Objective: The aim of this study was to investigate possible alterations of testicular parameters and certify if its use is really advantageous to the testis, since this could affect rat reproductive function. Materials and Methods: Forty-eight adult male Wistar rats were divided into four groups (Co = control, T1 = 3 mg propolis/kg/day, T2 = 6 mg/kg/day, T3 = 10 mg/kg/day) and were exposed during 56 days. The testes were assessed with morphometrical, stereological, and ultrastructural analyses. Cell proliferation and death were diagnosed, respectively, by immunocytochemistry. Connexin 43 (Cx43) and N-cadherin transcript levels were determined by reverse transcription-polymerase chain reaction. Results: Increased cell proliferation and Leydig cell volume were observed in T2, and in contrast, Cx43 upregulation and cell death were observed in T3. Both T2 and T3 showed ultrastructural abnormalities in testicular parenchyma. Conclusion: We recommend a cautious intake of propolis to avoid deleterious effects. SUMMARY Chronic intake of Brazilian green propolis induced N.-cadherin downregulation and decreased on seminiferous tubule volumeIncrease on connexin 43 expression and cell death and decrease in Leydig cell.(LC) number/testis with the concentration of 10 mg/kg/day were observedIncrease on cell proliferation, cytoplasmic proportion, and volume of LC with the concentration of 6 mg/kg/day was detectedThe presence of empty spaces between spermatids and malformed

  18. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study.

    PubMed

    Zlatković, Jelena; Todorović, Nevena; Tomanović, Nada; Bošković, Maja; Djordjević, Snežana; Lazarević-Pašti, Tamara; Bernardi, Rick E; Djurdjević, Aleksandra; Filipović, Dragana

    2014-08-01

    Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups

  19. Lipid peroxides and antioxidant enzymes in cisplatin-induced chronic nephrotoxicity in rats.

    PubMed

    González, Ricardo; Romay, Cheyla; Borrego, Aluet; Hernández, Frank; Merino, Nelson; Zamora, Zullyt; Rojas, Enis

    2005-08-14

    Cisplatin (CDDP), an anticancer drug, induces remarkable toxicity in the kidneys of animals and humans and it has been well documented that reactive oxygen species and the renal antioxidant system are strongly involved in acute renal damage induced by CDDP. The aim of the present study was to investigate whether or not the renal antioxidant system plays also an important role in chronic renal damage induced by repeated doses of CDDP (1 mg/kg intraperitoneally twice weekly during 10 weeks in rats). In order to elucidate it, serum creatinine and urea levels, renal glutathione and thiobarbituric acid-reactive substances (TBARS) content, as well as renal superoxide dismutase and glutathione peroxidase activities were measured in the kidney homogenates of chronically CDDP-treated rats and additionally histological studies were performed in the rat kidneys. The chronic treatment with CDDP induced a significant increase in creatinine and urea levels in serum, but the other parameters mentioned above were not significantly modified as compared to the values in nontreated rats. Taking into account these results, we conclude that chronic CDDP administration induces also severe nephrotoxicity, in contrast to CDDP acute application, without any significant modification in the activity of relevant antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, renal glutathione and lipid peroxides, by which the role of the antioxidant system in chronic nephrotoxicity induced by CDDP in rats is uncertain.

  20. Baclofen reversed thermal place preference in rats with chronic constriction injury.

    PubMed

    Salte, K; Lea, G; Franek, M; Vaculin, S

    2016-06-20

    Chronic constriction injury to the sciatic nerve was used as an animal model of neuropathic pain. Instead of frequently used reflex-based tests we used an operant thermal place preference test to evaluate signs of neuropathic pain and the effect of baclofen administration in rats with neuropathy. Chronic constriction injury was induced by four loose ligations of the sciatic nerve. Thermal place preference (45 °C vs. 22 °C and 45 °C vs. 11 °C) was measured after the ligation and after the administration of baclofen in sham and experimental rats. Rats with the chronic constriction injury spent significantly less time on the colder plate compared to sham operated animals at the combination 45 °C vs. 11 °C. After administration of baclofen (10 mg/kg s.c.), the aversion to the colder plate in rats with chronic constriction injury disappeared. At the combination 45 °C vs. 22 °C, no difference in time spent on colder and/or warmer plate was found between sham and experimental animals. These findings show the importance of cold allodynia evaluation in rats with chronic constriction injury and the effectiveness of baclofen in this neuropathic pain model.

  1. An effective treatment of atypical hemolytic uremic syndrome with plasma exchange and eculizumab: A case report.

    PubMed

    Sengul Samanci, Nilay; Ayer, Mesut; Ergen, Abdulkadir; Ozturk, Savas

    2015-06-01

    Atypical hemolytic uremic syndrome is a rare thrombotic microangiopathy caused by chronic defective regulation of the complement activation. This activation results in systemic endothelial damage leading to renal failure. Eculizumab, an anti-C5 antibody, is effective in limiting complement activation in patients with aHUS and has recently came out as a therapeutic option for aHUS. Here we present a case showing that first-line eculizumab treatment successfully prevents the induction of the terminal complement cascade and blocked the progression of thrombotic microangiopathy in aHUS.

  2. Case report of atypical hemolytic uremic syndrome with retinal arterial and venous occlusion treated with eculizumab

    PubMed Central

    Greenwood, Gregory T

    2015-01-01

    Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by chronic, uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy. Renal impairment and progression to end-stage renal disease are common in untreated patients with aHUS, and extrarenal manifestations are being increasingly characterized in the literature. Ocular involvement remains rare in aHUS. This report describes a patient with aHUS with bilateral central retinal artery and vein occlusion, vitreous hemorrhage, and blindness in addition to renal impairment. The patient’s hematologic and renal parameters and ocular manifestation improved following initiation of eculizumab therapy. PMID:26508891

  3. Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

    PubMed Central

    Ohnishi, A; Branch, R A; Jackson, K; Hamilton, R; Biaggioni, I; Deray, G; Jackson, E K

    1986-01-01

    The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension. PMID:3020089

  4. Effects of chronic ethanol administration on hepatic glycoprotein secretion in the rat

    SciTech Connect

    Sorrell, M.F.; Nauss, J.M.; Donohue, T.M. Jr.; Tuma, D.J.

    1983-03-01

    The effects of chronic ethanol feeding on protein and glycoprotein synthesis and secretion were studied in rat liver slices. Liver slices from rats fed ethanol for 4-5 wk showed a decreased ability to incorporate (/sup 14/C)glucosamine into medium trichloracetic acid-precipitable proteins when compared to the pair-fed controls; however, the labeling of hepatocellular glycoproteins was unaffected by chronic ethanol treatment. Immunoprecipitation of radiolabeled secretory (serum) glycoproteins with antiserum against rat serum proteins showed a similar marked inhibition in the appearance of glucosamine-labeled proteins in the medium of slices from ethanol-fed rats. Minimal effects, however, were noted in the labeling of intracellular secretory glycoproteins. Protein synthesis, as determined by measuring (/sup 14/C)leucine incorporation into medium and liver proteins, was decreased in liver slices from ethanol-fed rats as compared to the pair-fed controls. This was the case for both total proteins as well as immunoprecipitable secretory proteins, although the labeling of secretory proteins retained in the liver slices was reduced to a lesser extent than total radiolabeled hepatic proteins. When the terminal sugar, (/sup 14/C)fucose, was employed as a precursor in order to more closely focus on the final steps of hepatic glycoprotein secretion, liver slices obtained from chronic ethanol-fed rats exhibited impaired secretion of fucose-labeled proteins into the medium. When ethanol (5 or 10 mM) was added to the incubation medium containing liver slices from the ethanol-fed rats, the alterations in protein and glycoprotein synthesis and secretion caused by the chronic ethanol treatment were further potentiated. The results of this study indicate that liver slices prepared from chronic ethanol-fed rats exhibit both impaired synthesis and secretion of proteins and glycoproteins, and these defects are further potentiated by acute ethanol administration.

  5. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

    PubMed Central

    Lemaire, Mathieu; Frémeaux-Bacchi, Véronique; Schaefer, Franz; Choi, Murim; Tang, Wai Ho; Le Quintrec, Moglie; Fakhouri, Fadi; Taque, Sophie; Nobili, François; Martinez, Frank; Ji, Weizhen; Overton, John D.; Mane, Shrikant M.; Nürnberg, Gudrun; Altmüller, Janine; Thiele, Holger; Morin, Denis; Deschenes, Georges; Baudouin, Véronique; Llanas, Brigitte; Collard, Laure; Majid, Mohammed A.; Simkova, Eva; Nürnberg, Peter; Rioux-Leclerc, Nathalie; Moeckel, Gilbert W.; Gubler, Marie Claire; Hwa, John; Loirat, Chantal; Lifton, Richard P.

    2013-01-01

    Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure1. Atypical HUS (aHUS) can result from genetic or autoimmune factors2 that lead to pathologic complement cascade activation3. By exome sequencing we identify recessive mutations in DGKE (diacylglycerol kinase epsilon) that co-segregate with aHUS in 9 unrelated kindreds, defining a distinctive Mendelian disease. Affected patients present with aHUS before age 1, have persistent hypertension, hematuria and proteinuria (sometimes nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets, and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C, which promotes thrombosis. DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a pro-thrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treatment of aHUS patients. PMID:23542698

  6. [Role of the Shiga toxin in the hemolytic uremic syndrome].

    PubMed

    Creydt, Virginia Pistone; Nuñez, Pablo; Boccoli, Javier; Silberstein, Claudia; Zotta, Elsa; Goldstein, Jorge; Ibarra, Cristina

    2006-01-01

    In the last years, infection associated with Shiga toxin-producing Escherichia coli (STEC) and subsequent Hemolitic-Uremic Syndrome (HUS) became relevant as a public health since it was considered as one of the most important emergent patogen present in the food contaminated by cattle feces. STEC infection may be asymptomatic or begins with a watery diarrhea that may or may not progress to bloody diarrhea (hemorrhagic colitis) and HUS. In Argentina, HUS is the most common pediatric cause of acute renal insufficiency and the second cause of chronic renal failure. Up to now, STEC infection lacks of known effective treatment strategies that diminish risk of progression to HUS. The mechanisms by which Shiga toxin (Stx) induce HUS may help to find strategies to prevent or ameliorate HUS. In this article, recent progress that has contributed to understanding the disease pathogenesis of STEC is reviewed. New strategies to prevent further uptake of Shiga from the gut, either during the diarrheal phase or once HUS has developed are discussed.

  7. Role of Vitamin D in Uremic Vascular Calcification

    PubMed Central

    Zheng, Jing-Quan

    2017-01-01

    The risk of cardiovascular death is 10 times higher in patients with CKD (chronic kidney disease) than in those without CKD. Vascular calcification, common in patients with CKD, is a predictor of cardiovascular mortality. Vitamin D deficiency, another complication of CKD, is associated with vascular calcification in patients with CKD. GFR decline, proteinuria, tubulointerstitial injury, and the therapeutic dose of active form vitamin D aggravate vitamin D deficiency and reduce its pleiotropic effect on the cardiovascular system. Vitamin D supplement for CKD patients provides a protective role in vascular calcification on the endothelium by (1) renin-angiotensin-aldosterone system inactivation, (2) alleviating insulin resistance, (3) reduction of cholesterol and inhibition of foam cell and cholesterol efflux in macrophages, and (4) modulating vascular regeneration. For the arterial calcification, vitamin D supplement provides adjunctive role in regressing proteinuria, reverse renal osteodystrophy, and restoring calcification inhibitors. Recently, adventitial progenitor cell has been linked to be involved in the vascular calcification. Vitamin D may provide a role in modulating adventitial progenitor cells. In summary, vitamin D supplement may provide an ancillary role for ameliorating uremic vascular calcification. PMID:28286758

  8. Chronic ethanol intake leads to structural and molecular alterations in the rat endometrium.

    PubMed

    Martinez, Marcelo; Milton, Flora A; Pinheiro, Patricia Fernanda F; Almeida-Francia, Camila C D; Cagnon-Quitete, Valeria H A; Tirapelli, Luiz F; Padovani, Carlos Roberto; Chuffa, Luiz Gustavo A; Martinez, Francisco Eduardo

    2016-05-01

    We described the effects of low- and high-dose ethanol intake on the structure and apoptosis signaling of the uterine endometrium of UChA and UChB rats (animals with voluntary ethanol consumption). Thirty adult female rats, 90 days old, were divided into three groups (n = 10/group): UChA rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking < 1.9 g/kg/day; UChB rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking from 2 to 5 g/kg/day; control rats without ethanol (only water). After 120 days of treatment, rats displaying estrus were euthanized. Uterine epithelial cells of the UCh rats showed dilated cisterns of the rough endoplasmic reticulum, presence of lipid droplets, altered nuclear chromatin, and disrupted mitochondria. The UCh rats exhibited intense atrophied epithelial cells with smaller areas and perimeters of cytoplasm and nuclei. The endometrium of UChA rats showed higher levels of caspase-3 while Xiap and Bcl2 varied from moderate to weak. Both UChA and UChB rats exhibited a stronger immunoreaction to Ki-67 and IGFR-1 on epithelial and stromal cells. Chronic ethanol intake leads to structural and molecular alterations in the uterine endometrium of UCh rats, regardless of low- or high-dose consumption, promoting reproductive disorders.

  9. Glucose intolerance in uremic patients: the relative contributions of impaired beta-cell function and insulin resistance.

    PubMed

    Alvestrand, A; Mujagic, M; Wajngot, A; Efendic, S

    1989-04-01

    Glucose tolerance and tissue sensitivity to insulin were examined in 19 renal failure patients on chronic regular hemodialysis (group U) and in 6 matched control subjects with normal renal function (group A). Based on glucose tolerance as assessed by an oral glucose tolerance test (OGTT), glucose tolerance was normal in 5 (group U:N), borderline in 5 (group U:BL) and decreased in 9 uremic subjects (group U:D). Compared with group A the uremics demonstrated significantly (p less than 0.01) impaired insulin sensitivity as assessed by a continuous mixed infusion of somatostatin, insulin and glucose (SIGIT). In addition 19 non-diabetic subjects with normal fasting blood glucose and normal renal function, matching the uremic patients with respect to glucose tolerance as assessed by OGTT, were studied (group B). In group B impairments in both insulin secretion and insulin sensitivity tended to be more pronounced in subjects with decreased OGTT as compared with those with borderline OGTT. In contrast, insulin resistance was present to a similar degree in uremic subjects of group U:N, U:BL and U:D. During SIGIT endogenous insulin, glucagon and growth hormone (GH) were suppressed in both uremic and control subjects. This implies that insulin resistance in uremia is most likely not due to hyperglucagonemia or abnormal GH metabolism. During OGTT subjects of group U:N had significantly higher insulin response than subjects of group U:BL (p less than 0.02) and group U:D (p less than 0.01). Insulinogenic index was significantly higher in group U:N than in group U:BL (p less than 0.02) and group U:D (p = 0.01) and was higher in group U:BL than in group U:D (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Hemolytic uremic syndrome associated with Acinetobacter hemolyticus.

    PubMed

    da Silva, Paulo Sérgio Lucas; Lipinski, Rubens Wolfe

    2014-08-01

    Shiga toxin-producing Escherichia coli and Shigella dysenteriae have been associated with bloody diarrhea and hemolytic uremic syndrome (HUS) in humans. However, there have been only a couple of reports describing bloody diarrhea associated with Acinetobacter spp. and there are no reports of these bacteria causing HUS in children. Here, we report the case of a nine-month-old boy with bloody diarrhea who developed non-oliguric renal failure. The clinical and laboratory findings supported the diagnosis of Acinetobacter hemolyticus infection associated with HUS. The patient responded favorably to antibiotic therapy plus conservative treatment. In conclusion, Acinetobacter infection should be considered as a plausible cause of HUS in cases where E. coli infection is not involved. The rapid transformation ability of Acinetobacter is a matter of concern.

  11. Housing in pyramid counteracts neuroendocrine and oxidative stress caused by chronic restraint in rats.

    PubMed

    Bhat, M Surekha; Rao, Guruprasad; Murthy, K Dilip; Bhat, P Gopalakrishna

    2007-03-01

    The space within the great pyramid and its smaller replicas is believed to have an antistress effect. Research has shown that the energy field within the pyramid can protect the hippocampal neurons of mice from stress-induced atrophy and also reduce neuroendocrine stress, oxidative stress and increase antioxidant defence in rats. In this study, we have, for the first time, attempted to study the antistress effects of pyramid exposure on the status of cortisol level, oxidative damage and antioxidant status in rats during chronic restraint stress. Adult female Wistar rats were divided into four groups as follows: normal controls (NC) housed in home cage and left in the laboratory; restrained rats (with three subgroups) subject to chronic restraint stress by placing in a wire mesh restrainer for 6 h per day for 14 days, the restrained controls (RC) having their restrainers kept in the laboratory; restrained pyramid rats (RP) being kept in the pyramid; and restrained square box rats (RS) in the square box during the period of restraint stress everyday. Erythrocyte malondialdehyde (MDA) and plasma cortisol levels were significantly increased and erythrocyte-reduced glutathione (GSH) levels, erythrocyte glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were significantly decreased in RC and RS rats as compared to NC. However, these parameters were maintained to near normal levels in RP rats which showed significantly decreased erythrocyte MDA and plasma cortisol and significantly increased erythrocyte GSH levels, erythrocyte GSH-Px and SOD activities when compared with RS rats. The results showed that housing in pyramid counteracts neuroendocrine and oxidative stress caused by chronic restraint in rats.

  12. Behavior, physiology, and energy deposition in rats chronically exposed to 2450-MHz radiation

    SciTech Connect

    D'Andrea, J.A.; Gandhi, O.P.

    1987-11-01

    The research program was initiated to determine both the specific absorption rate (SAR) and the behavioral and physiological consequences of chronic c-w microwave radiation exposure at 2450 MHz in the laboratory rat. Whole-body average and local SARs at discrete sites within the body of rats and mice were determined experimentally using different exposure systems and analytical techniques. The whole-body average SAR and the distribution of SAR within the body depends on a variety of factors: type of exposure system, polarization of the field, size of the animal, and angle of radiation incident on the body. Three experiments were conducted to determine the effects of chronic exposure to 2450-MHz microwave radiation on several measures of rat behavior and physiology. Groups of rats were exposed intermittently to 2450-MHz radiation at power densities of 0.5 mW/sq. cm. or 2.5 mW/sq. cm. for 90 days.

  13. Salt-induced changes in cardiac phosphoproteome in a rat model of chronic renal failure.

    PubMed

    Su, Zhengxiu; Zhu, Hongguo; Zhang, Menghuan; Wang, Liangliang; He, Hanchang; Jiang, Shaoling; Hou, Fan Fan; Li, Aiqing

    2014-01-01

    Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model) or sham operation were treated for 2 weeks with a normal-(0.4% NaCl), or high-salt (4% NaCl) diet. We employed TiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for phosphoproteomic profiling of left ventricular free walls in these animals. A total of 1724 unique phosphopeptides representing 2551 non-redundant phosphorylation sites corresponding to 763 phosphoproteins were identified. During normal salt feeding, 89 (54%) phosphopeptides upregulated and 76 (46%) phosphopeptides downregulated in chronic renal failure rats relative to sham rats. In chronic renal failure rats, high salt intake induced upregulation of 84 (49%) phosphopeptides and downregulation of 88 (51%) phosphopeptides. Database searches revealed that most of the identified phospholproteins were important signaling molecules such as protein kinases, receptors and phosphatases. These phospholproteins were involved in energy metabolism, cell communication, cell differentiation, cell death and other biological processes. The Search Tool for the Retrieval of Interacting Genes analysis revealed functional links among 15 significantly regulated phosphoproteins in chronic renal failure rats compared to sham group, and 23 altered phosphoproteins induced by high salt intake. The altered phosphorylation levels of two proteins involved in heart damage, lamin A and phospholamban were validated. Expression of the downstream genes of these two proteins, desmin and SERCA2a, were also analyzed.

  14. [Effects of chronic Semax administration on exploratory activity and emotional reaction in white rats].

    PubMed

    Vilenskiĭ, D A; Levitskaia, N G; Andreeva, L A; Alfeeva, L Iu; Kamenskiĭ, A A; Miasoedov, N F

    2007-06-01

    Effects of chronic intranasal administration of ACTH(4-10) analog Semax (MEHFPGP) on exploratory activity, anxiety level, and depression-like behaviour were studied in white rats. The peptide was injected daily in dose 0.05 mg/kg during 10 or 14 days. It was shown that chronic Semax administration at 1-2 weeks induced anxiolytic and antidepressant effects but did not influenced the exploratory activity in non-stressogenic environment. The Semax effects may be the results of activation of the brain serotoninergic system as well as increased BDNF expression in the rat hippocampus.

  15. Induction of chronic pancreatic disease by trinitrobenzene sulfonic acid infusion into rat pancreatic ducts.

    PubMed

    Puig-Diví, V; Molero, X; Salas, A; Guarner, F; Guarner, L; Malagelada, J R

    1996-11-01

    Despite being a common disease in humans, little is known about the etiopathogenesis of and effective therapeutic approaches to chronic pancreatitis, due mainly to the fact that few simple animal models suitable to study inflammatory and fibrogenetic processes have been described in the pancreas. Trinitrobenzene sulfonic acid (TNBS) induces chronic colitis and cholangitis in the rat. We hypothesized that TNBS instillation into the pancreatic ducts could also result in the development of a chronic pancreatic disease. The biliopancreatic duct of rats was cannulated and tied close to the liver. TNBS [0.4 ml of 2% TNBS in phosphate-buffered saline (PBS)-10% ethanol, pH 8] was infused into the pancreas under a continuous controlled-pressure system. Control rats underwent the same procedure using vehicle only. Pathology assessment of TNBS-treated rats examined at 48 h was consistent with severe acute necrotizing pancreatitis, having a morality rate of 31% and serum amylase activity of 37.4 +/- 8.8 U/ml at 24 h and 13.3 +/- 1.7 U/ml at 48 h (p < 0.01 for both time points compared to PBS/ethanol-treated rats). Groups of 10 rats each were killed at 3, 4, and 6 week after the surgical procedure. Morphological examination revealed changes mimicking features of chronic pancreatitis in humans in 80% (32 of 40) of TNBS-treated rats, consisting in various degrees of periductal and lobular fibrosis, duct stenosis, patchy acute and chronic inflammatory cell infiltrates, and signs of gland atrophy. Animals developing chronic disease had a weight gain rate significantly lower than that of control rats. Serum amylase, fasting glucose, and a glucose tolerance test were not different in diseased or control rats. In conclusion, we were able to induce chronic fibrogenetic inflammatory disease in the pancreas after a single pulse instillation of TNBS into the pancreatic ducts. This might be a useful animal model to study the pathophysiology of inflammatory, fibrogenetic, and reparative

  16. Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat.

    PubMed

    Liles, John T; Ida, Kevin K; Joly, Kristin M; Chapo, Joseph; Plato, Craig F

    2011-08-01

    Contractile reserve decreases with advancing age and chronic isoproterenol (ISO) administration is a well-characterized model of cardiac hypertrophy known to impair cardiovascular function. This study evaluated whether nonsenescent, mature adult rats are more susceptible to detrimental effects of chronic ISO administration than younger adult rats. Rats received daily injections of ISO (0.1 mg/kg sc) or vehicle for 3 wk. ISO induced a greater impairment in contractile reserve [maximum of left ventricular pressure development (Δ+dP/dt(max))] in mature adult ISO-treated (MA-ISO) than in young adult ISO-treated rats (YA-ISO) in response to infusions of mechanistically distinct inotropes (digoxin, milrinone; 20-200 μl·kg(-1)·min(-1)), while basal and agonist-induced changes in heart rate and systolic arterial pressure (SAP) were not different across groups. ISO decreased expression of the calcium handling protein, sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a, in MA-ISO compared with YA, YA-ISO, and MA rats. Chronic ISO also induced greater increases in cardiac hypertrophy [left ventricular (LV) index: 33 ± 3 vs. 22 ± 5%] and caspase-3 activity (34 vs. 5%) in MA-ISO relative to YA-ISO rats. Moreover, β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased β-MHC and ANF expression. Although several studies report age-related declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life.

  17. Effects of chronic normobaric hypoxic and hypercapnic exposure in rats: Prevention of experimental chronic mountain sickness by hypercapnia

    NASA Astrophysics Data System (ADS)

    Lincoln, B.; Bonkovsky, H. L.; Ou, Lo-Chang

    1987-09-01

    A syndrome of experimental chronic mountain sickness can be produced in the Hilltop strain of Sprague-Dawley rats by chronic hypobaric hypoxic exposure. This syndrome is characterized by polycythemia, plasma hemoglobinemia, pulmonary hypertension and right ventricular hypertrophy with eventual failure and death. It has generally been assumed that these changes are caused by chronic hypoxemia, not by hypobaric exposure per se. We have now confirmed this directly by showing that chronic normobaric hypoxic exposure (10.5% O2) produces similar hematologic and hemodynamic changes. Further, the addition of hypercapnic exposure to the hypoxic exposure blunted or prevented the effects of the hypoxic exposure probably by stimulating respiration, thus increasing the rate of oxygen delivery to the cells. Changes in the rate-controlling enzymes of hepatic heme metabolism, 5-aminolevulinate synthase and heme oxygenase, and in cytochrome(s) P-450, the major hepatic hemoprotein(s), were also measured in hypoxic and hypercapnic rats. Hypoxia decreased 5-aminolevulinate synthase and increased cytochrome(s) P-450, probably by increasing the size of a “regulatory” heme pool within hepatocytes. These changes were also prevented by the addition of hypercapnic to hypoxic exposure.

  18. Acute and chronic ethanol intake: effects on spatial and non-spatial memory in rats.

    PubMed

    García-Moreno, Luis M; Cimadevilla, Jose M

    2012-12-01

    Abusive alcohol consumption produces neuronal damage and biochemical alterations in the mammal brain followed by cognitive disturbances. In this work rats receiving chronic and acute alcohol intake were evaluated in a spontaneous delayed non-matching to sample/position test. Chronic alcohol-treated rats had free access to an aqueous ethanol solution as the only available liquid source from the postnatal day 21 to the end of experiment (postnatal day 90). Acute alcoholic animals received an injection of 2 g/kg ethanol solution once per week. Subjects were evaluated in two tests (object recognition and spatial recognition) based on the spontaneous delayed non-matching to sample or to position paradigm using delays of 1 min, 15 min and 60 min. Results showed that chronic and acute alcohol intake impairs the rats' performance in both tests. Moreover, chronic alcohol-treated rats were more altered than acute treated animals in both tasks. Our results support the idea that chronic and acute alcohol administration during postnatal development caused widespread brain damage resulting in behavioral disturbances and learning disabilities.

  19. Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia.

    PubMed

    Lumbroso, Delphine; Joseph, Vincent

    2009-08-01

    We tested the hypothesis that neonatal exposure to hypoxia alters acclimatization to chronic hypoxia later in life. Rat pups were exposed to normobaric hypoxia (12% O(2); nHx group) in a sealed chamber, or to normoxia (21% O(2); nNx group) from the day before birth to postnatal day 10. The animals were then raised in normal conditions until reaching 12 wk of age. At this age, we assessed ventilatory and hematological acclimatization to chronic hypoxia by exposing male and female nHx and nNx rats for 2 wk to 10% O(2). Minute ventilation, metabolic rate, hypoxic ventilatory response, hematocrit, and hemoglobin levels were measured both before and after acclimatization. We also quantified right ventricular hypertrophy as an index of pulmonary hypertension both before and after acclimatization. There was a significant effect of neonatal hypoxia that decreases ventilatory response (relative to metabolic rate, VE/VCO(2)) to acute hypoxia before acclimatization in males but not in females. nHx rats had an impaired acclimatization to chronic hypoxia characterized by altered respiratory pattern and elevated hematocrit and hemoglobin levels after acclimatization, in both males and females. Right ventricular hypertrophy was present before and after acclimatization in nHx rats, indicating that neonatal hypoxia results in pulmonary hypertension in adults. We conclude that neonatal hypoxia impairs acclimatization to chronic hypoxia in adults and may be a factor contributing to the establishment of chronic mountain sickness in humans living at high altitude.

  20. Chronic intermittent hypoxia induces cardiac inflammation and dysfunction in a rat obstructive sleep apnea model

    PubMed Central

    Wei, Qin; Bian, Yeping; Yu, Fuchao; Zhang, Qiang; Zhang, Guanghao; Li, Yang; Song, Songsong; Ren, Xiaomei; Tong, Jiayi

    2016-01-01

    Abstract Chronic intermittent hypoxia is considered to play an important role in cardiovascular pathogenesis during the development of obstructive sleep apnea (OSA). We used a well-described OSA rat model induced with simultaneous intermittent hypoxia. Male Sprague Dawley rats were individually placed into plexiglass chambers with air pressure and components were electronically controlled. The rats were exposed to intermittent hypoxia 8 hours daily for 5 weeks. The changes of cardiac structure and function were examined by ultrasound. The cardiac pathology, apoptosis, and fibrosis were analyzed by H&E staining, TUNNEL assay, and picosirius staining, respectively. The expression of inflammation and fibrosis marker genes was analyzed by quantitative real-time PCR and Western blot. Chronic intermittent hypoxia/low pressure resulted in significant increase of left ventricular internal diameters (LVIDs), end-systolic volume (ESV), end-diastolic volume (EDV), and blood lactate level and marked reduction in ejection fraction and fractional shortening. Chronic intermittent hypoxia increased TUNNEL-positive myocytes, disrupted normal arrangement of cardiac fibers, and increased Sirius stained collagen fibers. The expression levels of hypoxia induced factor (HIF)-1α, NF-kB, IL-6, and matrix metallopeptidase 2 (MMP-2) were significantly increased in the heart of rats exposed to chronic intermittent hypoxia. In conclusion, the left ventricular function was adversely affected by chronic intermittent hypoxia, which is associated with increased expression of HIF-1α and NF-kB signaling molecules and development of cardiac inflammation, apoptosis and fibrosis. PMID:27924067

  1. Hypercaloric diet modulates effects of chronic stress: a behavioral and biometric study on rats.

    PubMed

    Oliveira, Carla de; Oliveira, Cleverson Moraes de; de Macedo, Isabel Cristina; Quevedo, Alexandre S; Filho, Paulo Ricardo Marques; Silva, Fernanda Ribeiro da; Vercelino, Rafael; de Souza, Izabel C Custodio; Caumo, Wolnei; Torres, Iraci L S

    2015-01-01

    Obesity is a chronic disease that has been associated with chronic stress and hypercaloric diet (HD) consumption. Increased ingestion of food containing sugar and fat ingredients (comfort food) is proposed to "compensate" chronic stress effects. However, this eating habit may increase body fat depositions leading to obesity. This study evaluated behavioral/physiological parameters seeking to establish whether there is an association between the effects of HD intake and stress, and to test the hypothesis that the development of anxious behavior and obesity during chronic stress periods depends on the type of diet. Sixty-day-old male Wistar rats (n = 100) were divided into four groups: standard chow, hypercaloric diet, chronic stress/standard chow and chronic stress/hypercaloric diet. Chronic stress was induced by restraint stress exposure for 1 h/day, for 80 d. At the end of this period, rat behavior was evaluated using open-field and plus-maze tests. The results showed that HD alone increased weight gain and adipose deposition in subcutaneous and mesenteric areas. However, stress reduced weight gain and adipose tissue in these areas. HD also increased naso-anal length and concurrent stress prevented this. Behavioral data indicated that stress increased anxiety-like behaviors and comfort food reduced these anxiogenic effects; locomotor activity increased in rats fed with HD. Furthermore, HD decreased corticosterone levels and stress increased adrenal weight. The data indicate that when rats are given HD and experience chronic stress this association reduces the pro-obesogenic effects of HD, and decreases adrenocortical activity.

  2. Neuroprotective effects of NSTyr on cognitive function and neuronal plasticity in rats of chronic cerebral hypoperfusion.

    PubMed

    Lin, Qi; Hai, Jian; Yao, Li-Yun; Lu, Yang

    2010-04-14

    The neuroprotective effects of N-stearoyl-L-tyrosine (NSTyr) on cognitive function and neuronal plasticity during chronic cerebral hypoperfusion (CCH) in rats were investigated. After induction of CCH, NSTyr was administered daily for 3 months intraperitoneally. Cognitive functions were evaluated by Morris water maze and hippocampal long-term potentiation (LTP). Neuropathological changes were examined using light micrograph and Fluoro-Jade B staining. Neuronal plasticity was assessed by measuring the expression of MAP-2, GAP-43 and synaptophysin on hippocampal regions of rats with immunohistochemistry and western blotting. CCH resulted in significant spatial memory impairment and inhibition of LTP, and led to neurodegeneration in the CA1 region of the hippocampus in the model rats compared with the sham-operated rats. In the model rats treated with NSTyr, cognitive function improved. The expression levels of MAP-2 and synaptophysin protein in hippocampal areas in the model rats were less than those in the sham-operated rats, and increased in the model rats treated with NSTyr. However, no statistical significance of GAP-43 expression among the sham, model and NSTyr groups was observed. These data indicate that NSTyr exerts protective effects on cognitive function of rats after CCH, which may be related to the changes of neurodegeneration and neuronal plasticity in the hippocampal area of rats.

  3. Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity.

    PubMed

    Deshpande, Laxmikant S; Phillips, Kristin; Huang, Beverly; DeLorenzo, Robert J

    2014-09-01

    Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment.

  4. Induction of maternal behavior in adult female rats following chronic morphine exposure during puberty.

    PubMed

    Byrnes, Elizabeth M; Rigero, Beth A; Bridges, Robert S

    2003-12-01

    The peripubertal period in the female rat is the time when the stimulatory effects of opioids on prolactin (PRL) secretion develop. In the adult rat, the administration of chronic high-dose morphine has been shown to attenuate the ability of opiates to stimulate PRL secretion. One function of PRL in adult virgin rats is the induction of maternal behavior. The present study examined whether chronic high-dose morphine exposure during the peripubertal period alters PRL-mediated induction of maternal behavior in adult female rats. Two groups of juvenile female rats were administered increasing doses of morphine or vehicle (s.c.) from age 30 to 50 days. As adults, these females either remained intact, or were ovariectomized and treated with a PRL-dependent, steroid hormone regimen that stimulates a rapid onset of maternal behavior. All females were then exposed daily to rat foster pups to determine whether peripubertal morphine exposure affected their latencies to induce maternal behavior. Morphine treatment resulted in a delay in vaginal opening and a temporary reduction in the rate of weight gain; however, the rate of onset of maternal behavior was unaffected by peripubertal morphine treatment. Thus, chronic morphine exposure in the pubertal female did not impact the expression of pup-induced maternal care.

  5. Electroacupuncture improves cardiac function and remodeling by inhibition of sympathoexcitation in chronic heart failure rats.

    PubMed

    Ma, Luyao; Cui, Baiping; Shao, Yongfeng; Ni, Buqing; Zhang, Weiran; Luo, Yonggang; Zhang, Shijiang

    2014-05-15

    Chronic heart failure (CHF) is responsible for significant morbidity and mortality worldwide, mainly as a result of neurohumoral activation. Acupuncture has been used to treat a wide range of diseases and conditions. In this study, we investigated the effects of electroacupuncture (EA) on the sympathetic nerve activity, heart function, and remodeling in CHF rats after ligation of the left anterior descending coronary artery. CHF rats were randomly selected to EA and control groups for acute and chronic experiments. In the acute experiment, both the renal sympathetic nerve activity and cardiac sympathetic afferent reflex elicited by epicardial application of capsaicin were recorded. In the chronic experiment, we performed EA for 30 min once a day for 1 wk to test the long-term EA effects on heart function, remodeling, as well as infarct size in CHF rats. The results show EA significantly decreased the renal sympathetic nerve activity effectively, inhibited cardiac sympathetic afferent reflex, and lowered the blood pressure of CHF rats. Treating CHF rats with EA for 1 wk dramatically increased left ventricular ejection fraction and left ventricular fraction shortening, reversed the enlargement of left ventricular end-systolic dimension and left ventricular end-diastolic dimension, and shrunk the infarct size. In this experiment, we demonstrated EA attenuates sympathetic overactivity. Additionally, long-term EA improves cardiac function and remodeling and reduces infarct size in CHF rats. EA is a novel and potentially useful therapy for treating CHF.

  6. Therapeutic effect of DA-9601 on chronic reflux gastritis induced by sodium taurocholate in rats

    PubMed Central

    Oh, Tae Young; Shin, Chang Yell; Sohn, Yong Sung; Kim, Dong Hwan; Ahn, Byoung Ok; Lee, Eun Bang; Park, Cho Hyun

    2005-01-01

    AIM: To investigate the therapeutic effects of DA-9601 on sodium taurocholate (TCA)-induced chronic reflux gastritis in SD rats. METHODS: In this study, we have investigated the therapeutic effects of DA-9601 on chronic erosive and atrophic gastritis induced by 6 mo of TCA administration (5 mmol/L in drinking water) in SD rats. RESULTS: Four weeks of DA-9601 administration (0.065%, 0.216% in rat chow), following the withdrawal of TCA treatment, resulted in a significant decrease in total length of erosions in rats in a dose-dependent manner. Furthermore, the indicators of atrophic gastritis, such as reduced mucosal thickness and reduction in the number of parietal cells, were improved by the administration of DA-9601 in a dose-related manner. DA-9601 also attenuated inflammatory cell infiltration and the proliferation of collagenous fiber in the gastric mucosa. The improvement in the reduction of the gastric mucus was observed in the rats receiving a high dose of DA-9601 (0.216%). The therapeutic effect of DA-9601 on experimental chronic erosive gastritis was superior to that of rebamipide (1.08% in rat chow). Biochemical analyses showed increased mucosal prostaglandin E2 and reduced glutathione levels by DA-9601 treatment. CONCLUSION: We suggest that DA-9601 is a promising agent for the treatment of chronic erosive and atrophic gastritis with an etiological factor of bile reflux. Increased mucosal prostaglandin E2 and reduced glutathione by DA-9601 treatment may be therapeutic mechanisms for chronic erosive and atrophic gastritis. PMID:16437712

  7. Chronic stress sensitizes rats to pancreatitis induced by cerulein: Role of TNF-α

    PubMed Central

    Binker, Marcelo G; Binker-Cosen, Andres A; Richards, Daniel; Gaisano, Herbert Y; de Cosen, Rodica H; Cosen-Binker, Laura I

    2010-01-01

    AIM: To investigate chronic stress as a susceptibility factor for developing pancreatitis, as well as tumor necrosis factor-α (TNF-α) as a putative sensitizer. METHODS: Rat pancreatic acini were used to analyze the influence of TNF-α on submaximal (50 pmol/L) cholecystokinin (CCK) stimulation. Chronic restraint (4 h every day for 21 d) was used to evaluate the effects of submaximal (0.2 μg/kg per hour) cerulein stimulation on chronically stressed rats. RESULTS: In vitro exposure of pancreatic acini to TNF-α disorganized the actin cytoskeleton. This was further increased by TNF-α/CCK treatment, which additionally reduced amylase secretion, and increased trypsin and nuclear factor-κB activities in a protein-kinase-C δ and ε-dependent manner. TNF-α/CCK also enhanced caspases’ activity and lactate dehydrogenase release, induced ATP loss, and augmented the ADP/ATP ratio. In vivo, rats under chronic restraint exhibited elevated serum and pancreatic TNF-α levels. Serum, pancreatic, and lung inflammatory parameters, as well as caspases’activity in pancreatic and lung tissue, were substantially enhanced in stressed/cerulein-treated rats, which also experienced tissues’ ATP loss and greater ADP/ATP ratios. Histological examination revealed that stressed/cerulein-treated animals developed abundant pancreatic and lung edema, hemorrhage and leukocyte infiltrate, and pancreatic necrosis. Pancreatitis severity was greatly decreased by treating animals with an anti-TNF-α-antibody, which diminished all inflammatory parameters, histopathological scores, and apoptotic/necrotic markers in stressed/cerulein-treated rats. CONCLUSION: In rats, chronic stress increases susceptibility for developing pancreatitis, which involves TNF-α sensitization of pancreatic acinar cells to undergo injury by physiological cerulein stimulation. PMID:21105189

  8. Chronic but not acute Li+ treatment prevents behavioral depression in rats.

    PubMed

    Teixeira, N A; Pereira, D G; Hermini, A H

    1995-09-01

    The effect of lithium administration on the learned helplessness model of depression was investigated. Female Wistar rats (190-210 g) received either tap water alone (N = 156) or 20 mM LiCL provided chronically (30 days; N = 127) or acutely (5 days; N = 22) in the drinking water. Three days before the end of treatment, each group was divided into two subgroups which received either inescapable shock (IS) or no shock (NS) treatment in shuttle boxes. All groups were subsequently submitted to an escape test on the following day and then sacrificed one day after the escape test, when blood samples were taken to measure serum Li+, Na+ and K+ concentrations by flame photometry. There were no significant differences in serum Na+ amongst the 4 groups. Chronically treated NS and IS rats both presented an increase in serum K+ compared to the control rats. The IS and not the NS chronically treated rats presented increased serum Li+ levels which cannot be accounted for in terms of differences in Li+ intake. The IS group treated chronically with lithium had a better escape performance than the IS group receiving either tap water or acute Li+ administration. We conclude that chronic but not acute Li+ treatment at a serum level within the prophylactic range (0.5 mEq/l) is able to prevent learned helplessness in the rat. These results agree with the data obtained in clinical practice indicating that Li+ is only effective after chronic administration and that Li(+)-induced hyperkalemia is a side effect.

  9. Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts.

    PubMed

    Gardner, Jason D; Murray, David B; Voloshenyuk, Tetyana G; Brower, Gregory L; Bradley, Jessica M; Janicki, Joseph S

    2010-02-01

    We have previously reported gender differences in ventricular remodeling and development of heart failure using the aortocaval fistula model of chronic volume overload in rats. In contrast to males, female rats exhibited no adverse ventricular remodeling and less mortality in response to volume overload. This gender-specific cardioprotection was lost following ovariectomy and was partially restored using estrogen replacement. However, it is not known if estrogen treatment would be as effective in males. The purpose of this study was to evaluate the structural and functional effects of estrogen in male rats subjected to chronic volume overload. Four groups of male rats were studied at 3 days and 8 wk postsurgery as follows: fistula and sham-operated controls, with and without estrogen treatment. Biochemical and histological studies were performed at 3 days postsurgery, with chronic structural and functional effects studied at 8 wk. Measurement of systolic and diastolic pressure-volume relationships was obtained using a blood-perfused isolated heart preparation. Both fistula groups developed significant ventricular hypertrophy after 8 wk of volume overload. Untreated rats with fistula exhibited extensive ventricular dilatation, which was coupled with a loss of systolic function. Estrogen attenuated left ventricular dilatation and maintained function in treated rats. Estrogen treatment was also associated with a reduction in oxidative stress and circulating endothelin-1 levels, as well as prevention of matrix metalloproteinase-2 and -9 activation and breakdown of ventricular collagen in the early stage of remodeling. These data demonstrate that estrogen attenuates ventricular remodeling and disease progression in male rats subjected to chronic volume overload.

  10. Different adaptation of the motor activity rhythm to chronic phase shifts between adolescent and adult rats.

    PubMed

    Albert, Nerea; da Silva, Crhistiane; Díez-Noguera, Antoni; Cambras, Trinitat

    2013-09-01

    Chronic phase shifts is a common feature in modern societies, which may induce sleep alterations and other health problems. The effects of phase shift on the circadian rhythms have been described to be more pronounced in old than in young animals. However, few works address the effects of chronic phase shifts during adolescence. Here we tested the development of the motor activity circadian rhythm of young rats under chronic phase shifts, which consisted on 6-h advances (A), 6h delays (D) or 6h advances and delays alternated every 5 days (AD) during the first 60 days after weaning. Moreover, the rhythmic pattern was compared to that of adult rats under the same lighting conditions. Results indicate that adolescent rats, independently on the lighting environment, developed a clear circadian rhythm, whose amplitude increased the first 50 days after weaning and showed a more stable circadian rhythm than adults under the same lighting conditions. In the case of A and AD groups, circadian disruption was observed only in adult rats. In all groups, the offset of activity correlated with light pattern better than the onset, and this correlation was always higher in the case of the rhythm of the pubertal rats. When AD groups were transferred to constant darkness, the group submitted to this condition during adolescence showed shorter period than that submitted in their adulthood. In conclusion, differently from adult rats, adolescent rats submitted to chronic phase shifts did not show circadian disruption and developed a single circadian rhythm, suggesting permanent changes in the circadian system.

  11. Tianeptine exerts neuroprotective effects in the brain tissue of rats exposed to the chronic stress model.

    PubMed

    Della, Franciela P; Abelaira, Helena M; Réus, Gislaine Z; Antunes, Altamir R; Dos Santos, Maria Augusta B; Zappelinni, Giovanni; Steckert, Amanda V; Vuolo, Francieli; Galant, Letícia S; Dal-Pizzol, Felipe; Kapczinski, Flávio; Quevedo, João

    2012-12-01

    Animal models of chronic stress represent valuable tools by which to investigate the behavioral, endocrine and neurobiological changes underlying stress-related psychopathologies, such as major depression, and the efficacy of antidepressant therapies. The present study was aimed at investigating the neurochemical effects of the antidepressant tianeptine in rats exposed to the chronic stress model. To this aim, rats were subjected to 40days of chronic unpredictable stressful stimuli, after which the animals received saline or tianeptine (15mg/kg) once a day for 7days. Additionally, IL-6, IL-1, TNF-α levels and oxidative stress parameters were assessed in the prefrontal cortex (PFC), hippocampus (HPC), amygdala (AMY) and nucleus accumbens (NAc) in all of the experimental groups studied. The results indicated that chronic mild stress and tianeptine did not exercise any effects on cytokines in all of the structures studied; in the PFC and AMY thiobarbituric acid reactive substances (TBARS) levels were decreased in control rats treated with tianeptine in the HPC; superoxide dismutase (SOD) activity was found to have decreased in stressed rats treated with saline in the PFC, HPC, AMY and NAc, and tianeptine reversed this effect; catalase (CAT) activity was found to have decreased in the PFC, HPC and NAc of stressed rats treated with saline, but was shown to have increased in stressed rats treated with tianeptine, and tianeptine also reversed the decreases in CAT activity in stressed rats treated with saline, suggesting that tianeptine exerted antioxidant activity. In conclusion, the present findings open new vistas on the pharmacological activity of tianeptine, in particular, concerning its ability to attenuate oxidative stress.

  12. Characterization of a new rat model for chronic inflammatory demyelinating polyneuropathies.

    PubMed

    Brun, Susana; Beaino, Wissam; Kremer, Laurent; Taleb, Omar; Mensah-Nyagan, Ayikoe Guy; Lam, Chanh D; Greer, Judith M; de Seze, Jérôme; Trifilieff, Elisabeth

    2015-01-15

    Our objective was to develop a chronic model of EAN which could be used as a tool to test treatment strategies for CIDP. Lewis rats injected with S-palmitoylated P0(180-199) peptide developed a chronic, sometimes relapsing-remitting type of disease. Our model fulfills electrophysiological criteria of demyelination with axonal degeneration, confirmed by immunohistopathology. The late phase of the chronic disease was characterized by accumulation of IL-17(+) cells and macrophages in sciatic nerves and by high serum IL-17 levels. In conclusion, we have developed a reliable and reproducible animal model resembling CIDP that can now be used for translational drug studies.

  13. Acute and chronic administration of immunomodulators induces anorexia in Zucker rats.

    PubMed

    Lugarini, F; Hrupka, B J; Schwartz, G J; Plata-Salaman, C R; Langhans, W

    2005-01-31

    To investigate the possible involvement of leptin signaling in lipopolysaccharide (LPS) anorexia, we compared the anorectic effect of LPS in genetically obese (fa/fa) Zucker rats and in their lean (Fa/?) counterparts. The effects of interleukin-1beta (IL-1beta) and muramyl dipeptide (MDP) were also tested. LPS [100 microg/kg body weight (BW)], IL-1beta (2 microg/kg BW) and MDP (2.2 mg/kg BW) injected intraperitoneally (i.p.) at lights out reduced food intake similarly in obese and lean rats. LPS injection at 500 or 1000 microg/kg BW (i.p.) also reduced food intake and BW similarly in obese and lean rats, but obese regained BW faster than lean rats. LPS (2.45 microg or 9.8 microg/h/rat) administered chronically with i.p. implanted osmotic pumps reduced food intake similarly on experimental day 1, regardless of the genotype. After day 3, the lean rats' anorectic response and recovery were dose-dependent, whereas the anorectic response in obese rats was minimally affected by dose (significant dose effect only on day 3). Again, obese rats regained lost BW faster than lean rats. These results do not support a role for leptin as the sole mediator of anorexia induced by bacterial products (LPS and MDP) and IL-1beta.

  14. Changes of sleep patterns in rats with chronic constriction injury under aversive conditions.

    PubMed

    Tokunaga, Shin; Takeda, Yasuhiro; Shinomiya, Kazuaki; Yamamoto, Wataru; Utsu, Yoshiaki; Toide, Katsuo; Kamei, Chiaki

    2007-11-01

    In the present study, we investigated the changes of sleep parameters in rats with chronic constriction injury (CCI) under aversive conditions. The electroencephalogram (EEG) in the frontal cortex of CCI rats and electromyogram (EMG) were measured over 6 h by placing rats on sandpaper as an aversive condition, to compare with rats placed on sawdust. Six days after CCI surgery, the rats exhibited significant mechanical allodynia, and also had neuropathic pain. When rats were placed on sawdust, no significant difference was observed between the CCI group and sham-operated control group in sleep latency, total waking time, total non-REM sleep time and total REM sleep time. On the other hand, when CCI rats were placed on sandpaper, a significant increase was observed in sleep latency and total waking time compared with the sham group; however, no significant difference was observed in the total non-REM sleep time and total REM sleep time between these two groups. These results indicate that an important factor of sleep disturbance in CCI rats is not only damage to the nerves but also being under aversive conditions. In addition, it was found that CCI rats placed on sandpaper as an aversive condition can serve as a new sleep disturbance model.

  15. Brown-colored deposits on hair of female rats chronically exposed to 60-Hz electric fields

    SciTech Connect

    Leung, F.C.; Rommereim, D.N.; Miller, R.A.; Anderson, L.E. )

    1990-01-01

    An increased incidence and severity of a brownish coloration of hair has been observed around the nose and on the ears of female rats that were chronically exposed to 60-Hz electric fields. Microscopic examination of the colored areas revealed a red-brown globular deposit on hair shafts in affected areas without signs of physical injury.

  16. Effect of quercitrin on lactose-induced chronic diarrhoea in rats.

    PubMed

    Gálvez, J; Sánchez de Medina, F; Jiménez, J; Torres, M I; Fernández, M I; Núñez, M C; Ríos, A; Gil, A; Zarzuelo, A

    1995-08-01

    Quercitrin (3-rhamnosylquercetin) is a bioflavonoid contained in several crude drugs traditionally used for its antidiarrhoeal activity. The antidiarrhoeic effect of quercitrin on experimental chronic diarrhoea in rats was studied. Adult rats were fed for 14 days with a synthetic diet in which all soluble carbohydrates were substituted by lactose, resulting in chronic diarrhoea with body weight loss, colonic hyperplasia, reduced average cell size, increased alkaline phosphatase activity, increased mucus production and cytopathological alterations of the enterocyte. The rest of the animals were allowed to recover from chronic diarrhoea for 3 or 7 days, by feeding them with a standard diet, and half of them were also given quercitrin orally (50 mg/kg day). Diarrhoea ceased 48 h after lactose withdrawal, and body weight recovery was apparent after 3 days. Nevertheless, most of the alterations of the colonic mucosa persisted at that time. Quercitrin-treated rats had less diarrhoeal output and did not show mucosal hyperplasia after three days of treatment. All animals had greatly recovered by the seventh day, but histological alterations were still present, although to a lesser extent in quercitrin-treated rats. Quercitrin and related flavonoids may play a role in intestinal repair following chronic mucosal injury.

  17. THERMOREGULATION IN THE RAT DURING CHRONIC, DIETARY EXPOSURE TO CHLORPYRIFOS, AN ORGANOPHOSPHATE INSECTICIDE.

    EPA Science Inventory

    Administration of chlorpyrifos (CHP) at a dose of 25 to 80 mg/kg (p.o.) To rats results in hypothermia followed by a fever lasting for several days. To understand if chronic, low level exposure to CHP affects thermoregulation in a comparable manner to acute administration, male L...

  18. Polymicrobial Chronic Infection Including Acinetobacter Baumannii in a Plated Segmental Defect in the Rat Femur

    DTIC Science & Technology

    2008-01-01

    Including Acinetobacter baumannii in a Plated Segmental Defect in the Rat Femur PRINCIPAL INVESTIGATOR: Dean T. Tsukayama, MD...FEB 2007 - 31 DEC 2007 4. TITLE AND SUBTITLE Polymicrobial Chronic Infection Including Acinetobacter baumannii 5a. CONTRACT NUMBER in a Plated...bone isolate of Acinetobacter baumannii exhibited very little osteolytic involvement when used alone in the model. Qualitative cultures indicated very

  19. CHRONIC TOXICITY OF 1,3,5-TRINITROBENZENE IN FISCHER 344 RATS

    EPA Science Inventory

    The chronic toxicity of 1,3,5-trinitrobenzene (TNB) in male and female Fischer 344 (F344) rats was evaluated by feeding a diet containing 0, 5, 60 and 300 ppm of TNB for 2 years. The calculated average TNB intake over 2 years for males and females was 0.22, 2.64, 13.44 and 0.23,...

  20. EFFECTS OF CHRONIC EXERCISE CONDITIONING ON THERMAL RESPONSES TO LIPOPOLYSACCHARIDE AND TURPENTINE ABSCESS IN FEMALE RATS.

    EPA Science Inventory

    Chronic exercise conditioning has been shown to alter basal thermoregulatory processes as well as the response to inflammatory agents. Two such agents, lipopolysaccharide (LPS) and turpentine (TPT) are inducers of fever in rats. LPS, given intraperitoneally (i.p.), involves a sys...

  1. Chronic exposure of rats to occupational textile noise causes cytological changes in adrenal cortex.

    PubMed

    Oliveira, Maria Joao R; Monteiro, Mariana P; Ribeiro, Andreia M; Pignatelli, Duarte; Aguas, Artur P

    2009-01-01

    Chronic exposure to industrial noise and its effects on biological systems. Occupational exposure to noise may result in health disorders. Our aim was to evaluate the effects of chronic exposure to high-intensity noise of textile industry cotton rooms on the adrenal morphology. The environmental noise of a cotton-mill room from a large textile factory of Northern Portugal was recorded and reproduced by an adopted electroacoustic setup in a sound-insulated animal room where the rats were housed. The sounds were reproduced at the original levels of approximately 92 dB, which was achieved by equalization and distribution of sound output in the room. Wistar rats were submitted to noise exposure, in the same time schedule as employed in textile plants. After one, three, five, and seven months, the adrenals were collected and analyzed by light microscopy. Analyzed by multivariate analysis of variance and post hoc Bonferroni correction for multiple comparisons of the means between the groups. Noise exposure induced time-dependent changes in adrenal cortex, with decrease of zona fasciculata (ZF) and increase of zona reticularis volumes, together with a significant depletion of lipid droplet density in ZF cells of exposed rats, in comparison to control rats. Chronic exposure of rats to textile industry noise triggers cytological changes in the adrenals that suggest the existence of a sustained stress response.

  2. Chronic treatment with qiliqiangxin ameliorates aortic endothelial cell dysfunction in diabetic rats.

    PubMed

    Chen, Fei; Wu, Jia-Le; Fu, Guo-Sheng; Mou, Yun; Hu, Shen-Jiang

    2015-03-01

    Qiliqiangxin (QL), a traditional Chinese medicine, has been shown to be beneficial for chronic heart failure. However, whether QL can also improve endothelial cell function in diabetic rats remains unknown. Here, we investigated the effect of QL treatment on endothelial dysfunction by comparing the effect of QL to that of benazepril (Ben) in diabetic Sprague-Dawley rats for 8 weeks. Cardiac function was evaluated by echocardiography and catheterization. Assays for acetylcholine-induced, endothelium-dependent relaxation (EDR), sodium nitroprusside-induced endothelium-independent relaxation, serum nitric oxide (NO), and nitric oxide synthase (NOS) as well as histological analyses were performed to assess endothelial function. Diabetic rats showed significantly inhibited cardiac function and EDR, decreased expression of serum NO and phosphorylation at Ser(1177) on endothelial NOS (eNOS), and impaired endothelial integrity after 8 weeks. Chronic treatment for 8 weeks with either QL or Ben prevented the inhibition of cardiac function and EDR and the decrease in serum NO and eNOS phosphorylation caused by diabetes. Moreover, either QL or Ben suppressed inducible NOS (iNOS) protein levels as well as endothelial necrosis compared with the diabetic rats. Additionally, QL prevented the increase in angiotensin-converting enzyme 1 and angiotensin II receptor type 1 in diabetes. Thus, chronic administration of QL improved serum NO production, EDR, and endothelial integrity in diabetic rat aortas, possibly through balancing eNOS and iNOS activity and decreasing renin-angiotensin system expression.

  3. Naked mole rats exhibit metabolic but not ventilatory plasticity following chronic sustained hypoxia.

    PubMed

    Chung, Danielle; Dzal, Yvonne A; Seow, Allison; Milsom, William K; Pamenter, Matthew E

    2016-03-30

    Naked mole rats are among the most hypoxia-tolerant mammals identified and live in chronic hypoxia throughout their lives. The physiological mechanisms underlying this tolerance, however, are poorly understood. Most vertebrates hyperventilate in acute hypoxia and exhibit an enhanced hyperventilation following acclimatization to chronic sustained hypoxia (CSH). Conversely, naked mole rats do not hyperventilate in acute hypoxia and their response to CSH has not been examined. In this study, we explored mechanisms of plasticity in the control of the hypoxic ventilatory response (HVR) and hypoxic metabolic response (HMR) of freely behaving naked mole rats following 8-10 days of chronic sustained normoxia (CSN) or CSH. Specifically, we investigated the role of the major inhibitory neurotransmitter γ-amino butyric acid (GABA) in mediating these responses. Our study yielded three important findings. First, naked mole rats did not exhibit ventilatory plasticity following CSH, which is unique among adult animals studied to date. Second, GABA receptor (GABAR) antagonism altered breathing patterns in CSN and CSH animals and modulated the acute HVR in CSN animals. Third, naked mole rats exhibited GABAR-dependent metabolic plasticity following long-term hypoxia, such that the basal metabolic rate was approximately 25% higher in normoxic CSH animals than CSN animals, and GABAR antagonists modulated this increase.

  4. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

    PubMed

    Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

    2016-12-01

    Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

  5. Impact of chronic stressors on the anxiety profile of pregnant rats.

    PubMed

    de Brito Guzzo, Soliani Flaviane Cristina; Rafael, Cabbia; Matheus Fitipaldi, Batistela; Amarylis Garcia, Almeida; Vinícius Dias, Kümpel; Luiz, Yamauchi Junior; Fernando, Frei; Telma Gonçalves Carneiro Spera de, Andrade

    2015-04-01

    The manifestation of anxiety during pregnancy can be caused by multiple factors and may have emotional and physical consequences for both the mother and the fetus. The prevalence of gestational anxiety has grown in recent years, making the development of studies for its comprehension essential. Thus, the aim of this investigation was to evaluate the effects of predictable and unpredictable chronic stressors on the anxiety profile of rats in three distinct stages of pregnancy (1st, 2nd and 3rd weeks). Wistar dams were divided into three groups: control, social separation and unpredictable chronic stress. Behavioral assessments were conducted in the Elevated Plus-Maze at the end of the 1st, 2nd and 3rd weeks of gestation. The results showed that there was increased anxiety in the proximity of parturition in control dams. Chronic stressors differentially affected the behavior of pregnant rats according to the gestational period where they were applied: social separation decreased anxiety at the end of the 3rd week, while unpredictable chronic stress caused increased anxiety, especially at the end of the 2nd gestational week. These results show that there is a critical time during pregnancy for the onset of anxiety in control rats, depending on the gestational stage. The exposure to different types of chronic stressors may result in distinct behaviors related to this disorder.

  6. Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats

    SciTech Connect

    Evans, E.B.; Seifen, E.; Kennedy, R.H.; Kafiluddi, R.; Paule, M.G.; Scallet, A.C.; Ali, S.F.; Slikker, W. Jr.

    1987-10-01

    This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)(/sup 3/H)dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.

  7. Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants.

    PubMed

    Scaini, Giselli; Santos, Patricia M; Benedet, Joana; Rochi, Natália; Gomes, Lara M; Borges, Lislaine S; Rezin, Gislaine T; Pezente, Daiana P; Quevedo, João; Streck, Emilio L

    2010-05-31

    Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10mg/kg), nortriptiline (15mg/kg), venlafaxine (10mg/kg) or saline in 1.0mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs.

  8. Chronic prostatic infection and inflammation by Propionibacterium acnes in a rat prostate infection model.

    PubMed

    Olsson, Jan; Drott, Johanna Bergh; Laurantzon, Lovisa; Laurantzon, Oscar; Bergh, Anders; Elgh, Fredrik

    2012-01-01

    Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic

  9. Hemolytic uremic syndrome associated with paraquat intoxication.

    PubMed

    Jang, Ha Nee; Bae, Eun Jin; Hwang, Kyungo; Kang, Yeojin; Yun, Seongeun; Cho, Hyun Seop; Chang, Se-Ho; Park, Dong Jun

    2014-06-01

    We report a case of a 66-year-old patient with paraquat intoxication resulting in the requirement for hemoperfusion, hemodialysis, and plasma exchange. His initial serum paraquat level was 0.24 µg/mL (0.0-0.1 µg/mL). Activated charcoal (50 g) was administered orally, and high-dose N-acetylcysteine (150 mg/kg) was administered intravenously. In addition, immediate 4 h hemoperfusion was also performed for three consecutive days after admission. Hemodialysis was started on the 4th day after admission because of uremia. On the 9th day after admission, laboratory findings demonstrated hemolytic uremic syndrome (HUS): microangiopathic hemolytic anemia (MAHA), thrombocytopenia, elevated reticulocyte count, and lactate dehydrogenase (LDH). Plasma exchange was performed three times consecutively. Anemia and thrombocytopenia were improved, and LDH was normalized after plasma exchange. Urine output increased to 2240 mL/day on the 18th day after admission, and hemodialysis was discontinued. He is currently being observed at our follow-up clinic without renal impairment or pulmonary dysfunction for 1.5 years since discharge. We should suspect paraquat-associated HUS when thrombocytopenia and anemia are maintained for a long time after paraquat intoxication.

  10. Effects of chronic 137Cs ingestion on barrier properties of jejunal epithelium in rats.

    PubMed

    Dublineau, I; Grison, S; Grandcolas, L; Baudelin, C; Paquet, F; Voisin, P; Aigueperse, J; Gourmelon, P

    2007-05-15

    Environmental contamination by 137Cs is of particular public health interest because of the various sources of fallout originating from nuclear weapons, radiological source disruptions, and the Chernobyl disaster. This dispersion may lead to a chronic ecosystem contamination and subsequent ingestion of contaminated foodstuffs. The aim of this study was to thus determine the impact of a chronic ingestion of low-dose 137Cs on small intestine functions in rats. The animals received 150 Bq per day in drinking water over 3 mo. At these environmental doses, 137Cs contamination did not modify the crypt and villus architecture. In addition, epithelial integrity was maintained following the chronic ingestion of 137Cs, as demonstrated by histological analyses (no breakdown of the surface mucosa) and electrical transepithelial parameters (no change in potential difference and tissue conductance). Furthermore, cesium contamination seemed to induce contradictory effects on the apoptosis pathway, with an increase in the gene expression of Fas/FasL and a decrease in the apoptotic cell number present in intestinal mucosa. No marked inflammation was observed following chronic ingestion of 137Cs, as indicated by neutrophil infiltration and gene expression of cytokines and chemokines. Results indicated no imbalance in the Th1/Th2 response induced by cesium at low doses. Finally, evaluation of the functionality of the jejunal epithelium in rats contaminated chronically with 137Cs did not demonstrate changes in the maximal response to carbachol, nor in the cholinergic sensitivity of rat jejunal epithelium. In conclusion, this study shows that chronic ingestion of 137Cs over 3 mo at postaccidental doses exerts few biological effects on the epithelium of rat jejunum with regard to morphology, inflammation status, apoptosis/proliferation processes, and secretory functions.

  11. Effects of milnacipran on cognitive flexibility following chronic stress in rats.

    PubMed

    Naegeli, Kale J; O'Connor, Joann A; Banerjee, Pradeep; Morilak, David A

    2013-03-05

    Cognitive dysfunction is a component of affective disorders, including depression. Chronic stress is a risk factor for depression, and we have shown that exposing rats to chronic unpredictable stress (CUS) induces a deficit of cognitive flexibility, the ability to modify behavior based on feedback from a changing environment. Deficits of cognitive flexibility, measured by extra-dimensional set-shifting on the Attentional Set-shifting Test (AST), are consistent with dysregulation of prefrontal cortical function, also characteristic of depression. We have shown that increasing norepinephrine in the medial prefrontal cortex facilitated set-shifting, and chronic treatment with the selective norepinephrine reuptake blocker, desipramine, restored cognitive flexibility in rats that had been compromised by CUS. Serotonin reuptake blockade also prevented CUS-induced deficits in cognitive flexibility, suggesting a role for both monoamines in this process. Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) with moderate preference for blocking norepinephrine reuptake. In this study, we tested the effects of chronic milnacipran treatment on cognitive set-shifting after CUS. Male Sprague-Dawley rats were treated chronically by minipump with milnacipran (30 mg/kg/day), the positive control drug, desipramine (5mg/kg/day), or vehicle, and exposed to CUS or unstressed control conditions. For CUS, a different acute stressor was presented daily for 14 days. On Day 17, rats were tested on the AST. Consistent with previous results, CUS impaired cognitive set-shifting. Further, chronic treatment with either milnacipran or desipramine preserved cognitive flexibility after CUS, suggesting that milnacipran may have efficacy in the management of cognitive dysfunction as a component of stress-related illnesses, including fibromyalgia and depression.

  12. Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver.

    PubMed

    Prakash, Chandra; Kumar, Vijay

    2016-09-01

    The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25 ppm for 12 weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity.

  13. Increased Expression of p-Akt correlates with Chronic Allograft Nephropathy in a Rat Kidney Model.

    PubMed

    Zhou, Li-Na; Wang, Ning; Dong, Yang; Zhang, Yiqin; Zou, Hequn; Li, Qingqin; Shi, Yangling; Chen, Ling; Zhou, Wenying; Han, Conghui; Wang, Yuxin

    2015-04-01

    Chronic allograft nephropathy (CAN) is the most common cause of chronic graft dysfunction leading to graft failure, our study investigates the expression and significance of p-Akt in the pathogenesis of CAN in rats. Kidneys of Fisher (F344) rats were orthotopically transplanted into Lewis (LEW) rats. The animals were evaluated at 4, 8, 12, 16, and 24 weeks post-transplantation for renal function and histopathology. Phosphorate Akt (p-Akt) protein expression was determined by Western blot and immunohistological assays. Our data show that 24-h urinary protein excretion in CAN rats increased significantly at week 16 as compared with F344/LEW controls. Allografts got severe interstitial infiltration of mononuclear cells at week 4 and week 8, but it was degraded as the time went on after week 16. Allografts markedly presented with severe interstitial fibrosis (IF) and tubular atrophy at 16 and 24 weeks. p-Akt expression was upregulated in rat kidneys with CAN, and the increase became more significant over time after transplantation. p-Akt expression correlated significantly with 24-h urinary protein excretion, serum creatinine levels, tubulointerstitial mononuclear cells infiltration, smooth muscle cells (SMCs) migration in vascular wall, and IF. It was concluded that p-Akt overexpression might be the key event that involved mononuclear cells infiltration and vascular SMCs migration at early stage, and IF and allograft nephroangiosclerosis at the late stage of CAN pathogenesis in rats.

  14. Chronic Δ9-Tetrahydrocannabinol during Adolescence Differentially Modulates Striatal CB1 Receptor Expression and the Acute and Chronic Effects on Learning in Adult Rats.

    PubMed

    Weed, Peter F; Filipeanu, Catalin M; Ketchum, Myles J; Winsauer, Peter J

    2016-01-01

    The purpose of this study was to determine whether chronic administration of Δ(9)-tetrahydrocannabinol (THC) during adolescence would (1) modify any sex-specific effects of THC on learning and (2) affect the development of tolerance to THC as an adult. Male and female rats received daily injections of saline or 5.6 mg/kg of THC from postnatal day 35-75, yielding four groups (female/saline, female/THC, male/saline, and male/THC). Rats were then trained on a procedure that assayed both learning and performance behavior and administered 0.32-18 mg/kg of THC acutely as adults (experiment 1). THC produced rate-decreasing and error-increasing effects in both sexes; however, female rats were more sensitive than male rats were to the rate-decreasing effects. Rats were then chronically administered 10 mg/kg of THC (experiment 2). Rats that received THC during adolescence developed tolerance to the rate-decreasing effects more slowly and less completely than did rats that received saline; in addition, females developed tolerance to the error-increasing effects of THC slower than males did. Western blot analysis of brain tissue indicated long-term changes in hippocampal and striatal cannabinoid type-1 receptor (CB1R) levels despite levels that were indistinguishable immediately after chronic treatment during adolescence. Striatal CB1R levels were increased in adult rats that received THC during adolescence; hippocampal CB1R levels varied by sex. In summary, female rats were more sensitive than male rats were to the acute and chronic effects of THC, and chronic administration of THC during adolescence produced long-term changes in CB1R levels that correlated with decreased tolerance development to the rate-decreasing effects of THC.

  15. Chronic loss of melanin-concentrating hormone affects motivational aspects of feeding in the rat.

    PubMed

    Mul, Joram D; la Fleur, Susanne E; Toonen, Pim W; Afrasiab-Middelman, Anthonieke; Binnekade, Rob; Schetters, Dustin; Verheij, Michel M M; Sears, Robert M; Homberg, Judith R; Schoffelmeer, Anton N M; Adan, Roger A H; DiLeone, Ralph J; De Vries, Taco J; Cuppen, Edwin

    2011-05-05

    Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding.Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch(+/+) or pmch(-/-) rats. However, acute administration of MCH to the AcbSh of adult pmch(-/-) rats elevated feeding behavior towards wild type levels. Finally, adult pmch(-/-) rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system.Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption.

  16. Chronic Loss of Melanin-Concentrating Hormone Affects Motivational Aspects of Feeding in the Rat

    PubMed Central

    Mul, Joram D.; la Fleur, Susanne E.; Toonen, Pim W.; Afrasiab-Middelman, Anthonieke; Binnekade, Rob; Schetters, Dustin; Verheij, Michel M. M.; Sears, Robert M.; Homberg, Judith R.; Schoffelmeer, Anton N. M.; Adan, Roger A. H.; DiLeone, Ralph J.; De Vries, Taco J.; Cuppen, Edwin

    2011-01-01

    Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding. Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch+/+ or pmch−/− rats. However, acute administration of MCH to the AcbSh of adult pmch−/− rats elevated feeding behavior towards wild type levels. Finally, adult pmch−/− rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system. Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption. PMID

  17. Rats selectively bred for differences in aerobic capacity have similar hypertensive responses to chronic intermittent hypoxia.

    PubMed

    Sharpe, Amanda L; Andrade, Mary Ann; Herrera-Rosales, Myrna; Britton, Steven L; Koch, Lauren G; Toney, Glenn M

    2013-08-01

    Exposure to chronic intermittent hypoxia (CIH) is an animal model that mimics the repetitive bouts of hypoxemia experienced by humans with sleep apnea. Rats exposed to CIH develop hypertension that depends on the activation of sympathetic nerve activity (SNA). Since obesity and metabolic syndrome have been linked to neurogenic hypertension and sleep apnea, and because sleep apnea can adversely affect aerobic exercise capacity, we tested the hypothesis that rats bred for selection of low aerobic capacity running (LCR) would have a greater hypertensive response to CIH than rats bred for high aerobic capacity running (HCR). Blockade of ganglionic transmission was performed to compare the contribution of SNA to the maintenance of resting mean arterial pressure (MAP). Next, hypertensive responses to 7 days of CIH were compared across LCR and HCR rats (14-16 mo old). Finally, the contribution of the hypothalamic paraventricular nucleus (PVN) to the maintenance of SNA and hypertension after CIH was determined and compared across groups. Although LCR rats were less active and had greater body weights than HCR rats, resting MAP, the contribution of ongoing SNA to the maintenance of MAP, and hypertensive responses to CIH were similar between groups. Contrary to our hypothesis, chemical inhibition of the PVN with muscimol (1 mmol/100 nl) caused a larger fall of MAP in HCR rats than in LCR rats. We conclude that LCR rats do not have resting hypertension or an exaggerated hypertensive response to CIH. Interestingly, the maintenance of CIH hypertension in LCR rats compared with HCR rats appears less reliant on ongoing PVN neuronal activity.

  18. Iron-restricted pair-feeding affects renal damage in rats with chronic kidney disease

    PubMed Central

    Naito, Yoshiro; Senchi, Aya; Sawada, Hisashi; Oboshi, Makiko; Horimatsu, Tetsuo; Okuno, Keisuke; Yasumura, Seiki; Ishihara, Masaharu; Masuyama, Tohru

    2017-01-01

    Background We have previously shown that dietary iron restriction prevents the development of renal damage in a rat model of chronic kidney disease (CKD). However, iron deficiency is associated with appetite loss. In addition, calorie restriction is reported to prevent the development of end-stage renal pathology in CKD rats. Thus, the beneficial effect of iron restriction on renal damage may depend on calorie restriction. Here, we investigate the effect of pair-feeding iron restriction on renal damage in a rat model of CKD. Methods First, to determine the amount of food intake, Sprague-Dawley (SD) rats were randomly given an ad libitum normal diet or an iron-restricted diet, and the food intake was measured. Second, CKD was induced by a 5/6 nephrectomy in SD rats, and CKD rats were given either a pair-feeding normal or iron-restricted diet. Results Food intake was reduced in the iron-restricted diet group compared to the normal diet group of SD rats for 16 weeks (mean food intake; normal diet group and iron-restricted diet group: 25 and 20 g/day, respectively). Based on the initial experiments, CKD rats received either a pair-feeding normal or iron-restricted diet (20 g/day) for 16 weeks. Importantly, pair-feeding iron restriction prevented the development of proteinuria, glomerulosclerosis, and tubulointerstitial damage in CKD rats. Interestingly, pair-feeding iron restriction attenuated renal expression of nuclear mineralocorticoid receptor in CKD rats. Conclusions Pair-feeding iron restriction affected renal damage in a rat model of CKD. PMID:28196143

  19. Induction of neuroserpin expression in rat frontal cortex after chronic antidepressant treatment and electroconvulsive treatment.

    PubMed

    Tanaka, Satoshi; Yamada, Misa; Kitahara, Sari; Higuchi, Teruhiko; Honda, Kazuo; Kamijima, Kunitoshi; Yamada, Mitsuhiko

    2006-02-01

    Using expressed sequence tag (EST) analysis, we previously identified certain molecular machinery that mediates antidepressant effects. To date, several partial cDNA fragments, termed antidepressant-related genes (ADRGs), have been isolated as ESTs from rat brain. In the present study, we identified two of the ADRGs to be rat neuroserpin. Using real-time quantitative PCR, we demonstrated increased neuroserpin mRNA expression in rat frontal cortex after chronic treatment with several classes of antidepressants, including imipramine, fluoxetine, sertraline, and venlafaxine. Electroconvulsive treatment (ECT), another therapeutic treatment for depression, also increased neuroserpin expression in rat frontal cortex. Neuroserpin is a serine protease inhibitor that is implicated in the regulation of synaptic plasticity, neuronal migration, and axogenesis in the central nervous system. In conclusion, our results support the hypothesis that neuroserpin-mediated plastic changes in frontal cortex may underlie the therapeutic action of antidepressants and ECT.

  20. Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains.

    PubMed

    Pucilowski, O; Overstreet, D H

    1993-01-01

    The purpose of this study was to verify the dopamine-sensitizing behavioral effect of chronic antidepressant treatment in two selectively bred rat strains: the hypercholinergic Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL). Two antidepressants, desipramine HCl (DMI) and sertraline HCl, were injected IP in separate groups of FSL and FRL rats in a dose of 16.5 mumol/kg twice daily for 16 days. Twenty-four hours after withdrawal, locomotor and hypothermic responses to 0.2 mg/kg of apomorphine, SC, were examined. Attenuation of the effect of apomorphine was observed in the open field: FRLs withdrawn from sertraline were significantly less mobile than control FRLs, and the same trend was found in FSL rats. Chronic DMI resulted in similar changes in the locomotor activity. Sertraline treatment decreased apomorphine-induced hypothermia by almost half in FSLs, whereas slight hyperthermia was induced in FRL rats instead. The present results suggest that in these selectively bred strains, a serotonergic antidepressant such as sertraline may have sensitized dopaminergic autoreceptors and/or desensitized postsynaptic receptors. Apomorphine-induced hypothermia could be mediated by serotonergic neuron function that may have been altered by chronic sertraline but not DMI treatment.

  1. Specific N-terminal CGRP fragments mitigate chronic hypoxic pulmonary hypertension in rats.

    PubMed

    Qing, Xin; Wimalawansa, Sunil J; Keith, Ingegerd M

    2003-01-31

    Chronic hypoxic pulmonary hypertension (HPH) is characterized by elevated pulmonary arterial pressure (P(PA)), right ventricular hypertrophy (RVH), pulmonary vascular remodeling, pulmonary edema and polycythemia. Currently, there is no safe and effective treatment for HPH. Calcitonin gene-related peptide (CGRP) is the most potent peptide vasodilator discovered thus far. We previously demonstrated that exogenous CGRP reversed HPH in rats. However, the CGRP1 receptor antagonist CGRP(8-37) and smaller inhibitory C-terminal CGRP fragments that can be formed by enzymatic cleavage in vivo may compromise the beneficial effects of endogenous or exogenous CGRP. We here examine the agonistic efficacy of N-terminal rat alpha-CGRP peptides containing the disulfide bridge (Cys(2)-Cys(7)) with amidated C-terminal in prevention of HPH. Chronic infusion of CGRP(1-8), CGRP(1-13), or CGRP(1-14) at 7 nmol/h/rat via the right jugular vein during 14 days of hypobaric hypoxia (10% inspired O(2)) significantly decreased the P(PA), RVH and pulmonary arterial medial thickness in comparison with controls, suggesting that these CGRP sequences can mitigate chronic HPH in rats. Systemic pressure was unchanged by infused peptides indicating no carry-over effect. In conclusion, N-terminal CGRP fragments (CGRP(1-8), CGRP(1-13) and CGRP(1-14)) may have a protective role in hypoxic pulmonary hypertension.

  2. Hypothalamic L-Histidine Decarboxylase Is Up-Regulated During Chronic REM Sleep Deprivation of Rats

    PubMed Central

    Hoffman, Gloria E.; Koban, Michael

    2016-01-01

    A competition of neurobehavioral drives of sleep and wakefulness occurs during sleep deprivation. When enforced chronically, subjects must remain awake. This study examines histaminergic neurons of the tuberomammillary nucleus of the posterior hypothalamus in response to enforced wakefulness in rats. We tested the hypothesis that the rate-limiting enzyme for histamine biosynthesis, L-histidine decarboxylase (HDC), would be up-regulated during chronic rapid eye movement sleep deprivation (REM-SD) because histamine plays a major role in maintaining wakefulness. Archived brain tissues of male Sprague Dawley rats from a previous study were used. Rats had been subjected to REM-SD by the flowerpot paradigm for 5, 10, or 15 days. For immunocytochemistry, rats were transcardially perfused with acrolein-paraformaldehyde for immunodetection of L-HDC; separate controls used carbodiimide-paraformaldehyde for immunodetection of histamine. Immunolocalization of histamine within the tuberomammillary nucleus was validated using carbodiimide. Because HDC antiserum has cross-reactivity with other decarboxylases at high antibody concentrations, titrations localized L-HDC to only tuberomammillary nucleus at a dilution of ≥ 1:300,000. REM-SD increased immunoreactive HDC by day 5 and it remained elevated in both dorsal and ventral aspects of the tuberomammillary complex. Our results suggest that up-regulation of L-HDC within the tuberomammillary complex during chronic REM-SD may be responsible for maintaining wakefulness. PMID:27997552

  3. Prior chronic nicotine impairs cued fear extinction but enhances contextual fear conditioning in rats.

    PubMed

    Tian, S; Gao, J; Han, L; Fu, J; Li, C; Li, Z

    2008-06-02

    Clinical observations have shown a link for the high comorbid rate between smoking and psychiatric disorders, including anxiety disorders. However, little is known about the neural mechanism underlying the progression from nicotine dependence to an anxiety disorder. A deficit in fear extinction in general is considered to contribute to anxiety disorders. The aim of the present study is to investigate the effects of chronic nicotine on fear extinction in rats. Rats were administrated s.c. nicotine twice per day for 14 days. Two weeks after the last injection rats received a cued or contextual fear conditioning session. Twenty-four hours and 48 h after conditioning, rats received an extinction training session and an extinction test session, respectively. Percent freezing was assessed during all phases of training. In the cued task, prior chronic nicotine did not affect the acquisition of fear response or the within-session fear extinction, but impaired the between-session fear extinction. In the contextual task, the same nicotine treatment schedule did not affect the acquisition of fear response or the within- and between-session fear extinction, but enhanced the retention of fear conditioning. This prior chronic nicotine-induced deficit in cued fear extinction and/or enhanced fear to context may be one of the critical components that contribute to the progression from nicotine dependence to an anxiety disorder.

  4. Effect of chronic exposure to aspartame on oxidative stress in the brain of albino rats.

    PubMed

    Iyyaswamy, Ashok; Rathinasamy, Sheeladevi

    2012-09-01

    This study was aimed at investigating the chronic effect of the artificial sweetener aspartame on oxidative stress in brain regions of Wistar strain albino rats. Many controversial reports are available on the use of aspartame as it releases methanol as one of its metabolite during metabolism. The present study proposed to investigate whether chronic aspartame (75 mg/kg) administration could release methanol and induce oxidative stress in the rat brain. To mimic the human methanol metabolism, methotrexate (MTX)-treated rats were included to study the aspartame effects. Wistar strain male albino rats were administered with aspartame orally and studied along with controls and MTX-treated controls. The blood methanol level was estimated, the animal was sacrificed and the free radical changes were observed in brain discrete regions by assessing the scavenging enzymes, reduced glutathione, lipid peroxidation (LPO) and protein thiol levels. It was observed that there was a significant increase in LPO levels, superoxide dismutase (SOD) activity, GPx levels and CAT activity with a significant decrease in GSH and protein thiol. Moreover, the increases in some of these enzymes were region specific. Chronic exposure of aspartame resulted in detectable methanol in blood. Methanol per se and its metabolites may be responsible for the generation of oxidative stress in brain regions.

  5. Effects of chronic lithium administration on renal acid excretion in humans and rats

    PubMed Central

    Weiner, I. David; Leader, John P.; Bedford, Jennifer J.; Verlander, Jill W.; Ellis, Gaye; Kalita, Priyakshi; Vos, Frederiek; de Jong, Sylvia; Walker, Robert J.

    2014-01-01

    Abstract Lithium therapy's most common side effects affecting the kidney are nephrogenic diabetes insipidus (NDI) and chronic kidney disease. Lithium may also induce a distal renal tubular acidosis. This study investigated the effect of chronic lithium exposure on renal acid–base homeostasis, with emphasis on ammonia and citrate excretion. We compared 11 individuals on long‐term lithium therapy with six healthy individuals. Under basal conditions, lithium‐treated individuals excreted significantly more urinary ammonia than did control subjects. Following an acute acid load, urinary ammonia excretion increased approximately twofold above basal rates in both lithium‐treated and control humans. There were no significant differences between lithium‐treated and control subjects in urinary pH or urinary citrate excretion. To elucidate possible mechanisms, rats were randomized to diets containing lithium or regular diet for 6 months. Similar to humans, basal ammonia excretion was significantly higher in lithium‐treated rats; in addition, urinary citrate excretion was also significantly greater. There were no differences in urinary pH. Expression of the critical ammonia transporter, Rhesus C Glycoprotein (Rhcg), was substantially greater in lithium‐treated rats than in control rats. We conclude that chronic lithium exposure increases renal ammonia excretion through mechanisms independent of urinary pH and likely to involve increased collecting duct ammonia secretion via the ammonia transporter, Rhcg. PMID:25501430

  6. Hypothalamic L-Histidine Decarboxylase Is Up-Regulated During Chronic REM Sleep Deprivation of Rats.

    PubMed

    Hoffman, Gloria E; Koban, Michael

    2016-01-01

    A competition of neurobehavioral drives of sleep and wakefulness occurs during sleep deprivation. When enforced chronically, subjects must remain awake. This study examines histaminergic neurons of the tuberomammillary nucleus of the posterior hypothalamus in response to enforced wakefulness in rats. We tested the hypothesis that the rate-limiting enzyme for histamine biosynthesis, L-histidine decarboxylase (HDC), would be up-regulated during chronic rapid eye movement sleep deprivation (REM-SD) because histamine plays a major role in maintaining wakefulness. Archived brain tissues of male Sprague Dawley rats from a previous study were used. Rats had been subjected to REM-SD by the flowerpot paradigm for 5, 10, or 15 days. For immunocytochemistry, rats were transcardially perfused with acrolein-paraformaldehyde for immunodetection of L-HDC; separate controls used carbodiimide-paraformaldehyde for immunodetection of histamine. Immunolocalization of histamine within the tuberomammillary nucleus was validated using carbodiimide. Because HDC antiserum has cross-reactivity with other decarboxylases at high antibody concentrations, titrations localized L-HDC to only tuberomammillary nucleus at a dilution of ≥ 1:300,000. REM-SD increased immunoreactive HDC by day 5 and it remained elevated in both dorsal and ventral aspects of the tuberomammillary complex. Our results suggest that up-regulation of L-HDC within the tuberomammillary complex during chronic REM-SD may be responsible for maintaining wakefulness.

  7. Identification of beta-aminoisobutyric acid in uremic serum.

    PubMed

    Gejyo, F; Kinoshita, Y; Ikenaka, T

    1976-08-02

    An unidentified ninhydrin-positive substance found in uremic sera but not found in normal sera was isolated by gel-filtration through Sephadex G-75 followed by high voltage paper electrophoresis (pH 3.5), and identified as beta-aminoisobutyric acid using paper chromatography and automated amino acid analyzer. The quantitative determination of beta-aminoisobutyric acid in serum revealed that the level of beta-aminoisobutyric acid in uremic sera was much higher than that of normal sera. Gas chromatographic determination of the enantiomorphs of beta-aminoisobutyric acid showed that uremic sera contain R- and S-isomers of the amino acid, but with the R-isomer as the dominating form.

  8. Chronic Normobaric Hypoxia Induces Pulmonary Hypertension in Rats: Role of NF-κB.

    PubMed

    Fan, Junming; Fan, Xiaofang; Li, Yang; Ding, Lu; Zheng, Qingqing; Guo, Jinbin; Xia, Dongmei; Xue, Feng; Wang, Yongyu; Liu, Shufang; Gong, Yongsheng

    2016-03-01

    To investigate whether nuclear factor-kappa B (NF-κB) activation is involved in chronic normobaric hypoxia-induced pulmonary hypertension (PH), rats were treated with saline or an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC, 150 mg/kg, sc, twice daily), and exposed to normoxia or chronic normobaric hypoxia with a fraction of inspired oxygen of ∼0.1 for 14 days. Lung tissue levels of NF-κB activity, and interleukin (IL)-1β, IL-6, and cyclooxygenase-2 mRNAs, were determined, and mean pulmonary arterial pressure, right ventricular hypertrophy, and right heart function were evaluated. Compared to the normoxia exposure group, rats exposed to chronic normobaric hypoxia showed an increased NF-κB activity, measured by increased nuclear translocation of p50 and p65 proteins, an increased inflammatory gene expression in the lungs, elevated mean pulmonary arterial blood pressure and mean right ventricular pressure, right ventricular hypertrophy, as assessed by right ventricle-to-left ventricle plus septum weight ratio, and right heart dysfunction. Treatment of hypoxia-exposed rats with PDTC inhibited NF-κB activity, decreased pulmonary arterial blood pressure and right ventricular pressure, and ameliorated right ventricular hypertrophy and right heart dysfunction. Hypoxia exposure increased protein kinase C activity and promoted pulmonary artery smooth muscle cell proliferation in vitro. Our data suggest that NF-κB activation may contribute to chronic normobaric hypoxia-induced PH.

  9. Chronic sleep deprivation alters the myosin heavy chain isoforms in the masseter muscle in rats.

    PubMed

    Cao, Ruihua; Huang, Fei; Wang, Peihuan; Chen, Chen; Zhu, Guoxiong; Chen, Lei; Wu, Gaoyi

    2015-05-01

    To investigate the changes in myosin heavy chain (MyHC) isoforms of rat masseter muscle fibres caused by chronic sleep deprivation and a possible link with the pathogenesis of disorders of the temporomandibular joint (TMJ). A total of 180 male rats were randomly divided into three groups (n=60 in each): cage controls, large platform controls, and chronic sleep deprivation group. Each group was further divided into three subgroups with different observation periods (7, 14, and 21 days). We investigated he expression of MyHC isoforms in masseter muscle fibres by real-time quantitative polymerase chain reaction (PCR), Western blotting, and immunohistochemical staining. In rats with chronic sleep deprivation there was increased MyHC-I expression in layers of both shallow and deep muscles at 7 and 21 days compared with the control groups, whereas sleep deprivation was associated with significantly decreased MyHC-II expression. At 21 days, there were no differences in MyHC-I or MyHC-II expression between the groups and there were no differences between the two control groups at any time point. These findings suggest that chronic sleep deprivation alters the expression of MyHC isoforms, which may contribute to the pathogenesis of disorders of the TMJ.

  10. Functional changes in piriform cortex pyramidal neurons in the chronic methamphetamine-treated rat.

    PubMed

    Hori, Nobuaki; Kadota, Tomoko; Akaike, Norio

    2015-01-01

    Chronic treatment of rats with methamphetamine (MAP) causes a range of functional changes to the central nervous system (CNS), including a toxicity that is widespread throughout the brain (Frost and Cadet 2000; Fasihpour et al. 2013). In this report, we examined the effect of chronic MAP treatment on pyramidal neurons of the rat piriform cortex, an area involved in sensory processing, associative learning and a model system for studies on synaptic plasticity. MAP treatment significantly depolarized the membrane potential and decreased neuronal input resistance. Furthermore, the voltage-dependence of both AMPA and NMDA responses was disturbed by chronic MAP treatment, and the extent of long-term potentiation (LTP) was decreased. Morphological changes of MAP-treated rat pyramidal neurons were observed as blebbing of the dendrite trees. The changes we observed represent detrimental effects on the function of piriform cortical neurons further illustrating deficits in synaptic plasticity extend beyond the hippocampus. These changes may contribute to behavioural deficits in chronic MAP-treated animals.

  11. Biliopancreatic duct injection of ethanol as an experimental model of acute and chronic pancreatitis in rats.

    PubMed

    Unal, Ethem; Atalay, Suleyman; Tolan, Huseyin Kerem; Yuksekdag, Sema; Yucel, Metin; Acar, Aylin; Basak, Fatih; Gunes, Pembegul; Bas, Gurhan

    2015-01-01

    In the present study, we described an easily reproducable experimental pancreatits model induced by biliopancreatic duct injection of ethyl alcohol. Seventy Wistar albino rats were divided equally into seven groups randomly: the control group (group 1), acute pancreatitis groups; induced by 20% ethanol (group 2), 48% ethanol (group 3), 80% ethanol (group 4), chronic pancreatitis groups; induced by 20% ethanol (group 5), 48% ethanol (group 6) and by 80% ethanol (group 7). Acute pancreatitis groups were sacrified on postoperative day 3, while the control group and chronic pancreatitis groups were killed on postoperative day 7. Histopathologic evaluation was done, and P < 0.05 was accepted as statistically significant. All rats in group 3 developed acute pancreatitis (100%). Inflammatory infiltration of neutrophils and mononuclear cells, interstitial edema, and focal necrotic areas were seen in the pancreatic tissues. Similarly, all rats in group 6 developed chronic pancreatitis (100%). Interstitial fibrosis, lymphotic infiltration, ductal dilatation, acinar cell atrophy, periductal hyperplasia were seen in the pancreatic tissues. Mortality was seen only in group 7. The biliopancreatic ductal injection of 48% ethanol induced acute and chronic pancreatitis has 100% success rate.

  12. Effects of the chronic restraint stress induced depression on reward-related learning in rats.

    PubMed

    Xu, Pan; Wang, Kezhu; Lu, Cong; Dong, Liming; Chen, Yixi; Wang, Qiong; Shi, Zhe; Yang, Yanyan; Chen, Shanguang; Liu, Xinmin

    2017-03-15

    Chronic mild or unpredictability stress produces a persistent depressive-like state. The main symptoms of depression include weight loss, despair, anhedonia, diminished motivation and mild cognition impairment, which could influence the ability of reward-related learning. In the present study, we aimed to evaluate the effects of chronic restraint stress on the performance of reward-related learning of rats. We used the exposure of repeated restraint stress (6h/day, for 28days) to induce depression-like behavior in rats. Then designed tasks including Pavlovian conditioning (magazine head entries), acquisition and maintenance of instrumental conditioning (lever pressing) and goal directed learning (higher fixed ratio schedule of reinforcement) to study the effects of chronic restraint stress. The results indicated that chronic restraint stress influenced rats in those aspects including the acquisition of a Pavlovian stimulus-outcome (S-O) association, the formation and maintenance of action-outcome (A-O) causal relation and the ability of learning in higher fixed ratio schedule. In conclusion, depression could influence the performances in reward-related learning obviously and the series of instrumental learning tasks may have potential as a method to evaluate cognitive changes in depression.

  13. Preventive effects of chronic exogenous growth hormone levels on diet-induced hepatic steatosis in rats

    PubMed Central

    2010-01-01

    Background Non-alcoholic fatty liver disease (NAFLD), which is characterized by hepatic steatosis, can be reversed by early treatment. Several case reports have indicated that the administration of recombinant growth hormone (GH) could improve fatty liver in GH-deficient patients. Here, we investigated whether chronic exogenous GH levels could improve hepatic steatosis induced by a high-fat diet in rats, and explored the underlying mechanisms. Results High-fat diet-fed rats developed abdominal obesity, fatty liver and insulin resistance. Chronic exogenous GH improved fatty liver, by reversing dyslipidaemia, fat accumulation and insulin resistance. Exogenous GH also reduced serum tumour necrosis factor-alpha (TNF-alpha) levels, and ameliorated hepatic lipid peroxidation and oxidative stress. Hepatic fat deposition was also reduced by exogenous GH levels, as was the expression of adipocyte-derived adipokines (adiponectin, leptin and resistin), which might improve lipid metabolism and hepatic steatosis. Exogenous GH seems to improve fatty liver by reducing fat weight, improving insulin sensitivity and correcting oxidative stress, which may be achieved through phosphorylation or dephosphorylation of a group of signal transducers and activators of hepatic signal transduction pathways. Conclusions Chronic exogenous GH has positive effects on fatty liver and may be a potential clinical application in the prevention or reversal of fatty liver. However, chronic secretion of exogenous GH, even at a low level, may increase serum glucose and insulin levels in rats fed a standard diet, and thus increase the risk of insulin resistance. PMID:20653983

  14. Chronic psychosocial stress makes rats more 'pessimistic' in the ambiguous-cue interpretation paradigm.

    PubMed

    Papciak, Justyna; Popik, Piotr; Fuchs, Eberhard; Rygula, Rafal

    2013-11-01

    Human decisions are often biased by emotions. Stressed and depressed individuals tend to make negative, pessimistic judgements while those in positive affective states are often more optimistic. Chronic psychosocial stress has previously been shown to induce a spectrum of behavioural and physiological changes in rats that are considered the correlates of depressive symptoms in humans. In this study, we investigate whether chronic social defeat makes animals more 'pessimistic'. To measure the changes in cognitive judgement bias, we applied the ambiguous-cue interpretation paradigm. In the operant boxes, the rats were trained to press one lever in response to one tone to receive a reward and to press another lever in response to a different tone to avoid punishment. Cognitive bias was tested by measuring the pattern of animals' responses to a tone of intermediate frequency (ambiguous-cue). To induce chronic psychosocial stress, we subjected the animals to daily social defeat in the resident-intruder paradigm for 3 weeks. We report that chronic psychosocial stress makes rats more pessimistic.

  15. Antihypertensive mechanisms of chronic captopril or N-acetylcysteine treatment in L-NAME hypertensive rats.

    PubMed

    Zicha, Josef; Dobesová, Zdenka; Kunes, Jaroslav

    2006-12-01

    Hypertension due to chronic inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine methyl ester (L-NAME) administration is characterized by both impaired NO-dependent vasodilation and enhanced sympathetic vasoconstriction. The aim of our study was to evaluate changes in the participation of major vasoactive systems in L-NAME-treated rats which were subjected to simultaneous antihypertensive (captopril) or antioxidant (N-acetylcysteine, NAC) treatment. Three-month-old Wistar males treated with L-NAME (60 mg/kg/day) for 5 weeks were compared to rats in which L-NAME treatment was combined with simultaneous chronic administration of captopril or NAC. Basal blood pressure (BP) and its acute responses to consecutive i.v. injections of captopril (10 mg/kg), pentolinium (5 mg/kg), L-NAME (30 mg/kg), tetraethylammonium (TEA, 16 mg/kg) and nitroprusside (NP, 20 microg/kg) were determined in conscious rats at the end of the study. The development of L-NAME hypertension was prevented by captopril treatment, whereas NAC treatment caused only a moderate BP reduction. Captopril treatment normalized the sympathetic BP component and significantly reduced residual BP (measured at full NP-induced vasodilation). In contrast, chronic NAC treatment did not modify the sympathetic BP component or residual BP, but significantly enhanced NO-dependent vasodilation. Neither captopril nor NAC treatment influenced the compensatory increase of TEA-sensitive vasodilation mediated by endothelium-derived hyperpolarizing factor in L-NAME-treated rats. Chronic captopril treatment prevented L-NAME hypertension by lowering of sympathetic tone, whereas chronic NAC treatment attenuated L-NAME hypertension by reduction in the vasodilator deficit due to enhanced NO-dependent vasodilation.

  16. Effect of chronic cyanide intoxication on memory in albino rats.

    PubMed

    Mathangi, D C; Namasivayam, A

    2000-01-01

    Cyanide is a chemical widely used in industry, and is a major environmental pollutant. Its toxicity is caused by inhibition of cytochrome oxidase resulting in histotoxic hypoxia. The effect of sublethal doses of cyanide on memory and hippocampal neurotransmitters was studied in male Wistar strain albino rats. Cyanide reduced the memory along with reduction in the levels of dopamine and 5-hydroxytryptamine in the hippocampus. Pre-existing malnutrition in the animals exaggerated these effects.

  17. Antiproliferation effect of the uremic toxin para‑cresol on endothelial progenitor cells is related to its antioxidant activity.

    PubMed

    Pan, Limin; Ye, Xiaoting; Ding, Jiguang; Zhou, Yu

    2017-04-01

    Endothelial dysfunction and impaired endothelial regenerative capacity are key contributors to the high incidence of cardiovascular disease in patients with chronic kidney disease (CKD). Uremic toxins are associated with this pathogenesis. Previous studies have revealed that a uremic toxin, para‑cresol (p‑cresol), exerts an antiproliferation effect on human endothelial progenitor cells (EPCs), but the mechanism remains unclear. In the present study, reactive oxygen species (ROS) were confirmed to function as signaling molecules that regulate growth factor‑dependent EPC proliferation. EPCs were treated with p‑cresol for 72 h, using a concentration range typically found in CKD patients. ROS production was analyzed by fluorescence microscopy and flow cytometry, and protein expression levels of nicotinamide adenine dinucleotide phosphate oxidase, a major source of ROS, were analyzed by western blot analysis. mRNA expression levels of antioxidant genes were assessed by reverse transcription‑quantitative polymerase chain reaction analysis. The results revealed that p‑cresol partially inhibits ROS production, and this effect may be associated with a significant reduction in cytochrome b‑245 alpha and beta chain expression in EPCs. An increase of glutathione peroxidase 4 mRNA expression was also detected. In conclusion, the present study revealed that the antiproliferation effect of p‑cresol on EPCs might act via its antioxidant activity. The results of the present study may facilitate understanding of uremic toxin toxicity on the cardiovascular system.

  18. Behavioral and neurochemical effects of chronic administration of reserpine and SKF-38393 in rats

    SciTech Connect

    Neisewander, J.L.; Lucki, I.; McGonigle, P. )

    1991-05-01

    Alterations in the density of dopamine receptor subtypes and behaviors mediated by the D1-selective agonist SKF-38393 were examined in rats treated chronically with reserpine, SKF-38393 or the combination of these drugs. Animals received either vehicle or reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with ({sup 3}H)SCH-23390 and D2 receptors labeled with ({sup 3}H)spiroperidol revealed that chronic administration of reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic drug treatments also altered behavioral responses. Chronic administration of SKF-38393 alone produced sensitization of the oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of SKF-38393 in rats treated with reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of reserpine alone produced a spontaneous oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist spiroperidol. These findings are discussed in terms of their relevance to Parkinson's disease and tardive dyskinesia.

  19. Effect of chronic estradiol administration on the acute pressor response to aortic coarctation in conscious rats.

    PubMed

    Salgado, M C; Castania, J A; Ballejo, G; Salgado, H C

    1995-08-01

    We investigated the effect of chronic estradiol administration on the pressor response elicited by acute (45 min) partial aortic constriction in conscious Wistar rats and on vascular reactivity to angiotensin II and vasopressin in vitro. Estradiol (10 micrograms kg-1 day-1, sc) or vehicle was administered for 7 days to young castrated male and female rats and to female rats that had stopped cycling (14-16 months of age). In the acute experiment of aortic coarctation in conscious rats, carotid pressure was monitored continuously before and for 45 min after partial abdominal aortic coarctation. In ovariectomized females the mean carotid pressure and heart rate before aortic coarctation were significantly lower in estradiol-treated animals (107 +/- 3 vs 119 +/- 3 mmHg and 360 +/- 31 vs 494 +/- 12 bpm). Estradiol did not affect the pressor response (145-150 mmHg) to aortic coarctation of castrated male rats or ovariectomized female rats but blunted the reflex bradycardia of ovariectomized rats. The onset of the pressor response to aortic coarctation was delayed in aged female rats as compared to the other groups. While estradiol treatment significantly accelerated the onset of hypertension in aged rats, it did not affect the pressor response of castrated animals. Full dose-response curves to angiotensin II and vasopressin were constructed in vitro in the isolated mesenteric arterial bed obtained from similarly treated groups. Estradiol did not affect the vasopressin sensitivity or responsiveness of any group, but caused a significant increase in angiotensin II sensitivity in ovariectomized rats only.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Effect of chronic d-fenfluramine administration on rat hypothalamic serotonin levels and release

    NASA Technical Reports Server (NTRS)

    Schaechter, Judith D.; Wurtman, Richard J.

    1988-01-01

    D-fenfluramine, an anorectic agent in rats and man, was administered daily at doses 1.25, 2.5, 5, or 10 mg/kg/day for 10 days, and sacrificed 6 days later. Hypothalamic serotonin (5-HT) levels were unchanged in rats receiving 1.25-5 mg/kg/day of d-fenfluramine but reduced by 22 percent (p less than 0.01) at the highest drug dose (10 mg/kg/day); hypothalamic 5-hydroxyindole acetic acid (5-HIAA) levels were reduced by 15 percent (p less than 0.05) or 28 percent (p less than 0.01) in rats receiving 5 or 10 mg/kg/day of the drug, respectively. Hypothalamic slices prepared from rats which were previously treated with any of the drug doses spontaneously released endogenous 5-HT at rates that did not differ from those of vehicle-treated rats. 5-HT released with electrical field-stimulation was unaffected by prior d-fenfluramine treatment at doses of 1.25-5 mg/kg/day, and was reduced by 20 percent (p less than 0.05) from slices prepared from rats which received 10 mg/kg/day. 5-HIAA efflux was also attenuated by the highest drug dose. These data indicate that chronic administration to rats of customary anorectic doses of d-fenfluramine (i.e. 0.06-1.25 mg/kg) fail to cause long-lasting reductions in brain 5-HT release.

  1. Protective action of tetramethylpyrazine on the medulla oblongata in rats with chronic hypoxia.

    PubMed

    Ding, Yan; Hou, Xuefei; Chen, Li; Li, Hui; Tang, Yuhong; Zhou, Hua; Zhao, Shu; Zheng, Yu

    2013-01-01

    Tetramethylpyrazine (TMP), one of the active ingredients of the Chinese herb Lingusticum Wallichii Frantchat (Chuan Xiong), plays an important role in neuroprotection. However, the protective effect of TMP on the medulla oblongata, the most important region of the brain for cardiovascular and respiratory control, during chronic hypoxia remains unclear. In this study, we examined the neuroprotective effect of TMP on the medulla oblongata after chronic hypoxic injury in rats. Male Sprague-Dawley rats were randomly divided into four groups: control group, TMP group, chronic hypoxia group, and chronic hypoxia+TMP group. Rats were exposed to hypoxia (10% (v/v) O₂) or normoxia for 6 h daily for 14 days. TMP (80 mg/kg) or vehicle (saline) was injected intraperitoneally 30 min before experimentation. Loss of neurons in the pre-Bötzinger complex, the nucleus ambiguus, the nucleus tractus solitarius, the hypoglossal nucleus and the facial nucleus were evaluated by Nissl staining. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured, and apoptosis was monitored using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. The level of Bcl-2 mRNA and Bax mRNA was quantitatively measured by RT-PCR analysis. TMP protected Nissl bodies of neurons from injury in all nuclei observed, and reduced the loss of neurons in the nucleus ambiguus, the nucleus tractus solitarius, and the hypoglossal nucleus in rats subjected to chronic hypoxia. TMP upregulated SOD activity and inhibited the increase in MDA content in the medulla oblongata of hypoxic rats. In addition, TMP decreased the rate of apoptosis index (the percentage of apoptotic cells against the total number of cells) in all medullary structures examined, excepting the nucleus ambiguus and inhibited the decrease in Bcl-2 mRNA levels in the medulla oblongata following hypoxia. Our findings indicate that TMP may protect the medullary structures that are involved in

  2. Environmental NO2 and CO Exposure: Ignored Factors Associated with Uremic Pruritus in Patients Undergoing Hemodialysis

    PubMed Central

    Huang, Wen-Hung; Lin, Jui-Hsiang; Weng, Cheng-Hao; Hsu, Ching-Wei; Yen, Tzung-Hai

    2016-01-01

    Uremic pruritus (UP), also known as chronic kidney disease–associated pruritus, is a common and disabling symptom in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of UP is multifactorial and poorly understood. Outdoor air pollution has well-known effects on the health of patients with allergic diseases through an inflammatory process. Air pollution–induced inflammation could occur in the skin and aggravate skin symptoms such as pruritus or impair epidermal barrier function. To assess the role of air pollutants, and other clinical variables on uremic pruritus (UP) in HD patients, we recruited 866 patients on maintenance HD. We analyzed the following variables for association with UP: average previous 12-month and 24-month background concentrations for nitrogen dioxide (NO2) and carbon monoxide (CO), and suspended particulate matter of <2.5 μm (PM2.5). In a multivariate logistic regression, hemodialysis duration, serum ferritin levels, low-density lipoprotein levels, and environmental NO2/CO levels were positively associated with UP, and serum albumin levels were negatively associated with UP. This cross-sectional study showed that air pollutants such as NO2 and CO might be associated with UP in patients with MHD. PMID:27507591

  3. Environmental NO2 and CO Exposure: Ignored Factors Associated with Uremic Pruritus in Patients Undergoing Hemodialysis

    NASA Astrophysics Data System (ADS)

    Huang, Wen-Hung; Lin, Jui-Hsiang; Weng, Cheng-Hao; Hsu, Ching-Wei; Yen, Tzung-Hai

    2016-08-01

    Uremic pruritus (UP), also known as chronic kidney disease–associated pruritus, is a common and disabling symptom in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of UP is multifactorial and poorly understood. Outdoor air pollution has well-known effects on the health of patients with allergic diseases through an inflammatory process. Air pollution–induced inflammation could occur in the skin and aggravate skin symptoms such as pruritus or impair epidermal barrier function. To assess the role of air pollutants, and other clinical variables on uremic pruritus (UP) in HD patients, we recruited 866 patients on maintenance HD. We analyzed the following variables for association with UP: average previous 12-month and 24-month background concentrations for nitrogen dioxide (NO2) and carbon monoxide (CO), and suspended particulate matter of <2.5 μm (PM2.5). In a multivariate logistic regression, hemodialysis duration, serum ferritin levels, low-density lipoprotein levels, and environmental NO2/CO levels were positively associated with UP, and serum albumin levels were negatively associated with UP. This cross-sectional study showed that air pollutants such as NO2 and CO might be associated with UP in patients with MHD.

  4. The uremic toxin methylguanidine increases the oxidative metabolism and accelerates the apoptosis of canine neutrophils.

    PubMed

    Bosco, A M; Almeida, B F M; Pereira, P P; Dos Santos, D B; Neto, Á J S; Ferreira, W L; Ciarlini, P C

    2017-03-01

    We investigated the hypothesis that the increased concentration of plasma methylguanidine (MG) increases oxidative metabolism and accelerates apoptosis of neutrophils from dogs with chronic kidney disease (CKD). To achieve this, the levels of MG were quantified in healthy (n=16) and uremic dogs with CKD stage 4 of according to the guidelines of the International Renal Interest Society (IRIS, 2015) (n=16) using high performance liquid chromatography (HPLC). To evaluate the isolated effect of MG on neutrophil oxidative metabolism and apoptosis, neutrophils isolated from 12 healthy dogs were incubated with the highest concentration of plasma MG (0.005g/L) observed in dogs with CKD. Neutrophil oxidative metabolism was assessed by flow cytometry, using the probes hydroethidine for superoxide production and 2',7'-dichlorofluorescein diacetate for hydrogen peroxide production, with or without phorbol myristate acetate (PMA) stimulus. Neutrophil apoptosis and viability were also evaluated in flow cytometer using the Annexin V-PE system, with or without the apoptosis-inducing effect of camptothecin. Uremic dogs presented higher concentrations of MG (p<0.0001), increased oxidative stress and primed neutrophils with higher apoptosis rate. The neutrophil abnormalities observed in vivo were also reproduced in vitro, using cells isolated from healthy dogs and incubated with MG. We obtained strong evidence that in dogs with CKD, increased MG levels contributed to oxidative stress and potentially compromised the non-specific immune response by altering the oxidative metabolism and viability of canine neutrophils.

  5. Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure.

    PubMed

    Wang, Jie; Du, Hongying; Jiang, Lihong; Ma, Xiaoxian; de Graaf, Robin A; Behar, Kevin L; Mason, Graeme F

    2013-08-27

    It has been reported that chronic and acute alcohol exposure decreases cerebral glucose metabolism and increases acetate oxidation. However, it remains unknown how much ethanol the living brain can oxidize directly and whether such a process would be affected by alcohol exposure. The questions have implications for reward, oxidative damage, and long-term adaptation to drinking. One group of adult male Sprague-Dawley rats was treated with ethanol vapor and the other given room air. After 3 wk the rats received i.v. [2-(13)C]ethanol and [1, 2-(13)C2]acetate for 2 h, and then the brain was fixed, removed, and divided into neocortex and subcortical tissues for measurement of (13)C isotopic labeling of glutamate and glutamine by magnetic resonance spectroscopy. Ethanol oxidation was seen to occur both in the cortex and the subcortex. In ethanol-naïve rats, cortical oxidation of ethanol occurred at rates of 0.017 ± 0.002 µmol/min/g in astroglia and 0.014 ± 0.003 µmol/min/g in neurons, and chronic alcohol exposure increased the astroglial ethanol oxidation to 0.028 ± 0.002 µmol/min/g (P = 0.001) with an insignificant effect on neuronal ethanol oxidation. Compared with published rates of overall oxidative metabolism in astroglia and neurons, ethanol provided 12.3 ± 1.4% of cortical astroglial oxidation in ethanol-naïve rats and 20.2 ± 1.5% in ethanol-treated rats. For cortical astroglia and neurons combined, the ethanol oxidation for naïve and treated rats was 3.2 ± 0.3% and 3.8 ± 0.2% of total oxidation, respectively. (13)C labeling from subcortical oxidation of ethanol was similar to that seen in cortex but was not affected by chronic ethanol exposure.

  6. Mesenchymal Stem Cells Improve Heart Rate Variability and Baroreflex Sensitivity in Rats with Chronic Heart Failure

    PubMed Central

    de Morais, Sharon Del Bem Velloso; da Silva, Luiz Eduardo Virgilio; Lataro, Renata Maria; Silva, Carlos Alberto Aguiar; de Oliveira, Luciano Fonseca Lemos; de Carvalho, Eduardo Elias Vieira; Simões, Marcus Vinicius; da Silva Meirelles, Lindolfo; Fazan, Rubens

    2015-01-01

    Heart failure induced by myocardial infarct (MI) attenuates the heart rate variability (HRV) and baroreflex sensitivity, which are important risk factors for life-threatening cardiovascular events. Therapies with mesenchymal stem cells (MSCs) have shown promising results after MI. However, the effects of MSCs on hemodynamic (heart rate and arterial pressure) variability and baroreflex sensitivity in chronic heart failure (CHF) following MI have not been evaluated thus far. Male Wistar rats received MSCs or saline solution intravenously 1 week after ligation of the left coronary artery. Control (noninfarcted) rats were also evaluated. MI size was assessed using single-photon emission computed tomography (SPECT). The left ventricular ejection fraction (LVEF) was evaluated using radionuclide ventriculography. Four weeks after MSC injection, the animals were anesthetized and instrumented for chronic ECG recording and catheters were implanted in the femoral artery to record arterial pressure. Arterial pressure and HRVs were determined in time and frequency domain (spectral analysis) while HRV was also examined using nonlinear methods: DFA (detrended fluctuation analysis) and sample entropy. The initial MI size was the same among all infarcted rats but was reduced by MSCs. CHF rats exhibited increased myocardial interstitial collagen and sample entropy combined with the attenuation of the following cardiocirculatory parameters: DFA indices, LVEF, baroreflex sensitivity, and HRV. Nevertheless, MSCs hampered all these alterations, except the LVEF reduction. Therefore, 4 weeks after MSC therapy was applied to CHF rats, MI size and myocardial interstitial fibrosis decreased, while baroreflex sensitivity and HRV improved. PMID:26059001

  7. Urinary folate excretion in chronic ethanol- and diet-treated rats

    SciTech Connect

    Collins, T.D.; McMartin, K.E.; Bairnsfather, L.

    1986-03-05

    Acute ethanol treatment of rats produces a marked increase in urinary folate excretion, which accumulates in correlation with the duration of ethanol treatment. In order to study the role of excess urinary folate excretion in the development of folate deficiency by chronic ethanol feeding, groups of male Sprague-Dawley rats were maintained for four months on one of the following liquid diets: ethanol, pair-fed control, ethanol minus folic acid, and pair-fed control minus folic acid. A fifth group was provided a control chow diet ad libitum. Blood ethanol levels were generally maintained between 80-150 mg/dl at various times of the day. Decrease in plasma and tissue folate levels occurred within four weeks in all liquid diet groups compared to chow rats and within two weeks for urinary folate levels. Greater effects were generally observed in both folate-deficient groups than in the control or ethanol group. Acute ethanol treatment of rats from the various diet groups produced increases in urinary folate excretion in all groups except the ethanol minus folic acid diet group. When the folate system of rats are compromised by dietary deprivation and/or chronic ethanol treatment, these results suggest that urinary folate excretion is greatly reduced as a conservation measure.

  8. Efficacy of Rho kinase inhibitor on cognitive impairment induced by chronic cerebral hypoperfusion in rats

    PubMed Central

    Zhang, Qiang; Zhang, Jun-Jian; Han, Zhong-Mou

    2015-01-01

    This work aims to explore the efficacy of Rho kinase inhibitor Fasudil on cognitive impairment induced by chronic cerebral hypoperfusion in rats. A total of 32 male adult Sprague Dawley (SD) rats were randomly divided into three groups: treatment group, control group and sham-operated group for severe carotid artery stenosis model. After two weeks, 8.35 mg/kg Fasudil and physiological saline were intraperitoneally applied twice per day in treatment group and control group, respectively. Morris water maze test was performed in each group to detect the changes of cognitive function and observe the hippocampal pathomorphology in rats after eight weeks. The average escape latency distinctly shortened (P < 0.01) and the percentage of swimming distance in the platform quadrant significantly increased (P < 0.01) in treatment group compared with those at corresponding time points in control group. The rate of carotid artery stenosis in rats had no statistical difference between treatment and control groups (P > 0.05). Fasudil effectively improved hippocampal pathomorphology. Rho kinase inhibitor obviously ameliorated cognitive impairment induced by chronic cerebral hypoperfusion in rats. PMID:25932185

  9. Chronic infusions of GABA into the medial prefrontal cortex induce spatial alternation deficits in aged rats.

    PubMed

    Meneses, S; Galicia, O; Brailowsky, S

    1993-10-21

    It has been proposed that functions associated with the prefrontal cortex could change as a consequence of aging. Previous experiments in young rats have demonstrated that anatomical lesions or chronic GABA infusions into this area produce deficits in spatial delayed alternation tasks. The present study examines the effect of chronic (7 days) GABA or saline infusion into the prefrontal cortex on the performance of delayed alternation task in old rats (24 months). The results suggested that aged rats needed more sessions to acquire the delayed alternation task. GABA infusions into the prefrontal cortex produced deficits in spatial alternation tasks similar to those previously observed in young rats. Performance rapidly recovered after the infusion period. Histological analysis showed similar lesion size in both groups. The results suggest that aged prefrontal cortex and/or related areas participating in the acquisition of the delayed alternation task are more sensitive to aging processes. Furthermore, the prefrontal cortex is important for the retention of a previously learned spatial delayed alternation task. The structures involved in functional recovery from these deficits appear to be fully functional in aged rats.

  10. Critical appraisal of eculizumab for atypical hemolytic uremic syndrome.

    PubMed

    Palma, Lilian M Pereira; Langman, Craig B

    2016-01-01

    The biology of atypical hemolytic uremic syndrome has been shown to involve inability to limit activation of the alternative complement pathway, with subsequent damage to systemic endothelial beds and the vasculature, resulting in the prototypic findings of a thrombotic microangiopathy. Central to this process is the formation of the terminal membrane attack complex C5b-9. Recently, application of a monoclonal antibody that specifically binds to C5, eculizumab, became available to treat patients with atypical hemolytic uremic syndrome, replacing plasma exchange or infusion as primary therapy. This review focuses on the evidence, based on published clinical trials, case series, and case reports, on the efficacy and safety of this approach.

  11. Impact on behavioral changes due to chronic use of sertraline in Wistar albino rats

    PubMed Central

    Mukherjee, Shatavisa; Sen, Sukanta; Biswas, Arunava; Barman, Tapan Kumar; Tripathi, Santanu Kumar

    2015-01-01

    Aim: Despite having better tolerability and a wide range of clinical applications over other antidepressants, selective serotonin reuptake inhibitors (SSRIs) are also known to be associated with serious adverse effects like suicidal ideation on chronic use. The present study had explored the impact of the chronic use of sertraline, an SSRI, on the behavioral changes in Wistar albino rats. Materials and Methods: The study was conducted on 30 Wistar albino rats of either sex; divided into five groups. Four groups were subjected to chronic mild stress induced by using various stressors randomly scheduled in a week and continued for a period of 3 weeks. The stressed rodents were subjected to sertraline treatment for 9 weeks in different human therapeutic doses extrapolated to animal doses. Behavioral changes were monitored, assessed, and evaluated throughout the treatment phase with the help of tests such as locomotor activity test, forced swim test, tail suspension test, antianxiety test, and sucrose preference test (SPT). Results: All tests except SPT, demonstrated significant (P < 0.05) reduction in depressive-like activity in the stressed rodents by the mid-treatment phase, followed by an abrupt onset of the depressive state by the end of the treatment phase. SPT showed a significant (P < 0.05) increase in sucrose consumption throughout the treatment phase. Conclusion: Behavioral changes following chronic sertraline administration conferred gradual remission of depression state on initial treatment phase, followed by a reversal of effect on chronic use. PMID:26729959

  12. Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat.

    PubMed

    Alvarez, Pedro; Green, Paul G; Levine, Jon D

    2014-06-01

    While raised levels of monocyte chemoattractant protein 1 (MCP-1) have been observed in patients with chronic muscle pain, direct evidence for its role as an algogen in skeletal muscle is still lacking. In the rat, MCP-1 induces a dose-dependent mechanical hyperalgesia lasting for up to 6weeks. Following recovery, rats exhibited a markedly prolonged hyperalgesia to an intramuscular injection of prostaglandin E2, hyperalgesic priming. Intrathecal pretreatment with isolectin B4 (IB4)-saporin, which selectively destroys IB4-positive (IB4+) nociceptors, markedly decreased MCP-1-induced hyperalgesia and prevented the subsequent development of priming. To evaluate the involvement of MCP-1 in stress-induced chronic pain we administered, intrathecally, antisense (AS) or mismatch oligodeoxynucleotides directed against CCR2 (the canonical receptor for MCP-1) mRNA, during the exposure to water-avoidance stress, a model of stress-induced persistent muscle pain. The AS treatment attenuated this hyperalgesia, whereas IB4-saporin abolished water-avoidance stress-induced muscle hyperalgesia and prevented stress-induced hyperalgesic priming. These results indicate that MCP-1 induces persistent muscle hyperalgesia and a state of latent chronic sensitization to other algogens, by action on its cognate receptor on IB4+ nociceptors. Because MCP-1 also contributes to stress-induced widespread chronic muscle pain, it should be considered as a player in chronic musculoskeletal pain syndromes.

  13. Neurotoxic Doses of Chronic Methamphetamine Trigger Retrotransposition of the Identifier Element in Rat Dorsal Dentate Gyrus

    PubMed Central

    Moszczynska, Anna; Burghardt, Kyle J.; Yu, Dongyue

    2017-01-01

    Short interspersed elements (SINEs) are typically silenced by DNA hypermethylation in somatic cells, but can retrotranspose in proliferating cells during adult neurogenesis. Hypomethylation caused by disease pathology or genotoxic stress leads to genomic instability of SINEs. The goal of the present investigation was to determine whether neurotoxic doses of binge or chronic methamphetamine (METH) trigger retrotransposition of the identifier (ID) element, a member of the rat SINE family, in the dentate gyrus genomic DNA. Adult male Sprague-Dawley rats were treated with saline or high doses of binge or chronic METH and sacrificed at three different time points thereafter. DNA methylation analysis, immunohistochemistry and next-generation sequencing (NGS) were performed on the dorsal dentate gyrus samples. Binge METH triggered hypomethylation, while chronic METH triggered hypermethylation of the CpG-2 site. Both METH regimens were associated with increased intensities in poly(A)-binding protein 1 (PABP1, a SINE regulatory protein)-like immunohistochemical staining in the dentate gyrus. The amplification of several ID element sequences was significantly higher in the chronic METH group than in the control group a week after METH, and they mapped to genes coding for proteins regulating cell growth and proliferation, transcription, protein function as well as for a variety of transporters. The results suggest that chronic METH induces ID element retrotransposition in the dorsal dentate gyrus and may affect hippocampal neurogenesis. PMID:28272323

  14. Neuroinflammation and Behavior in HIV-1 Transgenic Rats Exposed to Chronic Adolescent Stress.

    PubMed

    Rowson, Sydney A; Harrell, Constance S; Bekhbat, Mandakh; Gangavelli, Apoorva; Wu, Matthew J; Kelly, Sean D; Reddy, Renuka; Neigh, Gretchen N

    2016-01-01

    Highly active antiretroviral therapy (HAART) has improved prognosis for people living with HIV (PLWH) and dramatically reduced the incidence of AIDS. However, even when viral load is controlled, PLWH develop psychiatric and neurological disorders more frequently than those living without HIV. Adolescents with HIV are particularly susceptible to the development of psychiatric illnesses and neurocognitive impairments. While both psychiatric and neurocognitive disorders have been found to be exacerbated by stress, the extent to which chronic stress and HIV-1 viral proteins interact to impact behavior and relevant neuroinflammatory processes is unknown. Determination of the individual contributions of stress and HIV to neuropsychiatric disorders is heavily confounded in humans. In order to isolate the influence of HIV-1 proteins and chronic stress on behavior and neuroinflammation, we employed the HIV-1 transgenic (Tg) rat model, which expresses HIV-1 proteins with a gag and pol deletion, allowing for viral protein expression without viral replication. This Tg line has been characterized as a model of HAART-controlled HIV-1 infection due to the lack of viral replication but continued presence of HIV-1 proteins. We exposed male and female adolescent HIV-1 Tg rats to a mixed-modality chronic stress paradigm consisting of isolation, social defeat and restraint, and assessed behavior, cerebral vascularization, and neuroinflammatory endpoints. Stress, sex, and presence of the HIV-1 transgene impacted weight gain in adolescent rats. Female HIV-1 Tg rats showed decreases in central tendency during the light cycle in the open field regardless of stress exposure. Both male and female HIV-1 Tg rats exhibited decreased investigative behavior in the novel object recognition task, but no memory impairments. Adolescent stress had no effect on the tested behaviors. Microglia in female HIV-1 Tg rats exhibited a hyper-ramified structure, and gene expression of complement factor B was

  15. The effect of chronic ethanol on glutamate binding in human and rat brain

    SciTech Connect

    Cummins, J.T.; Sack, M.; von Hungen, K. Univ. of California School of Medicine, Los Angeles )

    1990-01-01

    Quantitative autoradiographic techniques demonstrate that chronic alcohol administration causes a decrease in ({sup 3}H)-glutamate binding to hippocampal N-methyl-D-aspartate (NMDA) receptors. A 14% decrease in ({sup 3}H)-glutamate binding in the hippocampal CA{sub 1} region is seen both in the rat after five days of ethanol administration and in postmortem hippocampal tissues from alcoholics. In the rat, 24 hr ethanol withdrawal values are intermediate between control and alcohol binding levels. There was no significant effect of ethanol on ({sup 3}H)-glutamate binding in the cortex or caudate.

  16. Neuroinflammation and Behavior in HIV-1 Transgenic Rats Exposed to Chronic Adolescent Stress

    PubMed Central

    Rowson, Sydney A.; Harrell, Constance S.; Bekhbat, Mandakh; Gangavelli, Apoorva; Wu, Matthew J.; Kelly, Sean D.; Reddy, Renuka; Neigh, Gretchen N.

    2016-01-01

    Highly active antiretroviral therapy (HAART) has improved prognosis for people living with HIV (PLWH) and dramatically reduced the incidence of AIDS. However, even when viral load is controlled, PLWH develop psychiatric and neurological disorders more frequently than those living without HIV. Adolescents with HIV are particularly susceptible to the development of psychiatric illnesses and neurocognitive impairments. While both psychiatric and neurocognitive disorders have been found to be exacerbated by stress, the extent to which chronic stress and HIV-1 viral proteins interact to impact behavior and relevant neuroinflammatory processes is unknown. Determination of the individual contributions of stress and HIV to neuropsychiatric disorders is heavily confounded in humans. In order to isolate the influence of HIV-1 proteins and chronic stress on behavior and neuroinflammation, we employed the HIV-1 transgenic (Tg) rat model, which expresses HIV-1 proteins with a gag and pol deletion, allowing for viral protein expression without viral replication. This Tg line has been characterized as a model of HAART-controlled HIV-1 infection due to the lack of viral replication but continued presence of HIV-1 proteins. We exposed male and female adolescent HIV-1 Tg rats to a mixed-modality chronic stress paradigm consisting of isolation, social defeat and restraint, and assessed behavior, cerebral vascularization, and neuroinflammatory endpoints. Stress, sex, and presence of the HIV-1 transgene impacted weight gain in adolescent rats. Female HIV-1 Tg rats showed decreases in central tendency during the light cycle in the open field regardless of stress exposure. Both male and female HIV-1 Tg rats exhibited decreased investigative behavior in the novel object recognition task, but no memory impairments. Adolescent stress had no effect on the tested behaviors. Microglia in female HIV-1 Tg rats exhibited a hyper-ramified structure, and gene expression of complement factor B was

  17. Influence of chronic intermittent hypoxia on growth associated protein 43 expression in the hippocampus of young rats.

    PubMed

    Chen, Yan; Zhao, Chunling; Zhang, Chunlai; Luo, Lirong; Yu, Guang

    2012-06-05

    This study aimed to explore the pathological change to hippocampal neurons and the expression of growth associated protein 43 in 21-day-old young rats following chronic intermittent hypoxia. Hematoxylin-eosin staining results showed varying degrees of degeneration and necrosis in hippocampal neurons depending on the modeling time. Immunohistochemistry revealed that growth associated protein 43 expression in young rats following chronic intermittent hypoxia decreased, but that levels were still higher than those of normal rats at each time point, especially 4 weeks after modeling. During 1-5 weeks after modeling, a slow growth in rat weight was observed. Experimental findings indicate that chronic intermittent hypoxia may induce growth dysfunction and necrosis of hippocampal neurons, as well as increase the expression of growth associated protein 43 in young rats.

  18. Chronic administration of anabolic steroids disrupts pubertal onset and estrous cyclicity in rats.

    PubMed

    Clark, Ann S; Kelton, Megan C; Whitney, Andrew C

    2003-02-01

    Use of anabolic-androgenic steroids (AASs) is becoming increasingly popular among adolescent girls, yet the effects of AASs on female physiology and development are not well understood. The present study compared the effects of chronic exposure to three individual AASs, stanozolol (0.05-5 mg/kg), 17alpha-methyltestosterone (0.5-5 mg/kg), and methandrostenolone (0.5-5 mg/kg) on the onset of puberty and estrous cyclicity in the rat. Female rats received daily injections of AASs for 30 days (Postnatal Day [PN] 21-51). Rats receiving the highest dose of each of the AASs (5 mg/kg) displayed vaginal opening at a younger age than rats receiving the oil vehicle. The day of first vaginal estrus was delayed in rats receiving stanozolol (5 mg/kg) or 17alpha-methyltestosterone (0.5-5 mg/kg) but not in rats receiving methandrostenolone. At the highest dose (5 mg/kg), each of the AASs reduced the incidence of regular estrous cyclicity during the treatment period. Concurrent administration (on PN21-51) of the androgen receptor antagonist, flutamide (10 mg/kg, twice daily), reversed the effects of 17alpha-methyltestosterone (5 mg/kg) on vaginal opening. Flutamide administration also eliminated the effects of stanozolol (5 mg/kg) and 17alpha-methyltestosterone (5 mg/kg) on the day of first vaginal estrus. In contrast, rats receiving flutamide and methandrostenolone (5 mg/kg) exhibited first vaginal estrus earlier than controls. The present results indicate that chronic exposure to AASs during development has deleterious effects on the female neuroendocrine axis and that these effects appear be mediated via multiple mechanisms.

  19. Acute and chronic effects of honey and its carbohydrate constituents on calcium absorption in rats.

    PubMed

    Ariefdjohan, Merlin W; Martin, Berdine R; Lachcik, Pamela J; Weaver, Connie M

    2008-04-23

    The effects of honey and its carbohydrate constituents (glucose, fructose, and raffinose) on calcium absorption in rats were investigated in acute and chronic feeding studies. In the acute study, rats ( n = 120) were gavaged with an oral solution consisting of (a) 10 microCi (45)Ca, (b) 25 mg of calcium as calcium acetate, and (c) one of the following: 0 mg of honey (control), or 200, 500, or 800 mg of honey, a glucose-fructose mixture, 10.75 mg of raffinose, or 200 mg of raffinose. Another group received (45)Ca intraperitoneally. Femurs were collected 2 days later and analyzed for (45)Ca content. Rats given 500 and 800 mg of honey showed 25.5 and 33.6% increases in calcium absorption ( P<0.05), respectively, over the control group. Groups given the glucose-fructose mixture or 200 mg of raffinose had a significantly higher increase in calcium absorption than the control group (17.1 and 25.6%, respectively). In the chronic study, rats (n=96) were fed for 8 weeks with either 0% honey (control), 5% honey, 10% honey, or a glucose-fructose-raffinose (GFR) mixture. Femurs of GFR-fed rats had significantly lower calcium content, (45)Ca absorption, width, and BMD (at distal region) than control rats. Groups fed honey did not show the negative effects of GFR on bone, but had no advantage over the control group. No significant differences were observed in femur length, density, strength, or BMC among any treatment group compared to the control group. These results indicate that although a positive dose-response effect of honey and its carbohydrate constituents on calcium absorption was observed in the acute study, this effect disappeared upon long-term feeding in rats, implying adaptation had occurred.

  20. Analgesic action of suspended moxibustion in rats with chronic visceral hyperalgesia correlates with enkephalins in the spinal cord☆

    PubMed Central

    Yi, Tao; Qi, Li; Wu, Huangan; Ma, Xiaopeng; Liu, Huirong; Wang, Xiaomei

    2012-01-01

    Rats that modeled chronic visceral hyperalgesia received suspended moxibustion at bilateral Tianshu (ST25) and Shangjuxu (ST37) once daily over a period of 7 days. Results show that suspended moxibustion significantly depressed abdominal withdrawal reflex scores and increased enkephalin concentration in the spinal cord. The experimental findings suggest that spinal enkephalins contributed to the analgesic effect of suspended moxibustion in rats with chronic visceral hyperalgesia. PMID:25767503

  1. Long-term course and mechanisms of progression of renal disease in hemolytic uremic syndrome.

    PubMed

    Repetto, Horatio A

    2005-08-01

    In the classic form of hemolytic uremic syndrome associated with toxins of gram-negative enterobacteria, mortality in the acute stage has been lower than 5% since 1978 (data from the Nephrology Committee, Argentine Society of Pediatrics). Children usually die because of severe involvement of the central nervous system, intestine, or myocardium and its complications, or because of intercurrent infection. Treatment in this phase is supportive, and efforts should be put into prevention of infection by Shiga-like toxin-producing enterohemorrhagic Escherichia coli. Of the 95% who survive, approximately one third is at risk for having chronic sequelae. Motor, sensory, or intellectual deficits, intestinal strictures, myocardial infarctions, or diabetes are infrequent. The more-frequent chronic renal lesion is characterized by the hyperfunction of nephrons remaining after the acute necrotizing lesion, which leads to progressive scarring, and not by persistence or recurrence of the microangiopathic process. Three courses of progression to end-stage renal failure have been described. Children with most severe forms do not recover from acute renal failure and enter directly into a dialysis and transplantation program. A second group recovers renal function partially, with persistent proteinuria and frequently hypertension; progression to end-stage renal failure occurs in 2 to 5 years. The third group may recover normal serum creatinine and creatinine clearance, with persistent proteinuria. They are at risk of progressing to chronic renal failure and end-stage renal disease after more than 5 years, and sometimes as late as 20 years, after the acute disease. Treatment should aim at preventing the mechanisms associated with progressive renal scarring. Transplantation is indicated in this form of hemolytic uremic syndrome, because there is little, if any, risk of recurrence, and the prognosis is similar to that of transplantation for other diseases.

  2. Baicalin influences the dendritic morphology of newborn neurons in the hippocampus of chronically stressed rats.

    PubMed

    Jiang, Xinghua; Xu, Junmei; Zou, Dingquan; Yang, Lin; Wang, Yaping

    2013-02-25

    Chronic stress models, established in adult Sprague-Dawley rats through a 14-day subcutaneous injection of 40 mg/kg corticosterone, once per day, were given a daily oral feeding of 50 mg/kg baicalin. The study was an attempt to observe the effect of baicalin on neurogenesis in chronically stressed rats. Results showed that subcutaneous injection of corticosterone significantly decreased the total number of doublecortin-positive neurons in the hippocampus. The reduced cell number caused by corticosterone was mainly due to the decrease of class II doublecortin-positive neurons, but the class I doublecortin-positive neurons were unaffected. Baicalin treatment increased the number of both class I and class II doublecortin-positive neurons. In addition, doublecortin-positive neurons showed less complexity in dendritic morphology after corticosterone injection, and this change was totally reversed by baicalin treatment. These findings suggest that baicalin exhibits a beneficial effect on adult neurogenesis.

  3. Intestinal transport of hexoses in the rat following chronic heat exposure

    NASA Technical Reports Server (NTRS)

    Carpenter, M.; Musacchia, X. J.

    1979-01-01

    The study examines intestinal transport of sugars (D-glucose and D-galactose) in vitro and assesses organ maintenance in chronically heat-exposed rats. The results suggest that the response of intestinal absorption to heat exposure in the rat involves changes in intestinal weight and in glucose utilization. Despite the reduction in total intestinal weight, the ability of intestinal tissue to transport hexose per unit weight remains stable. Differences in intestinal weight and glucose utilization between pair-fed and heat-exposed animals suggest that the intestinal response to chronic heat exposure is not solely a function of the amount of food consumed. Alterations of hexose transport appear to be related to altered glucose metabolism and not altered transport capacity.

  4. Neuroplasticity-dependent and -independent mechanisms of chronic deep brain stimulation in stressed rats

    PubMed Central

    Bambico, F R; Bregman, T; Diwan, M; Li, J; Darvish-Ghane, S; Li, Z; Laver, B; Amorim, B O; Covolan, L; Nobrega, J N; Hamani, C

    2015-01-01

    Chronic ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) improves depressive-like behaviour in rats via serotonergic and neurotrophic-related mechanisms. We hypothesise that, in addition to these substrates, DBS-induced increases in hippocampal neurogenesis may also be involved. Our results show that stress-induced behavioural deficits in the sucrose preference test, forced swim test, novelty-suppressed feeding test (NSFT) and elevated plus maze were countered by chronic vmPFC DBS. In addition, stressed rats receiving stimulation had significant increases in hippocampal neurogenesis, PFC and hippocampal brain-derived neurotrophic factor levels. To block neurogenesis, stressed animals given DBS were injected with temozolomide. Such treatment reversed the anxiolytic-like effect of stimulation in the NSFT without significantly affecting performance in other behavioural tests. Taken together, our findings suggest that neuroplastic changes, including neurogenesis, may be involved in specific anxiolytic effects of DBS without affecting its general antidepressant-like response. PMID:26529427

  5. EXPERIMENTAL INDUCTION OF CHRONIC PULMONARY DISEASE IN GENETICALLY SUSCEPTIBLE RAT MODEL

    EPA Science Inventory



    Experimental induction of chronic pulmonary disease in genetically susceptible rat model. M.C.Schladweiler, BS 1, A.D.Ledbetter 1, K.E.Pinkerton, PhD 2, K.R.Smith, PhD 2, P.S.Gilmour, PhD 1, P.A.Evansky 1, D.L.Costa, ScD 1, W.P.Watkinson, PhD 1, J.P.Nolan 1 and U.P.Kodava...

  6. Effects of chronic and acute stress on rat behaviour in the forced-swim test.

    PubMed

    Suvrathan, Aparna; Tomar, Anupratap; Chattarji, Sumantra

    2010-11-01

    Stress and depression may share common neural plasticity mechanisms. Importantly, the development and reversal of stress-induced plasticity requires time. These temporal aspects, however, are not captured fully in the forced-swim test (FST), a behavioural model for testing antidepressant efficacy, used originally in naïve animals. The present study probed whether and how a rodent model of stress affects behaviour in the FST over time. We found that the intensity and duration of stress are critical in the development of depressive symptoms in male Wistar rats (n = 37) as tested in the FST. Chronic immobilization stress (2 h/day for 10 days) elicited a range of responses, from low to high values of immobility in the FST on day 1, and subsequent immobility on day 2 was inversely related to individual day 1 values. As a whole, chronically stressed rats did not exhibit any significant change in immobility either on day 1 or day 2 compared to control rats. However, climbing behaviour was reduced uniformly from day 1 to day 2, despite the differences in immobility. In contrast, a separate group of rats (n = 30) subjected to the same chronic stressor displayed a significant reduction in open-arm exploration in the elevated plus maze, indicative of a robust increase in anxiety-like behaviour. Furthermore, when the 10-day chronic stress paradigm was reduced to a single 2-h episode of immobilization stress, it triggered a uniform day 1 to day 2 increase in immobility, which was not persistent 10 days later. These results highlight a need for closer examination of the ways in which stress-induced modulation of behaviour in the FST may be used and interpreted in future studies aimed at exploring connections between stress and depression.

  7. Effects of chronic administration of caffeine and stress on feeding behavior of rats.

    PubMed

    Pettenuzzo, Leticia Ferreira; Noschang, Cristie; von Pozzer Toigo, Eduardo; Fachin, Andrelisa; Vendite, Deusa; Dalmaz, Carla

    2008-10-20

    Anorectic effects of caffeine are controversial in the literature, while stress and obesity are growing problems in our society. Since many stressed people are coffee drinkers, the objective of the present study was to evaluate the effect of stress and chronic administration of caffeine on feeding behavior and body weight in male and female rats. Wistar rats (both males and females) were divided into 3 groups: control (receiving water), caffeine 0.3 g/L and caffeine 1.0 g/L (in the drinking water). These groups were subdivided into non-stressed and stressed (repeated-restraint stress for 40 days). During the entire treatment, chow consumption was monitored and rats were weighed monthly. Afterwards, feeding behavior was evaluated during 3-min trials in food-deprived and ad libitum fed animals and also in repeated exposures, using palatable food (Froot Loops and Cheetos). Chronic administration of caffeine did not affect rat chow consumption or body weight gain, but diminished the consumption of both salty (Cheetos) and sweet (Froot Loops) palatable food. In the repeated trial tests, stress diminished savory snack consumption in the later exposures [I.S. Racotta, J. Leblanc, D. Richard The effect of caffeine on food intake in rats: involvement of corticotropin-releasing factor and the sympatho-adrenal system. Pharmacol Biochem Behav. 1994, 48:887-892; S.D. Comer, M. Haney, R.W. Foltin, M.W. Fischman Effects of caffeine withdrawal on humans living in a residential laboratory. Exp Clin Psychopharmacol. 1997, 5:399-403; A. Jessen, B. Buemann, S. Toubro, I.M. Skovgaard, A. Astrup The appetite-suppressant effect of nicotine is enhanced by caffeine. Diab Ob Metab. 2005, 7:327-333; J.M. Carney Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats. Br J Pharmacol. 1982, 75:451-454] and caffeine diminished consumption of both palatable foods (savory and sweet) during the early and later exposures. Most responses to caffeine were stronger

  8. Psychomotor Vigilance Task Performance During and Following Chronic Sleep Restriction in Rats

    PubMed Central

    Deurveilher, Samuel; Bush, Jacquelyn E.; Rusak, Benjamin; Eskes, Gail A.; Semba, Kazue

    2015-01-01

    Study Objectives: Chronic sleep restriction (CSR) impairs sustained attention in humans, as commonly assessed with the psychomotor vigilance task (PVT). To further investigate the mechanisms underlying performance deficits during CSR, we examined the effect of CSR on performance on a rat version of PVT (rPVT). Design: Adult male rats were trained on a rPVT that required them to press a bar when they detected irregularly presented, brief light stimuli, and were then tested during CSR. CSR consisted of 100 or 148 h of continuous cycles of 3-h sleep deprivation (using slowly rotating wheels) alternating with a 1-h sleep opportunity (3/1 protocol). Measurements and Results: After 28 h of CSR, the latency of correct responses and the percentages of lapses and omissions increased, whereas the percentage of correct responses decreased. Over 52–148 h of CSR, all performance measures showed partial or nearly complete recovery, and were at baseline levels on the first or second day after CSR. There were large interindividual differences in the magnitude of performance impairment during CSR, suggesting differential vulnerability to the effects of sleep loss. Wheel-running controls showed no changes in performance. Conclusions: A 28-h period of the 3/1 chronic sleep restriction (CSR) protocol disrupted performance on a sustained attention task in rats, as sleep deprivation does in humans. Performance improved after longer periods of CSR, suggesting allostatic adaptation, contrary to some reports of progressive deterioration in psychomotor vigilance task performance during CSR in humans. However, as observed in humans, there were individual differences among rats in the vulnerability of their attention performance to CSR. Citation: Deurveilher S, Bush JE, Rusak B, Eskes GA, Semba K. Psychomotor vigilance task performance during and following chronic sleep restriction in rats. SLEEP 2015;38(4):515–528. PMID:25515100

  9. Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle.

    PubMed

    Camerino, Giulia Maria; Pellegrino, Maria Antonietta; Brocca, Lorenza; Digennaro, Claudio; Camerino, Diana Conte; Pierno, Sabata; Bottinelli, Roberto

    2011-04-15

    Statins and fibrates can cause myopathy. To further understand the causes of the damage we performed a proteome analysis in fast-twitch skeletal muscle of rats chronically treated with different hypolipidemic drugs. The proteomic maps were obtained from extensor digitorum longus (EDL) muscles of rats treated for 2-months with 10mg/kg atorvastatin, 20 mg/kg fluvastatin, 60 mg/kg fenofibrate and control rats. The proteins differentially expressed were identified by mass spectrometry and further analyzed by immunoblot analysis. We found a significant modification in 40 out of 417 total spots analyzed in atorvastatin treated rats, 15 out of 436 total spots in fluvastatin treated rats and 21 out of 439 total spots in fenofibrate treated rats in comparison to controls. All treatments induced a general tendency to a down-regulation of protein expression; in particular, atorvastatin affected the protein pattern more extensively with respect to the other treatments. Energy production systems, both oxidative and glycolytic enzymes and creatine kinase, were down-regulated following atorvastatin administration, whereas fenofibrate determined mostly alterations in glycolytic enzymes and creatine kinase, oxidative enzymes being relatively spared. Additionally, all treatments resulted in some modifications of proteins involved in cellular defenses against oxidative stress, such as heat shock proteins, and of myofibrillar proteins. These results were confirmed by immunoblot analysis. In conclusions, the proteomic analysis showed that either statin or fibrate administration can modify the expression of proteins essential for skeletal muscle function suggesting potential mechanisms for statin myopathy.

  10. Behavioral responses of high and low active male rats to the chronic ingestion of desipramine.

    PubMed

    Echandía, E L; Broitman, S T; Fóscolo, M R

    1985-06-01

    Male rats arbitrarily selected for high and low motor activity (HA and LA-rats) were submitted to the chronic ingestion (30 days) of desipramine (DSP) in doses of about 1.5, 3 and 6 mg/kg/24 hr. Their motor activity was assessed in an animal activity monitor providing a measure of total horizontal movements and vertical movements and in a hole-board providing a measure of locomotion, head-dipping and grooming. There were significant differences between HA and LA-rats in their behavioral response to DSP treatment. At the doses used DSP did not affect horizontal and vertical movements and hole-board locomotion or exploration in HA-rats (Experiment 1). In LA-rats, however (Experiment 2), these motor activities were significantly stimulated by DSP. Such effect was dose dependent; 1.5 mg/kg/24 hr was ineffective while 6 mg/kg/24 hr produced a clear cut reversion of hypoactivity. It is speculated that DSP treatment increased resistance of LA-rats to the mild stress caused by testing.

  11. Chronic caffeine intake increases androgenic stimuli, epithelial cell proliferation and hyperplasia in rat ventral prostate

    PubMed Central

    Sarobo, Carolina; Lacorte, Lívia M; Martins, Marcela; Rinaldi, Jaqueline C; Moroz, Andrei; Scarano, Wellerson R; Delella, Flavia K; Felisbino, Sérgio L

    2012-01-01

    Coffee intake has been associated with a low risk of developing cancer, including prostate cancer, which is one of the most commonly diagnosed cancer in men. However, few studies have evaluated the chronic effects of caffeine, which is the most abundant methylxanthine in coffee, on prostate morphology and physiology. In the present study, we investigated the effects of chronic, low-dose caffeine intake on rat prostate morphology from puberty to adulthood. Five-week-old male Wistar rats were randomized into two experimental groups: caffeine-treated (20 ppm in drinking water, n = 12) and control (n = 12). The ventral and dorsolateral prostates were dissected, weighted and submitted to morphological, morphometrical and immunohistochemical analysis of cellular proliferation, apoptosis and androgen receptor (AR) tissue expression. The testosterone (T) and dihydrotestosterone (DHT) concentrations were measured in the plasma. Our results show that caffeine intake increased the concentrations of T and DHT, organ weight, epithelial cell proliferation and AR tissue expression in the ventral prostatic lobe. All the ventral prostates from the caffeine-treated animals presented various degrees of epithelial and stromal hyperplasia. Our results suggest that chronic caffeine intake from puberty increases androgenic signalling and cell proliferation in the rat prostate gland and can be related to the development of benign prostatic hyperplasia. PMID:23136995

  12. Superoxide production after acute and chronic treatment with methylphenidate in young and adult rats.

    PubMed

    Gomes, Karin M; Inácio, Cecília G; Valvassori, Samira S; Réus, Gislaine Z; Boeck, Carina R; Dal-Pizzol, Felipe; Quevedo, João

    2009-11-06

    The prescription of methylphenidate (MPH) has dramatically increased in this decade for attention deficit hyperactivity disorder (ADHD) treatment. The action mechanism of MPH is not completely understood and studies have been demonstrated that MPH can lead to neurochemical adaptations. Superoxide radical anion is not very reactive per se. However, severe species derived from superoxide radical anion mediate most of its toxicity. In this study, the superoxide level in submitochondrial particles was evaluated in response to treatment with MPH in the age-dependent manner in rats. MPH was administrated acutely or chronically at doses of 1, 2 or 10 mg/kg i.p. The results showed that the acute administration of MPH in all doses in young rats increased the production of superoxide in the cerebellum and only in the high dose (10mg/kg) in the hippocampus, while chronic treatment had no effect. However, acute treatment in adult rats had no effect on production of superoxide, but chronic treatment decreased the production of superoxide in the cerebellum at the lower doses. Our data suggest that the MPH treatment can influence on production of superoxide in some brain areas, but this effect depends on age of animals and treatment regime with MPH.

  13. Genetics Home Reference: atypical hemolytic-uremic syndrome

    MedlinePlus

    ... abnormalities lead to kidney damage and, in many cases, kidney failure and ESRD. Although gene mutations increase the risk of atypical hemolytic-uremic syndrome , studies suggest that they are often not sufficient to cause the disease. In people with certain genetic changes, the signs ...

  14. Should dialysis modalities be designed to remove specific uremic toxins?

    PubMed

    Baurmeister, Ulrich; Vienken, Joerg; Ward, Richard A

    2009-01-01

    The definition of optimal dialysis therapy remains elusive. Randomized clinical trials have neither supported using urea as a surrogate marker for uremic toxicity nor provided clear cut evidence in favor of larger solutes. Thus, where to focus resources in the development of new membranes, and therapies remains unclear. Three basic questions remain unanswered: (i) what solute(s) should be used as a marker for optimal dialysis; (ii) should dialytic therapies be designed to remove a specific solute; and (iii) how can current therapies be modified to provide better control of uremic toxicity? Identification of a single, well-defined uremic toxin appears to be unlikely as new analytical tools reveal an increasingly complex uremic milieu. As a result, it is probable that membranes and therapies should be designed for the nonspecific removal of a wide variety of solutes retained in uremia. Removal of the widest range of solutes can best be achieved using existing therapies that incorporate convection in conjunction with longer treatment times and more frequent treatments. Membranes capable of removing solutes over an expanded effective molecular size range can already be fabricated; however, their use will require novel approaches to conserve proteins, such as albumin.

  15. [Uremic toxins: the case of protein-bound compounds].

    PubMed

    Basile, Carlo; Libutti, Pasquale; Teutonico, Annalisa; Lomonte, Carlo

    2010-01-01

    Uremic retention solutes, if biologically or biochemically active, are called ''uremic toxins''. The retention of these solutes has a negative impact on many functions of the organism, particularly the cardiovascular system. The classification which is applied today is based on the kinetic behavior of the uremic retention solutes during dialysis: 1) small water-soluble molecules (< 500 Daltons); 2) middle molecules (> 500 Daltons); 3) protein-bound compounds. The latter are the object of the present review. The most important among them are p-cresol, p-cresyl sulfate, homocysteine, phenols, and indoles. No interventional studies are currently available that show the effect of an improvement in the removal of protein-bound compounds on patient outcomes, simply because most of the alternative dialysis strategies proposed so far are not superior to standard dialysis in removing protein-bound compounds. The question as to how to improve the removal of these solutes therefore remains unanswered. Alternative strategies might include adsorption therapies, either administered orally or during the extracorporeal treatment. In conclusion, the uremic syndrome is a complex clinical entity which involves a large number of retention solutes, many more than the small water-soluble molecules. Dialysis strategies should therefore aim to remove not only urea but also retention solutes, mainly because middle and protein-bound molecules appear to be correlated more frequently with deleterious biological, biochemical and clinical effects.

  16. [Chronic administration of estradiol to ovariectomized female Wistar rats causes development of hypoxic pulmonary hypertension].

    PubMed

    Kovaleva, Iu O; Artem'eva, M M; Medvedev, O S; Medvedeva, N A

    2013-01-01

    We have studied the role of female sex hormone estradiol in the development of hypoxic pulmonary arterial hypertension. Previously, it was shown that the development of pulmonary hypertension in Wistar female rats is accompanied by a twofold increase in the estradiol level. Ovariectomy reduces the degree of pulmonary hypertension in these animals. In this work, the effect of various chronic doses of exogenous estradiol (5 and 15 microg/kg per day) on the development of hypoxic pulmonary hypertension in Wistar female rats has been studied. Pulmonary hypertension was induced by exposure to hypobaric hypoxia (10 h a day for 2 weeks) at simulated altitude of 5000 m (O2 concentration reduced to 10%). The administration of estradiol in different doses (5 and 15 microg/kg per day) for 21 day initiated the development of pulmonary hypertension in ovariectomized Wistar female rats.

  17. Chronic organic manganese administration in the rat does not damage dopaminergic nigrostriatal neurons.

    PubMed

    Yong, V W; Perry, T L; Godolphin, W J; Jones, K A; Clavier, R M; Ito, M; Foulks, J G

    1986-01-01

    In an attempt to produce an animal model of Parkinson's disease, we injected rats repeatedly with high doses of methylcyclopentadienyl manganese tricarbonyl (MMT), a compound which has been reported to lower striatal dopamine content in mice. Chronic MMT administration for up to 5 months, even though it produced a substantial elevation in brain manganese content during the period of exposure, did not destroy dopaminergic nigrostriatal neurons. This was assessed by measurements of tyrosine hydroxylase activity and contents of dopamine and its metabolites in the striatum, and by histological examination of the substantia nigra. Our results differ from those of others who administered manganese chloride in drinking water to rats. This discrepancy is unlikely to be a consequence of differences in duration of exposure or route of administration. It could be due to our having used an organic rather than an inorganic manganese compound, or to a species difference in vulnerability to organic manganese between rats and mice.

  18. Alterations of the oxidative status in rat hippocampus and prodepressant effect of chronic testosterone enanthate administration.

    PubMed

    Joksimović, Jovana; Selaković, Dragica; Jakovljević, Vladimir; Mihailović, Vladimir; Katanić, Jelena; Boroja, Tatjana; Rosić, Gvozden

    2017-03-24

    In a last few decades, anabolic-androgenic steroids (AASs) abuse has become serious health concern especially among adolescents. AASs abuse has been reported to be involved in pathogenesis of various mood disorders, including depression. In order to evaluate the effects of chronic (6 weeks) testosterone enanthate (TE) treatment in supraphysiological dose and exercise on depression-like behavior in rats, 32 male rats were divided into four groups: control (C), testosterone enanthate (T, 20 mg/kg/w, s.c.), exercise (E, swimming for 1 h/day), and combined group-testosterone enanthate plus exercise (T + E). TE produced prodepressant effect in tail suspension test (TST) parameters compared to the control and exercise groups, while exercise induced the opposite effect. Simultaneous TE administration along with exercise attenuated the antidepressant effect of exercise reversing the parameters of TST to the control values. Oxidative stress markers in rat hippocampus were significantly altered following applied protocols. TE administration increased index of lipid peroxidation (TBARS) and decreased superoxide dismutase activity (SOD), while exercise induced the opposite effect, with no change in glutathione (GSH) levels. Our results indicate that TE chronic treatment resulted in clear depressive-like behavior, even abolishing beneficial antidepressant effects of exercise in TST that was accompanied with increased oxidative damage in rat hippocampus. The antidepressant effect of exercise correlated with the improvement of redox status in hippocampal tissue. Behavioral parameters obtained in TST significantly correlated with the levels of oxidative stress markers.

  19. Potential antiinflammatory effects of acupuncture in a chronic stress model of depression in rats.

    PubMed

    Lu, Jun; Shao, Run-Hui; Hu, Li; Tu, Ya; Guo, Jian-You

    2016-04-08

    Accumulating evidence indicates that inflammation may contribute to the pathophysiology of depression. Acupuncture in traditional Chinese medicine has been considered an effective treatment for depression. However, whether the mechanisms that underlie the antidepressant effect of acupuncture are related to its antiinflammatory properties remains unclear. In the present study, rats were exposed to chronic unpredictable mild stress (CUMS) for 28 days to induce depressive-like behavior. Body weight, sucrose preference, and locomotor activity in the open field were measured. After the behavioral tests, reverse transcription polymerase chain reaction was used to determine the mRNA expression of proinflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6], and tumor necrosis factor-α [TNF-α]), and enzyme-linked immunosorbent assay was used to detect cytokine concentrations. CUMS rats exhibited decrease in body weight, sucrose preference, and locomotor activity in the open field test. Chronic acupuncture and fluoxetine treatment reversed CUMS-induced depressive-like behavior. Compared with control rats, the mRNA and protein expression of IL-1β, IL-6, and TNF-α in the hippocampus and prefrontal cortex and cytokine concentrations in serum significantly increased in CUMS rats. Acupuncture and fluoxetine treatment significantly decreased the levels of proinflammatory cytokines in the hippocampus, prefrontal cortex, and serum. These results suggest that acupuncture has antidepressant-like effects, and its mechanism of action appears to involve the inhibition of proinflammatory cytokines.

  20. Effects of intrathecal kynurenate on arterial pressure during chronic osmotic stress in conscious rats.

    PubMed

    Veitenheimer, Britta; Osborn, John W

    2013-01-15

    Increased plasma osmolality elevates mean arterial pressure (MAP) through activation of the sympathetic nervous system, but the neurotransmitters released in the spinal cord to regulate MAP during osmotic stress remain unresolved. Glutamatergic neurons of the rostral ventrolateral medulla project to sympathetic preganglionic neurons in the spinal cord and are likely activated during conditions of osmotic stress; however, this has not been examined in conscious rats. This study investigated whether increased MAP during chronic osmotic stress depends on activation of spinal glutamate receptors. Rats were chronically instrumented with an indwelling intrathecal (i.t.) catheter for antagonist delivery to the spinal cord and a radiotelemetry transmitter for continuous monitoring of MAP and heart rate. Osmotic stress induced by 48 h of water deprivation (WD) increased MAP by ~15 mmHg. Intrathecal kynurenic acid, a nonspecific antagonist of ionotropic glutamate receptors, decreased MAP significantly more after 48 h of WD compared with the water-replete state. Water-deprived rats also showed a greater fall in MAP in response to i.t. 2-amino-5-phosphonovalerate. Finally, i.t. kynurenic acid also decreased MAP more in an osmotically driven model of neurogenic hypertension, the DOCA-salt rat, compared with normotensive controls. Our results suggest that spinally released glutamate mediates increased MAP during 48-h WD and DOCA-salt hypertension.

  1. Acute and sub-chronic toxicity of aqueous extracts of Chenopodium ambrosioides leaves in rats.

    PubMed

    da Silva, Marcel Gianni C; Amorim, Raimundo Neilson L; Câmara, Carlos C; Fontenele Neto, José Domingues; Soto-Blanco, Benito

    2014-09-01

    The present study aimed to evaluate the toxicity of aqueous extract of Chenopodium ambrosioides leaves. To measure acute toxicity, rats were administered 0, 0.3, 1.0, or 3.0 g/kg of aqueous extract from C. ambrosioides leaves by gavage. To analyze sub-chronic toxicity, rats were treated by oral gavage for 15 consecutive days with 0, 0.3, or 1.0 g/kg of extract of C. ambrosioides leaves. No animals from either trial exhibited any signs of toxicity. In the acute study, the highest dose of the extract led to an increase in the serum activities of alanine transaminase (ALT) and aspartate transaminase (AST) and a decrease in the serum levels of urea. In the sub-chronic test, rats treated with 1.0 g/kg for 15 days exhibited increased serum ALT activity and creatinine levels and mild cytoplasmic vacuolation of hepatocytes. The results indicate that aqueous extract from C. ambrosioides leaves produce slight hepatotoxic lesions in rats.

  2. Decrease in Circulating Fatty Acids Is Associated with Islet Dysfunction in Chronically Sleep-Restricted Rats

    PubMed Central

    Zhan, Shanshan; Wu, Yangyang; Sun, Peng; Lin, Haiyan; Zhu, Yunxia; Han, Xiao

    2016-01-01

    Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, body weight was decreased and energy expenditure was increased in sleep-restricted rats. The effects of chronic sleep disturbance on metabolites in serum were examined using 1H NMR metabolomics and GC-FID/MS analysis. Six metabolites (lipoproteins, triglycerides, isoleucine, valine, choline, and phosphorylcholine) exhibited significant alteration, and all the fatty acid components were decreased, which suggested fatty acid metabolism was impaired after sleep loss. Moreover, increased blood glucose, reduced serum insulin, decreased glucose tolerance, and impaired glucose-stimulated insulin secretion of islets were also observed in sleep-restricted rats. The islet function of insulin secretion could be partially restored by increasing dietary fat to sleep-disturbed rats suggested that a reduction in circulating fatty acids was related to islet dysfunction under sleep deficiency-induced environmental stress. This study provides a new perspective on the relationship between insufficient sleep and lipid/glucose metabolism, which offers insights into the role of stressful challenges in a healthy lifestyle. PMID:27983645

  3. Sub-chronic exposure to paraoxon neither induces nor exacerbates diabetes mellitus in Wistar rat.

    PubMed

    Nurulain, Syed M; Petroianu, Georg; Shafiullah, Mohamed; Kalász, Huba; Oz, Murat; Saeed, Tariq; Adem, Abdu; Adeghate, Ernest

    2013-10-01

    There is an increasing belief that organophosphorus compounds (OPCs) impair glucose homeostasis and cause hyperglycemia and diabetes mellitus. The present study was undertaken to investigate the putative diabetogenic effect of sub-lethal and sub-chronic exposure to paraoxon (POX), an extremely hazardous OPC used in pesticides. The effect of paraoxon on streptozotocin-induced diabetic rats was also examined. Each rat was injected with 100 nmol of POX 5 days per week for 6 weeks. Blood glucose levels and red blood cell acetylcholinesterase activity were measured weekly. Biochemical analysis and morphological studies were performed at the end of the experiment. The results revealed that POX neither induces nor exacerbates diabetes mellitus in experimental rats. Liver and kidney/body weight ratios revealed statistically insignificant differences when compared with controls. Biochemical analysis of urine samples showed a small but not significant increase in protein level in all groups. Urine bilirubin was significantly higher in the diabetes + POX group when compared with the control group. The number of blood cells in urine was significantly higher in the POX-treated group compared with the control group. Hyperglycemia was noted in the diabetes and diabetes + POX groups, but neither in the saline control nor in POX-treated normal rats. Electron microscopy of POX-treated pancreas did not show any morphological changes in beta cells. These results suggest that POX does not cause diabetes mellitus at sub-lethal sub-chronic exposure.

  4. Wakame (Undaria pinnatifida ) modulates hyperphosphatemia in a rat model of chronic renal failure.

    PubMed

    Katai, Kanako; Iwamoto, Aya; Kimura, Yuka; Oshima, Yuki; Arioka, Saori; Morimi, Yuki; Omuro, Ayaka; Nakasa, Teruko

    2015-01-01

    In chronic renal failure, inorganic phosphate (Pi) retention speeds up the progression to end-stage renal disease. The current therapy for hyperphosphatemia in patients with chronic renal failure consists of dietary Pi restriction combined with administration of Pi binders, but each therapy has practical problems. Thus, the discovery of foods or nutrients that inhibit Pi absorption may be useful for the treatment of hyperphosphatemia. In the present study, we investigated whether wakame (Undaria pinnatifida) is a useful food for the prevention of hyperphosphatemia in a rat model of renal failure. Feeding a diet containing 5% wakame significantly decreased plasma and urinary Pi levels and increased the amount of fecal Pi. In addition, wakame significantly reduced plasma blood urea nitrogen and plasma Pi levels in 5/6 nephrectomized rats fed a high-Pi diet. Biochemical analyses showed that the reduction of intestinal Pi absorption is the main reason for the decrease in plasma Pi levels in rats fed a diet containing wakame. In addition, feeding alginic acid and fucoidan, major components of wakame fiber, was effective in reducing plasma Pi levels in normal rats. Finally, we concluded that wakame may be a useful food for the prevention of hyperphosphatemia in rodents.

  5. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption

    PubMed Central

    Xie, Guoxiang; Zhong, Wei; Li, Houkai; Li, Qiong; Qiu, Yunping; Zheng, Xiaojiao; Chen, Huiyuan; Zhao, Xueqing; Zhang, Shucha; Zhou, Zhanxiang; Zeisel, Steven H.; Jia, Wei

    2013-01-01

    Our understanding of the bile acid metabolism is limited by the fact that previous analyses have primarily focused on a selected few circulating bile acids; the bile acid profiles of the liver and gastrointestinal tract pools are rarely investigated. Here, we determined how chronic ethanol consumption altered the bile acids in multiple body compartments (liver, gastrointestinal tract, and serum) of rats. Rats were fed a modified Lieber-DeCarli liquid diet with 38% of calories as ethanol (the amount equivalent of 4–5 drinks in humans). While conjugated bile acids predominated in the liver (98.3%), duodenum (97.8%), and ileum (89.7%), unconjugated bile acids comprised the largest proportion of measured bile acids in serum (81.2%), the cecum (97.7%), and the rectum (97.5%). In particular, taurine-conjugated bile acids were significantly decreased in the liver and gastrointestinal tract of ethanol-treated rats, while unconjugated and glycine-conjugated species increased. Ethanol consumption caused increased expression of genes involved in bile acid biosynthesis, efflux transport, and reduced expression of genes regulating bile acid influx transport in the liver. These results provide an improved understanding of the systemic modulations of bile acid metabolism in mammals through the gut-liver axis.—Xie, G., Zhong, W., Li, H., Li, Q., Qiu, Y., Zheng, X., Chen, H., Zhao, X., Zhang, S., Zhou, Z., Zeisel, S. H., Jia, W. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. PMID:23709616

  6. Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats.

    PubMed

    Chen, J; Winston, J H; Sarna, S K

    2013-09-17

    The role of inflammation in inducing visceral hypersensitivity (VHS) in ulcerative colitis patients remains unknown. We tested the hypothesis that acute ulcerative colitis-like inflammation does not induce VHS. However, it sets up molecular conditions such that chronic stress following inflammation exaggerates single-unit afferent discharges to colorectal distension. We used dextran sodium sulfate (DSS) to induce ulcerative colitis-like inflammation and a 9-day heterotypic chronic stress protocol in rats. DSS upregulated Nav1.8 mRNA in colon-responsive dorsal root ganglion (DRG) neurons, TRPV1 in colonic muscularis externae (ME) and BDNF in spinal cord without affecting the spike frequency in spinal afferents or VMR to CRD. By contrast, chronic stress did not induce inflammation but it downregulated Kv1.1 and Kv1.4 mRNA in DRG neurons, and upregulated TRPA1 and nerve growth factor in ME, which mediated the increase of spike frequency and VMR to CRD. Chronic stress following inflammation exacerbated spike frequency in spinal afferent neurons. TRPA1 antagonist suppressed the sensitization of afferent neurons. DSS-inflammation did not affect the composition or excitation thresholds of low-threshold and high-threshold fibers. Chronic stress following inflammation increased the percent composition of high-threshold fibers and lowered the excitation threshold of both types of fibers. We conclude that not all types of inflammation induce VHS, whereas chronic stress induces VHS in the absence of inflammation.

  7. [The glutathione system in the blood of rats and morphological changes of the pancreas under experimental acute and chronic pancreatitis].

    PubMed

    Makarchuk, V A; Ushakova, H O; Krylova, O O

    2013-01-01

    In experiment on laboratory rats the models of acute and chronic pancreatitis were developed to study the changes of lipoperoxidation-antioxidant protection system depending on morphological changes of the pancreas. The acute and chronic pancreatitis is accompanied with intensification of lipoperoxidation and gradual inhibition of antioxidant system due to development of subsequent chronization of the pathological process.

  8. Chronic imipramine treatment differentially alters the brain and plasma amino acid metabolism in Wistar and Wistar Kyoto rats.

    PubMed

    Nagasawa, Mao; Otsuka, Tsuyoshi; Yasuo, Shinobu; Furuse, Mitsuhiro

    2015-09-05

    In the present study, the amino acids which have the possibility for the therapeutic efficacy of imipramine were explored and compared between Wistar Kyoto rats, an animal model of depression, and Wistar rats as a normal model. The antidepressant-like effect caused by chronic imipramine treatment was confirmed by decreased immobility in the forced swimming test. Chronic imipramine administration altered the amino acid dynamics in the brain. In the striatum, the concentrations of asparagine, glutamine and methionine were significantly increased by chronic imipramine administration. In the thalamus and hypothalamus, chronic imipramine administration significantly decreased the valine concentration. On the other hand, no amino acid was altered by chronic imipramine administration in the hippocampus, brain stem and cerebellum. In addition, lower concentration of asparagine in the prefrontal cortex of WKY rats was improved by chronic imipramine administration. This amelioration only in WKY rats may be a specific effect of chronic imipramine administration under the depressive state. In conclusion, chronic imipramine administration altered the several amino acid dynamics in the brain. Modification of the amino acid metabolism in the brain may provide a new strategy in the development of therapeutic treatment of major depression.

  9. Effects of chronic noise on glucose metabolism and gut microbiota–host inflammatory homeostasis in rats

    PubMed Central

    Cui, Bo; Gai, Zhihui; She, Xiaojun; Wang, Rui; Xi, Zhuge

    2016-01-01

    Chronic noise exposure has been implicated in increased risk of diabetes. However, there is limited experimental evidence of the mechanisms linking chronic noise stress and glucose metabolism. We addressed this in the present study by examining glucose metabolism, immune response, and changes in gut microbiota/host inflammatory homeostasis in rats exposed to noise for 30 consecutive days. Chronic noise exposure increased blood glucose and corticosterone levels for at least 14 days after cessation of noise. Stressed rats also exhibited elevated levels of glycogen and triglyceride in the liver and impaired hepatic insulin production via insulin-induced insulin receptor/insulin receptor substrate 1/glycogen synthase kinase 3β signalling, which persisted for 3–14 days after cessation of noise exposure. Chronic noise altered the percentage of Proteobacteria and Actinobacteria in the gut, increasing Roseburia but decreasing Faecalibacterium levels in the cecum relative to controls. Immunoglobulin A, interleukin 1β, and tumor necrosis factor α levels were also elevated in the intestine of these animals, corresponding to noise-induced abnormalities in glucose regulation and insulin sensitivity. These results suggest that lifelong environmental noise exposure could have cumulative effects on diabetes onset and development resulting from alterations in gut microbiota composition and intestinal inflammation. PMID:27811997

  10. The effects of chronic photoperiod shifting on the physiology of female Long-Evans rats.

    PubMed

    Deibel, Scott H; Hong, Nancy S; Himmler, Stephanie M; McDonald, Robert J

    2014-04-01

    As the prevalence of shift work is increasing, it is important to elucidate the impact that shift work has on health. Because of the alternating work schedules present in rotating shift work and working at night, shift workers are in a chronic state of circadian disruption. Animal models of circadian disruption are useful because they offer more experimental control than the largely correlational human shift work studies. The effects of chronic circadian disruption on food preference, glucose tolerance, corticosterone secretion, and performance in a stress-inducing task were investigated in female Long-Evans rats. A 64-day photoperiod shifting paradigm was used to induce circadian disruption. Surprisingly, neither the photoperiod shifted animals, nor the control animals demonstrated a preference for either an unhealthy or healthy diet. Nor was there a difference between the groups in weight gained during photoperiod shifting. However, the photoperiod shifted rats gained significantly more weight than control animals, without eating more food during discriminative fear conditioning to context (DFCTC). Surprisingly, chronic photoperiod shifting appeared to facilitate retention in the DFCTC task. The photoperiod shifted animals also had increased serum glucose values during fasting and after a glucose challenge test. The photoperiod shifted animals only had elevated corticosterone during the final two phases of photoperiod shifting. This study demonstrates that chronic photoperiod shifting elicits weight gain when exposed to a stressful event and impairs glucose tolerance in the same individual.

  11. Acute and chronic effects of nicotine on serotonin uptake in prefrontal cortex and hippocampus of rats.

    PubMed

    Awtry, Tammy L; Werling, Linda L

    2003-12-01

    We sought to investigate the effect of nicotine exposure (chronic and acute) on serotonin transporter (SERT) activity in two regions of the brain important for behavioral effects of nicotine. We first looked at the effects of chronic nicotine exposure (0.7 mg/kg nicotine, twice a day for 10 days) on [(3)H]5-HT uptake in prefrontal cortex (PFC) and hippocampus of rats. A significant increase in [(3)H]5-HT uptake was observed in synaptosomes prepared from both regions. To rule out the possibility that the increases were due to the last injection given, in a separate set of experiments a single injection of nicotine was administered the evening before sacrifice. No change in uptake occurred in either region, suggesting that the increases in uptake caused by nicotine was an effect of chronic exposure and not to an acute treatment. SERT binding studies, using prefrontocortical or hippocampal membrane preparations, revealed that chronic nicotine exposure significantly increased B(max) which correlated to an increase in SERT density. Lastly, we looked at the short-term effect of nicotine on [(3)H]5-HT uptake. Rats received a single nicotine injection 15-75 min before sacrifice. PFC synaptosomes displayed a time-dependent increase in uptake, whereas hippocampal synaptosomes showed an increase at only one time point.

  12. Unpredictable chronic mild stress induced behavioral deficits: a comparative study in male and female rats.

    PubMed

    Farhan, Muhammad; Ikram, Huma; Kanwal, Sumera; Haleem, Darakhshan Jabeen

    2014-07-01

    Stress is an important precipitant factor for depression. Changes in various body systems that occur in depression are similar to those observed in response to stress. Chronic stress may alter behavioral, neurochemical and physiological responses to drug challenges and novel stressors. Unpredictable chronic mild stress (UCMS) also produces alteration in the serotonergic (5-HT; 5-hydroxytryptamine) neurotransmission. Unpredictable chronic mild stress (UCMS) could be used as an animal model of depression. Neurochemical and behavioral effects of UCMS can be reversed by antidepressant agents, suggesting an important role of serotonin. In rodents, UCMS can elicit depression-like symptoms. The objective of the present study was to evaluate and compare the behavioral deficits induced by chronic mild stress in male and female rats and finding out the vulnerability of the two groups. Male and female rats exposed to UCMS exhibited a significant decrease in cumulative food intake as well as in growth rate. Loco motor activity in home cage and open field was also decreased. Results may contribute to our understanding of the interaction between stress and behavioral functions have to depressive disorders.

  13. Nerve Growth Factor Decreases in Sympathetic and Sensory Nerves of Rats with Chronic Heart Failure

    PubMed Central

    Lu, Jian

    2014-01-01

    Nerve growth factor (NGF) plays a critical role in the maintenance and survival of both sympathetic and sensory nerves. Also, NGF can regulate receptor expression and neuronal activity in the sympathetic and sensory neurons. Abnormalities in NGF regulation are observed in patients and animals with heart failure (HF). Nevertheless, the effects of chronic HF on the levels of NGF within the sympathetic and sensory nerves are not known. Thus, the ELISA method was used to assess the levels of NGF in the stellate ganglion (SG) and dorsal root ganglion (DRG) neurons of control rats and rats with chronic HF induced by myocardial infarction. Our data show for the first time that the levels of NGF were significantly decreased (P < 0.05) in the SG and DRG neurons 6–20 weeks after ligation of the coronary artery. In addition, a close relation was observed between the NGF levels and the left ventricular function. In conclusion, chronic HF impairs the expression of NGF in the sympathetic and sensory nerves. Given that sensory afferent nerves are engaged in the sympathetic nervous responses to somatic stimulation (i.e. muscle activity during exercise) via a reflex mechanism, our data indicate that NGF is likely responsible for the development of muscle reflex-mediated abnormal sympathetic responsiveness observed in chronic HF. PMID:24913185

  14. Adolescent exposure to chronic delta-9-tetrahydrocannabinol blocks opiate dependence in maternally deprived rats.

    PubMed

    Morel, Lydie J; Giros, Bruno; Daugé, Valérie

    2009-10-01

    Maternal deprivation in rats specifically leads to a vulnerability to opiate dependence. However, the impact of cannabis exposure during adolescence on this opiate vulnerability has not been investigated. Chronic dronabinol (natural delta-9 tetrahydrocannabinol, THC) exposure during postnatal days 35-49 was made in maternal deprived (D) or non-deprived (animal facility rearing, AFR) rats. The effects of dronabinol exposure were studied after 2 weeks of washout on the rewarding effects of morphine measured in the place preference and oral self-administration tests. The preproenkephalin (PPE) mRNA levels and the relative density and functionality of CB1, and mu-opioid receptors were quantified in the striatum and the mesencephalon. Chronic dronabinol exposure in AFR rats induced an increase in sensitivity to morphine conditioning in the place preference paradigm together with a decrease of PPE mRNA levels in the nucleus accumbens and the caudate-putamen nucleus, without any modification for preference to oral morphine consumption. In contrast, dronabinol treatment on D-rats normalized PPE decrease in the striatum, morphine consumption, and suppressed sensitivity to morphine conditioning. CB1 and mu-opioid receptor density and functionality were not changed in the striatum and mesencephalon of all groups of rats. These results indicate THC potency to act as a homeostatic modifier that would worsen the reward effects of morphine on naive animals, but ameliorate the deficits in maternally D-rats. These findings point to the self-medication use of cannabis in subgroups of individuals subjected to adverse postnatal environment.

  15. Chronic ethanol treatment changes the number of beta-receptors in rat brain microvessels

    SciTech Connect

    Lucchi, L.; Cazzaniga, A.; Picotti, G.B.; Covelli, V.; Magnoni, M.S.; Borriero, L.; Spano, P.F.; Trabucchi, M.

    1984-01-01

    The effect of chronic ethanol consumption on the binding (125I)-iodohydroxybenzylpindolol to beta-adrenergic receptors in rat brain microvessels has been studied. The results show that chronic ethanol treatment increases the number of beta-receptors present in brain microvessels without changing the binding affinity of the binding site for the beta-adrenoceptor ligand. This effect is apparently not associated with changes in peripheral adrenergic tone, since no differences in platelet epinephrine or norepinephrine concentrations were found between ethanol-treated and control animals. An increase in beta-receptor density in brain microvessels might contribute to the alterations of cerebral blood flow and oxygen consumption reported during chronic ethanol intoxication.

  16. Chronic Co-species Housing Mice and Rats Increased the Competitiveness of Male Mice.

    PubMed

    Liu, Ying-Juan; Li, Lai-Fu; Zhang, Yao-Hua; Guo, Hui-Fen; Xia, Min; Zhang, Meng-Wei; Jing, Xiao-Yuan; Zhang, Jing-Hua; Zhang, Jian-Xu

    2017-01-10

    Rats are predators of mice in nature. Nevertheless, it is a common practice to house mice and rats in a same room in some laboratories. In this study, we investigated the behavioral and physiological responsively of mice in long-term co-species housing conditions. Twenty-four male mice were randomly assigned to their original raising room (control) or a rat room (co-species-housed) for more than 6 weeks. In the open-field and light-dark box tests, the behaviors of the co-species-housed mice and controls were not different. In a 2-choice test of paired urine odors [rabbit urine (as a novel odor) vs. rat urine, cat urine (as a natural predator-scent) vs. rabbit urine, and cat urine vs. rat urine], the co-species-housed mice were more ready to investigate the rat urine odor compared with the controls and may have adapted to it. In an encounter test, the rat-room-exposed mice exhibited increased aggression levels, and their urines were more attractive to females. Correspondingly, the levels of major urinary proteins were increased in the co-species-housed mouse urine, along with some volatile pheromones. The serum testosterone levels were also enhanced in the co-species-housed mice, whereas the corticosterone levels were not different. The norepinephrine, dopamine, and 5-HT levels in the right hippocampus and striatum were not different between the 2. Our findings indicate that chronic co-species housing results in adaptation in male mice; furthermore, it appears that long-term rat-odor stimuli enhance the competitiveness of mice, which suggests that appropriate predator-odor stimuli may be important to the fitness of prey animals.

  17. Plasmodium vivax induced hemolytic uremic syndrome: An uncommon manifestation that leads to a grave complication and treated successfully with renal transplantation.

    PubMed

    Jhorawat, Rajesh; Beniwal, Pankaj; Malhotra, Vinay

    2015-01-01

    We are reporting a case of hemolytic uremic syndrome, a rare manifestation of Plasmodium vivax malaria. A young driver was admitted with acute febrile illness, decreased urine output, anemia, thrombocytopenia, jaundice, and increased serum lactate dehydrogenase. He showed a partial response to antimalarial drugs. However, he was readmitted with worsening renal parameters. His kidney biopsy revealed chronic thrombotic microangiopathy. He remained dialysis dependent and later underwent renal transplantation successfully, with excellent graft function at 1-year.

  18. Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

    PubMed Central

    Romero, Freddy; Shah, Dilip; Duong, Michelle; Stafstrom, William; Hoek, Jan B.; Kallen, Caleb B.; Lang, Charles H.

    2014-01-01

    Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and

  19. Effect of superoxide anion scavenger on rat hearts with chronic intermittent hypoxia.

    PubMed

    Pai, Peiying; Lai, Ching Jung; Lin, Ching-Yuang; Liou, Yi-Fan; Huang, Chih-Yang; Lee, Shin-Da

    2016-04-15

    Only very limited information regarding the protective effects of the superoxide anion scavenger on chronic intermittent hypoxia-induced cardiac apoptosis is available. The purpose of this study is to evaluate the effects of the superoxide anion scavenger on cardiac apoptotic and prosurvival pathways in rats with sleep apnea. Forty-two Sprague-Dawley rats were divided into three groups, rats with normoxic exposure (Control, 21% O2, 1 mo), rats with chronic intermittent hypoxia exposure (Hypoxia, 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo), and rats with pretreatment of the superoxide anion scavenger and chronic intermittent hypoxia exposure (Hypoxia-O2 (-)-Scavenger, MnTMPyP pentachloride, 1 mg/kg ip per day; 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo) at 5-6 mo of age. After 1 mo, the protein levels and apoptotic cells of excised hearts from three groups were measured by Western blotting and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay. The superoxide anion scavenger decreased hypoxia-induced myocardial architecture abnormalities, left ventricular hypertrophy, and TUNEL-positive apoptosis. The superoxide anion scavenger decreased hypoxia-induced Fas ligand, Fas death receptors, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas-dependent apoptotic pathway) as well as Bad, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptotic pathway), endonuclease G (EndoG), apoptosis-inducing factor (AIF), and TUNEL-positive apoptosis. The superoxide anion scavenger increased IGF-1, IGF-1R, p-PI3k, p-Akt, p-Bad, Bcl-2, and Bcl-xL (survival pathway). Our findings imply that the superoxide anion scavenger might prevent cardiac Fas-mediated and mitochondrial-mediated apoptosis and enhance the IGF-1-related survival pathway in chronic intermittent hypoxia. The superoxide anion scavenger may prevent chronic sleep apnea-enhanced cardiac apoptotic pathways and enhances

  20. Chronic social instability increases anxiety-like behavior and ethanol preference in male Long Evans rats.

    PubMed

    Roeckner, Alyssa R; Bowling, Alexandra; Butler, Tracy R

    2017-02-13

    Chronic stress during adolescence is related to increased prevalence of anxiety disorders and alcohol use disorders in humans. This phenotype has been consistently recapitulated in animal models with male subjects, but models using female subjects are fewer. The aim of these studies was to test the hypothesis that chronic social instability (CSI) during adolescence engenders increased anxiety-like behavior, increased corticosterone, and greater ethanol intake and/or preference than control groups in male and female rats. A chronic social instability (CSI) procedure was conducted in separate cohorts of female and male adolescent Long Evans rats. CSI included daily social isolation for 1h, and then pair housing with a novel cage mate for 23h until the next 1h isolation period from PND 30-46. Control groups included social stability (SS), chronic isolation (ISO), and acute social instability (aSI). At PND 49-50, anxiety-like behavior was assessed on the elevated plus maze, and on PND 51 tails bloods were obtained for determination of corticosterone (CORT) levels. This was followed by 4weeks of ethanol drinking in a home cage intermittent access ethanol drinking paradigm (PND 55-81 for males, PND 57-83 for females). Planned contrast testing showed that the male CSI group had greater anxiety-like behavior compared controls, but group differences were not apparent for CORT. CSI males had significantly higher levels of ethanol preference during drinking weeks 2-3 compared to all other groups and compared to SS and ISO groups in week 4. For the female cohort, we did not observe consistent group differences in anxiety-like behavior, CORT levels were unexpectedly lower in the ISO group only compared to the other groups, and group differences were not apparent for ethanol intake/preference. In conclusion, chronic stress during adolescence in the form of social instability increases anxiety-like behavior and ethanol preference in male rats, consistent with other models of

  1. The effects of chronic alcohol consumption and exercise on the skeleton of adult male rats

    NASA Technical Reports Server (NTRS)

    Reed, Adam H.; McCarty, Heidi L.; Evans, Glenda L.; Turner, Russell T.; Westerlind, Kim C.

    2002-01-01

    BACKGROUND: Lifestyle factors are known to affect skeletal development and integrity. Specifically, running has been reported to increase risk of fatigue fractures, whereas chronic alcohol consumption has been shown to reduce bone formation and bone mass. The combined effect of exercise and alcohol on the skeleton has yet to be explored, although alcohol consumption is common among certain physically active populations (e.g., military recruits, college athletes). It was hypothesized that chronic alcohol consumption would accentuate the inherent risk associated with endurance running exercise. METHODS: Six-month-old male Sprague Dawley rats were assigned to one of five groups: baseline, exercise-alcohol diet, exercise-normal diet, sham-alcohol diet, and sham-normal diet. Alcohol-fed rats (35% caloric intake) received a liquid diet ad libitum. Normal animals were pair-fed the identical diet with a maltose dextrin caloric substitute. Exercise was conducted on a motorized treadmill 5 days/wk for 16 weeks. Sham rats were placed on a stationary treadmill for matching time periods. Fluorochrome labels were administered 3 days before baseline and at 10 and 2 days before animals were killed. Heart, soleus, and rectus femoris muscles were wet weighed to assess the effects of training. Tibiae were collected for static and dynamic histomorphometric measurements on cancellous and cortical bone. RESULTS: Muscle weights were larger in the exercised rats versus the sham rats. Alcohol had no significant effect on skeletal muscle weight but did result in larger heart weights in both alcohol-treated groups. Cancellous and periosteal bone formation rates were significantly decreased in the alcohol-fed rats versus rats on the normal diet and were associated with a significant reduction in trabecular thickness in the tibial metaphysis. Cortical and cross-sectional areas were also significantly lower in the alcohol-fed groups compared with the non-alcohol-fed groups. Exercise had no

  2. Effects of grape seed polyphenols on oxidative damage in liver tissue of acutely and chronically exercised rats.

    PubMed

    Belviranlı, Muaz; Gökbel, Hakkı; Okudan, Nilsel; Büyükbaş, Sadık

    2013-05-01

    The objective of the present study was to investigate the effects of grape seed extract (GSE) supplementation on oxidative stress and antioxidant defense markers in liver tissue of acutely and chronically exercised rats. Rats were randomly assigned to six groups: Control (C), Control Chronic Exercise (CE), Control Acute Exercise (AE), GSE-supplemented Control (GC), GSE-supplemented Chronic Exercise(GCE) and GSE-supplemented Acute Exercise (GAE). Rats in the chronic exercise groups were subjected to a six-week treadmill running and in the acute exercise groups performed an exhaustive running. Rats in the GSE supplemented groups received GSE (100 mg.kg(-1) .day(-1) ) in drinking water for 6 weeks. Liver tissues of the rats were taken for the analysis of malondialdehyde (MDA), nitric oxide (NO) levels and total antioxidant activity (AOA) and xanthine oxidase (XO) activities. MDA levels decreased with GSE supplementation in control groups but increased in acute and chronic exercise groups compared to their non-supplemented control. NO levels increased with GSE supplementation. XO activities were higher in AE group compared to the CE group. AOA decreased with GSE supplementation. In conclusion, while acute exercise triggers oxidative stress, chronic exercise has protective role against oxidative stress. GSE has a limited antioxidant effect on exercise-induced oxidative stress in liver tissue.

  3. Long-term effects of chronic oral Ritalin administration on cognitive and neural development in adolescent wistar kyoto rats.

    PubMed

    Pardey, Margery C; Kumar, Natasha N; Goodchild, Ann K; Clemens, Kelly J; Homewood, Judi; Cornish, Jennifer L

    2012-09-12

    The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin®). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed "normal" (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin® (2 × 2 mg/kg/day) or distilled water (dH2O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH2O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in "normal" WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls.

  4. Long-Term Effects of Chronic Oral Ritalin Administration on Cognitive and Neural Development in Adolescent Wistar Kyoto Rats

    PubMed Central

    Pardey, Margery C.; Kumar, Natasha N.; Goodchild, Ann K.; Clemens, Kelly J.; Homewood, Judi; Cornish, Jennifer L.

    2012-01-01

    The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin®). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed “normal” (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin® (2 × 2 mg/kg/day) or distilled water (dH2O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH2O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in “normal” WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls. PMID:24961199

  5. Enhanced activation of RVLM-projecting PVN neurons in rats with chronic heart failure.

    PubMed

    Xu, Bo; Zheng, Hong; Patel, Kaushik P

    2012-04-15

    Previous studies have indicated that there is increased activation of the paraventricular nucleus (PVN) in rats with chronic heart failure (CHF); however, it is not clear if the preautonomic neurons within the PVN are specifically overactive. Also, it is not known if these neurons have altered responses to baroreceptor or osmotic challenges. Experiments were conducted in rats with CHF (6-8 wk after coronary artery ligation). Spontaneously active neurons were recorded in the PVN, of which 36% were antidromically activated from the rostral ventrolateral medulla (RVLM). The baseline discharge rate in RVLM-projecting PVN (PVN-RVLM) neurons from CHF rats was significantly greater than in sham-operated (sham) rats (6.0 ± 0.6 vs. 2.6 ± 0.3 spikes/s, P < 0.05). Picoinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonovaleric acid significantly decreased the basal discharge of PVN-RVLM neurons by 80% in CHF rats compared with 37% in sham rats. Fifty-two percent of spontaneously active PVN-RVLM neurons responded to changes in the mean arterial pressure (MAP). The changes in discharge rate in PVN-RVLM neurons after a reduction in MAP (+52 ± 7% vs. +184 ± 61%) or an increase in MAP (-42 ± 8% vs. -71 ± 6%) were significantly attenuated in rats with CHF compared with sham rats. Most PVN-RVLM neurons (63%), including all barosensitive PVN-RVLM neurons, were excited by an internal carotid artery injection of hypertonic NaCl (2.1 osmol/l), whereas a smaller number (7%) were inhibited. The increase in discharge rate in PVN-RVLM neurons to hypertonic stimulation was significantly enhanced in rats with CHF compared with sham rats (134 ± 15% vs. 92 ± 13%). Taken together, these data suggest that PVN-RVLM neurons are more active under basal conditions and this overactivation is mediated by an enhanced glutamatergic tone in rats with CHF. Furthermore, this enhanced activation of PVN-RVLM neurons may contribute to the altered responses to

  6. Beneficial effect of prolonged heme oxygenase 1 activation in a rat model of chronic heart failure

    PubMed Central

    Collino, Massimo; Pini, Alessandro; Mugelli, Niccolò; Mastroianni, Rosanna; Bani, Daniele; Fantozzi, Roberto; Papucci, Laura; Fazi, Marilena; Masini, Emanuela

    2013-01-01

    SUMMARY We and others have previously demonstrated that heme oxygenase 1 (HO-1) induction by acute hemin administration exerts cardioprotective effects. Here, we developed a rat model of heart failure to investigate whether a long-term induction of HO-1 by chronic hemin administration exerted protective effects. Sprague Dawley rats that underwent permanent ligation of the left coronary artery were closely monitored for survival rate analysis and sacrificed on day 28 post-operation. Administration of hemin (4 mg/kg body weight) every other day for 4 weeks induced a massive increase in HO-1 expression and activity, as shown by the increased levels of the two main metabolic products of heme degradation, bilirubin and carbon monoxide (CO). These effects were associated with significant improvement in survival and reduced the extension of myocardial damage. The ischemic hearts of the hemin-treated animals displayed reduced oxidative stress and apoptosis in comparison with the non-treated rats, as shown by the decreased levels of lipid peroxidation, free-radical-induced DNA damage, caspase-3 activity and Bax expression. Besides, chronic HO-1 activation suppressed the elevated levels of myeloperoxidase (MPO) activity, interleukin 1β (IL-1β) production and tumor necrosis factor-α (TNFα) production that were evoked by the ischemic injury, and increased the plasma level of the anti-inflammatory cytokine IL-10. Interestingly, HO-1 inhibitor zinc protoporphyrin IX (ZnPP-IX; 1 mg/kg) lowered bilirubin and CO concentrations to control values, thus abolishing all the cardioprotective effects of hemin. In conclusion, the results demonstrate that chronic HO-1 activation by prolonged administration of hemin improves survival and exerts protective effects in a rat model of myocardial ischemia by exerting a potent antioxidant activity and disrupting multiple levels of the apoptotic and inflammatory cascade. PMID:23592614

  7. Even a Chronic Mild Hyperglycemia Affects Membrane Fluidity and Lipoperoxidation in Placental Mitochondria in Wistar Rats

    PubMed Central

    Figueroa-García, María del Consuelo; Espinosa-García, María Teresa; Martinez-Montes, Federico; Palomar-Morales, Martín; Mejía-Zepeda, Ricardo

    2015-01-01

    It is known the deleterious effects of diabetes on embryos, but the effects of diabetes on placenta and its mitochondria are still not well known. In this work we generated a mild hyperglycemia model in female wistar rats by intraperitoneal injection of streptozotocin in 48 hours-old rats. The sexual maturity onset of the female rats was delayed around 6–7 weeks and at 16 weeks-old they were mated, and sacrificed at day 19th of pregnancy. In placental total tissue and isolated mitochondria, the fatty acids composition was analyzed by gas chromatography, and lipoperoxidation was measured by thiobarbituric acid reactive substances. Membrane fluidity in mitochondria was measured with the excimer forming probe dipyrenylpropane and mitochondrial function was measured with a Clark-type electrode. The results show that even a chronic mild hyperglycemia increases lipoperoxidation and decreases mitochondrial function in placenta. Simultaneously, placental fatty acids metabolism in total tissue is modified but in a different way than in placental mitochondria. Whereas the chronic mild hyperglycemia induced a decrease in unsaturated to saturated fatty acids ratio (U/S) in placental total tissue, the ratio increased in placental mitochondria. The measurements of membrane fluidity showed that fluidity of placenta mitochondrial membranes increased with hyperglycemia, showing consistency with the fatty acids composition through the U/S index. The thermotropic characteristics of mitochondrial membranes were changed, showing lower transition temperature and activation energies. All of these data together demonstrate that even a chronic mild hyperglycemia during pregnancy of early reproductive Wistar rats, generates an increment of lipoperoxidation, an increase of placental mitochondrial membrane fluidity apparently derived from changes in fatty acids composition and consequently, mitochondrial malfunction. PMID:26630275

  8. Even a Chronic Mild Hyperglycemia Affects Membrane Fluidity and Lipoperoxidation in Placental Mitochondria in Wistar Rats.

    PubMed

    Figueroa-García, María del Consuelo; Espinosa-García, María Teresa; Martinez-Montes, Federico; Palomar-Morales, Martín; Mejía-Zepeda, Ricardo

    2015-01-01

    It is known the deleterious effects of diabetes on embryos, but the effects of diabetes on placenta and its mitochondria are still not well known. In this work we generated a mild hyperglycemia model in female wistar rats by intraperitoneal injection of streptozotocin in 48 hours-old rats. The sexual maturity onset of the female rats was delayed around 6-7 weeks and at 16 weeks-old they were mated, and sacrificed at day 19th of pregnancy. In placental total tissue and isolated mitochondria, the fatty acids composition was analyzed by gas chromatography, and lipoperoxidation was measured by thiobarbituric acid reactive substances. Membrane fluidity in mitochondria was measured with the excimer forming probe dipyrenylpropane and mitochondrial function was measured with a Clark-type electrode. The results show that even a chronic mild hyperglycemia increases lipoperoxidation and decreases mitochondrial function in placenta. Simultaneously, placental fatty acids metabolism in total tissue is modified but in a different way than in placental mitochondria. Whereas the chronic mild hyperglycemia induced a decrease in unsaturated to saturated fatty acids ratio (U/S) in placental total tissue, the ratio increased in placental mitochondria. The measurements of membrane fluidity showed that fluidity of placenta mitochondrial membranes increased with hyperglycemia, showing consistency with the fatty acids composition through the U/S index. The thermotropic characteristics of mitochondrial membranes were changed, showing lower transition temperature and activation energies. All of these data together demonstrate that even a chronic mild hyperglycemia during pregnancy of early reproductive Wistar rats, generates an increment of lipoperoxidation, an increase of placental mitochondrial membrane fluidity apparently derived from changes in fatty acids composition and consequently, mitochondrial malfunction.

  9. Effects of chronic ethanol consumption on rat upper gastrointestinal system: functional and histologic findings.

    PubMed

    Yazir, Yusufhan; Tugay, Melih; Utkan, Zafer; Utkan, Tijen

    2012-11-01

    The purpose of the present study was to determine the effect of chronic alcohol consumption on reactivity of esophageal tunica muscularis mucosae (TMM) and lower esophageal sphincter (LES) smooth muscle. Six male rats in alcohol-fed group received ethanol (7.2% v/v) in a modified liquid diet for 4 weeks. Two control groups were used; six rats in the standard diet-fed group received rat chow and water for 4 weeks. Six rats in sucrose-fed group were given sucrose and received a liquid diet. The smooth muscle reactivity of TMM and LES strips from ethanol-fed and control animals was evaluated in organ chambers. Also histologic study was undertaken to show effects of chronic alcohol consumption. Maximum contractile responses of TMM to KCl and carbachol were decreased in the ethanol-fed group compared to the control groups. Relaxant responses to serotonin were decreased in the ethanol-fed group compared to the control groups. In TMM, isoproterenol- and papaverine-induced relaxant responses were similar in the ethanol-fed and control groups. In LES smooth muscle, relaxant responses to papaverine or isoproterenol were similar in the control groups and the ethanol-fed group. There was no change in agonist potency among the groups. The relaxation response elicited by nicotine and sodium nitroprusside (SNP) or contractile response elicited by carbachol and 80 mM KCl was decreased with maximum responses and pD(2) values, in the ethanol-fed group compared to that of the control groups in LES. Decreased nNOS immunoreactivity in myenteric plexus was found in alcohol-exposed group compared to control groups. Our findings suggest that chronic alcohol consumption impairs relaxant and contractile responses of both TMM and LES smooth muscle and it may contribute to gastroesophageal reflux commonly seen after alcohol binges.

  10. Chronic Psychosocial Stress Impairs Bone Homeostasis: A Study in the Social Isolation Reared Rat

    PubMed Central

    Schiavone, Stefania; Morgese, Maria G.; Mhillaj, Emanuela; Bove, Maria; De Giorgi, Angelo; Cantatore, Francesco P.; Camerino, Claudia; Tucci, Paolo; Maffulli, Nicola; Cuomo, Vincenzo; Trabace, Luigia

    2016-01-01

    Chronic psychosocial stress is a key player in the onset and aggravation of mental diseases, including psychosis. Although a strong association between this psychiatric condition and other medical co-morbidities has been recently demonstrated, few data on the link between psychosis and bone homeostasis are actually available. The aim of this study was to investigate whether chronic psychosocial stress induced by 4 or 7 weeks of social isolation in drug-naïve male Wistar rats could alter bone homeostasis in terms of bone thickness, mineral density and content, as well as markers of bone formation and resorption (sclerostin, cathepsin K, and CTX-I). We found that bone mineral density was increased in rats exposed to 7 weeks of social isolation, while no differences were detected in bone mineral content and area. Moreover, 7 weeks of social isolation lead to increase of femur thickness with respect to controls, suggesting the development of a hyperostosis condition. Isolated rats showed no changes in sclerostin levels, a marker of bone formation, compared to grouped animals. Conversely, bone resorption markers were significantly altered after 7 weeks of social isolation in terms of decrease in cathepsin K and increase of CTX-I. No alterations were found after 4 weeks of isolation rearing. Our observations suggest that chronic psychosocial stress might affect bone homeostasis, more likely independently from drug treatment. Thus, the social isolation model might help to identify possible new therapeutic targets to treat the burden of chronic psychosocial stress and to attempt alternative therapy choices. PMID:27375486

  11. Electroacupuncture Restores 5-HT System Deficit in Chronic Mild Stress-Induced Depressed Rats

    PubMed Central

    Tu, Ya; Yang, Xiuyan; Liu, Ping

    2016-01-01

    Objective. The current study is designed to investigate the antidepressant efficacy of electroacupuncture (EA) treatment by evaluating its effect on the synthesis, metabolism, reuptake, and receptors of 5-hydroxytryptamine (5-HT), so as to clarify the molecular mechanisms of EA for antidepression. Materials and Methods. Solitary combined with the chronic unpredictable mild stress (CUMS) was used to establish the rat model with depression. The depressed rats were supplied with EA treatment for 4 weeks, and the behavior change and the following indices including 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), monoamine oxidase A (MAO-A), tryptophan hydroxylase (TPH), 5-HT transporter (SERT), 5-HT1A, and 5-HT2A in hippocampus and prefrontal cortex were examined. Results. EA treatment significantly improved the behavior of rats and increased 5-HT level in hippocampus of depressed rats. Similarly, EA treatment could significantly increase protein and mRNA expression of TPH and 5-HT1A during 5-HT synthesis process in hippocampus of depressed rats. However, EA treatment had no effect on the activity of MAO-A and the expression of SERT protein and mRNA. Conclusion. Antidepressant efficacy of EA treatment can be accomplished through enhancing 5-HT synthesis, upregulating 5-HT1A level, and improving 5-HT content in brain and synaptic gaps. PMID:27994633

  12. Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

    PubMed Central

    Lee, An-Sheng; Chen, Wei-Yu; Chan, Hua-Chen; Chung, Ching-Hu; Peng, Hsien-Yu; Chang, Chia-Ming; Su, Ming-Jai; Chen, Chu-Huang; Chang, Kuan-Cheng

    2017-01-01

    The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD. PMID:28094801

  13. Effect of chronic intracerebroventricular angiotensin II infusion on vasopressin release in rats

    NASA Technical Reports Server (NTRS)

    Sterling, G. H.; Chee, O.; Riggs, R. V.; Keil, L. C.

    1980-01-01

    The effects of the chronic infusion of angiotensin II into the lateral cerebral ventricle on the release of arginine vasopressin in rats are investigated. Rats were subjected to a continuous infusion of angiotensin at a rate of 1 microgram/h for five days, during which they were offered water, isotonic saline or hypertonic saline ad libitum or 40 ml water/day, and fluid intake, changes in body weight, plasma sodium ion concentrations and plasma and pituitary arginine vasopressin levels were measured. Angiotensin II is found to increase the fluid intake of rats given isotonic saline and decrease plasma sodium ion levels with no changes in plasma or pituitary arginine vasopressin in those given water or isotonic saline. However, in rats given hypertonic saline, plasma sodium concentrations remained at control levels while plasma vasopressin increased, and in water-restricted rats the effects of angiotensin II were intermediate. Results thus demonstrate that angiotensin II-stimulated arginine vasopressin release is reduced under conditions in which plasma sodium ion concentration becomes dilute, compatible with a central role of angiotensin in the regulation of salt and water balance.

  14. L-carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain.

    PubMed

    Ueno, Yuji; Koike, Masato; Shimada, Yoshiaki; Shimura, Hideki; Hira, Kenichiro; Tanaka, Ryota; Uchiyama, Yasuo; Hattori, Nobutaka; Urabe, Takao

    2015-03-01

    Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine. L-carnitine-treated rats exhibited significantly reduced escape latency in the Morris water maze task at 28 days after chronic hypoperfusion. Western blot analysis indicated that L-carnitine increased levels of phosphorylated high-molecular weight neurofilament (pNFH), concurrent with a reduction in phosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN), and increased phosphorylated Akt and mammalian target of rapamycin (mTOR) at 28 days after chronic hypoperfusion. L-carnitine reduced lipid peroxidation and oxidative DNA damage, and enhanced oligodendrocyte marker expression and myelin sheath thickness after chronic hypoperfusion. L-carnitine regulates the PTEN/Akt/mTOR signaling pathway, and enhances axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving WMLs and cognitive impairment in a rat chronic hypoperfusion model.

  15. L-carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain

    PubMed Central

    Ueno, Yuji; Koike, Masato; Shimada, Yoshiaki; Shimura, Hideki; Hira, Kenichiro; Tanaka, Ryota; Uchiyama, Yasuo; Hattori, Nobutaka; Urabe, Takao

    2015-01-01

    Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine. L-carnitine-treated rats exhibited significantly reduced escape latency in the Morris water maze task at 28 days after chronic hypoperfusion. Western blot analysis indicated that L-carnitine increased levels of phosphorylated high-molecular weight neurofilament (pNFH), concurrent with a reduction in phosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN), and increased phosphorylated Akt and mammalian target of rapamycin (mTOR) at 28 days after chronic hypoperfusion. L-carnitine reduced lipid peroxidation and oxidative DNA damage, and enhanced oligodendrocyte marker expression and myelin sheath thickness after chronic hypoperfusion. L-carnitine regulates the PTEN/Akt/mTOR signaling pathway, and enhances axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving WMLs and cognitive impairment in a rat chronic hypoperfusion model. PMID:25465043

  16. Chronic, Severe Hypertension Does Not Impair Spatial Learning and Memory in Sprague-Dawley Rats

    PubMed Central

    Kadish, Inga; van Groen, Thomas; Wyss, J. Michael

    2001-01-01

    This study tested the hypothesis that long-term hypertension impairs spatial learning and memory in rats. In 6-wk-old Sprague-Dawley rats, chronic hypertension was induced by placing one of three sizes of stainless steel clips around the descending aorta (above the renal artery), resulting in a 20–80-mm Hg increase of arterial pressure in all arteries above the clip, that is, the upper trunk and head. Ten months later, the rats were tested for 5 d in a repeated-acquisition water maze task, and on the fifth day, they were tested in a probe trial; that is, there was no escape platform present. At the end of the testing period, the nonsurgical and sham control groups had similar final escape latencies (16 ± 4 sec and 23 ± 9 sec, respectively) that were not significantly different from those of the three hypertensive groups. Rats with mild hypertension (140–160 mm Hg) had a final escape latency of 25 ± 6 sec, whereas severely hypertensive rats (170–199 mm Hg) had a final escape latency of 21 ± 7 sec and extremely hypertensive rats (>200 Hg) had a final escape latency of 19 ± 5 sec. All five groups also displayed a similar preference for the correct quadrant in the probe trial. Together, these data suggest that sustained, severe hypertension for over 10 mo is not sufficient to impair spatial learning and memory deficits in otherwise normal rats. PMID:11274256

  17. Ventilatory and chemoreceptor responses to hypercapnia in neonatal rats chronically exposed to moderate hyperoxia.

    PubMed

    Bavis, Ryan W; Li, Ke-Yong; DeAngelis, Kathryn J; March, Ryan J; Wallace, Josefine A; Logan, Sarah; Putnam, Robert W

    2017-03-01

    Rats reared in hyperoxia hypoventilate in normoxia and exhibit progressive blunting of the hypoxic ventilatory response, changes which are at least partially attributed to abnormal carotid body development. Since the carotid body also responds to changes in arterial CO2/pH, we tested the hypothesis that developmental hyperoxia would attenuate the hypercapnic ventilatory response (HCVR) of neonatal rats by blunting peripheral and/or central chemoreceptor responses to hypercapnic challenges. Rats were reared in 21% O2 (Control) or 60% O2 (Hyperoxia) until studied at 4, 6-7, or 13-14days of age. Hyperoxia rats had significantly reduced single-unit carotid chemoafferent responses to 15% CO2 at all ages; CO2 sensitivity recovered within 7days after return to room air. Hypercapnic responses of CO2-sensitive neurons of the caudal nucleus tractus solitarius (cNTS) were unaffected by chronic hyperoxia, but there was evidence for a small decrease in neuronal excitability. There was also evidence for augmented excitatory synaptic input to cNTS neurons within brainstem slices. Steady-state ventilatory responses to 4% and 8% CO2 were unaffected by developmental hyperoxia in all three age groups, but ventilation increased more slowly during the normocapnia-to-hypercapnia transition in 4-day-old Hyperoxia rats. We conclude that developmental hyperoxia impairs carotid body chemosensitivity to hypercapnia, and this may compromise protective ventilatory reflexes during dynamic respiratory challenges in newborn rats. Impaired carotid body function has less of an impact on the HCVR in older rats, potentially reflecting compensatory plasticity within the CNS.

  18. Subacute stress and chronic stress interact to decrease intestinal barrier function in rats.

    PubMed

    Lauffer, Adriana; Vanuytsel, Tim; Vanormelingen, Christophe; Vanheel, Hanne; Salim Rasoel, Shadea; Tóth, Joran; Tack, Jan; Fornari, Fernando; Farré, Ricard

    2016-01-01

    Psychological stress increases intestinal permeability, potentially leading to low-grade inflammation and symptoms in functional gastrointestinal disorders. We assessed the effect of subacute, chronic and combined stress on intestinal barrier function and mast cell density. Male Wistar rats were allocated to four experimental groups (n = 8/group): 1/sham; 2/subacute stress (isolation and limited movement for 24 h); 3/chronic crowding stress for 14 days and 4/combined subacute and chronic stress. Jejunum and colon were collected to measure: transepithelial electrical resistance (TEER; a measure of epithelial barrier function); gene expression of tight junction molecules; mast cell density. Plasma corticosterone concentration was increased in all three stress conditions versus sham, with highest concentrations in the combined stress condition. TEER in the jejunum was decreased in all stress conditions, but was significantly lower in the combined stress condition than in the other groups. TEER in the jejunum correlated negatively with corticosterone concentration. Increased expression of claudin 1, 5 and 8, occludin and zonula occludens 1 mRNAs was detected after subacute stress in the jejunum. In contrast, colonic TEER was decreased only after combined stress, and the expression of tight junction molecules was unaltered. Increased mast cell density was observed in the chronic and combined stress condition in the colon only. In conclusion, our data show that chronic stress sensitizes the gastrointestinal tract to the effects of subacute stress on intestinal barrier function; different underlying cellular and molecular alterations are indicated in the small intestine versus the colon.

  19. Alterations in VEGF expression induced by antidepressant drugs in female rats under chronic social stress

    PubMed Central

    Nowacka-Chmielewska, Marta Maria; Paul-Samojedny, Monika; Bielecka-Wajdman, Anna Maria; Barski, Jarosław Jerzy; Obuchowicz, Ewa

    2017-01-01

    Vascular endothelial growth factor (VEGF) is thought to serve a role in neurogenesis and the stress response. Although a definite link between the action of antidepressants and VEGF has not been identified, it is assumed that VEGF, as a neurotrophic factor, serves an important role in the effects of antidepressant treatment. To examine this, the present study subjected adult female rats to four weeks of social instability stress and measured the effect of antidepressant treatment on the expression of VEGF. Firstly, endocrine markers of stress and body weight were measured in parallel with behavioral tests prior to and following subjection to stress. Then, the effect of 28-day daily treatment with desipramine (DMI; 10 mg/kg), fluoxetine (5 mg/kg) or tianeptine (10 mg/kg) on the number of copies of VEGF mRNA in the amygdala, hippocampus and hypothalamus, and on serum VEGF protein levels, of rats subjected to chronic stress was determined. In addition, the weight of the adrenal glands was measured following subjection to stress. Exposure to chronic stress was found to increase the rats' sucrose preference, and diminish their tendency for general exploration and time spent in the open. The relative adrenal weights of the stressed rats were significantly increased compared with the control. Plasma concentrations of corticosterone and adrenocorticotropic hormone were not significantly augmented. In addition, the present study identified that stress elevated VEGF mRNA expression in all studied neural structures. Furthermore, the results identified that the stress-induced increase in VEGF mRNA expression in the amygdala and hypothalamus was attenuated by long-term administration of DMI. Conversely, a decrease in serum VEGF concentration was observed in stressed rats, which was not reversed by treatment with antidepressants. In conclusion, the current study suggests that under conditions of stress, VEGF serves a role in the mechanism of action of DMI, through modulating

  20. Alterations in VEGF expression induced by antidepressant drugs in female rats under chronic social stress.

    PubMed

    Nowacka-Chmielewska, Marta Maria; Paul-Samojedny, Monika; Bielecka-Wajdman, Anna Maria; Barski, Jarosław Jerzy; Obuchowicz, Ewa

    2017-02-01

    Vascular endothelial growth factor (VEGF) is thought to serve a role in neurogenesis and the stress response. Although a definite link between the action of antidepressants and VEGF has not been identified, it is assumed that VEGF, as a neurotrophic factor, serves an important role in the effects of antidepressant treatment. To examine this, the present study subjected adult female rats to four weeks of social instability stress and measured the effect of antidepressant treatment on the expression of VEGF. Firstly, endocrine markers of stress and body weight were measured in parallel with behavioral tests prior to and following subjection to stress. Then, the effect of 28-day daily treatment with desipramine (DMI; 10 mg/kg), fluoxetine (5 mg/kg) or tianeptine (10 mg/kg) on the number of copies of VEGF mRNA in the amygdala, hippocampus and hypothalamus, and on serum VEGF protein levels, of rats subjected to chronic stress was determined. In addition, the weight of the adrenal glands was measured following subjection to stress. Exposure to chronic stress was found to increase the rats' sucrose preference, and diminish their tendency for general exploration and time spent in the open. The relative adrenal weights of the stressed rats were significantly increased compared with the control. Plasma concentrations of corticosterone and adrenocorticotropic hormone were not significantly augmented. In addition, the present study identified that stress elevated VEGF mRNA expression in all studied neural structures. Furthermore, the results identified that the stress-induced increase in VEGF mRNA expression in the amygdala and hypothalamus was attenuated by long-term administration of DMI. Conversely, a decrease in serum VEGF concentration was observed in stressed rats, which was not reversed by treatment with antidepressants. In conclusion, the current study suggests that under conditions of stress, VEGF serves a role in the mechanism of action of DMI, through modulating

  1. Effects of moderate and chronic exercise on the nitrergic system and behavioral parameters in rats.

    PubMed

    Pietrelli, Adriana; López-Costa, Juan José; Goñi, Ricardo; López, Esther María; Brusco, Alicia; Basso, Nidia

    2011-05-10

    Several reports suggest that nitric oxide (NO) could play a critical role on synaptic plasticity related to physical activity improving learning and memory; thus, physical exercise would have important effects on cerebral health. In order to analyze the long-term effects of chronic moderate physical training on the morphology and activity of nitrergic neurons belonging to the cerebral cortex, hippocampus and striatum, and their relationship with behavioral parameters. Wistar rats were aerobically trained (AT) up to the age of 18months and compared to sedentary controls (SC). At the end of the training protocol behavioral parameters were analyzed in an eight-arms radial maze. Rats were sacrificed by perfusion fixation with 4% paraformaldehyde. Brains were dissected out and coronal sections containing the three mentioned areas were obtained. The neurons expressing nitric oxide synthase (NOS) were stained using the technique of NADPH-diaphorase (NADPH-d) and their morphological and densitometric parameters were quantified by image analysis. Afterwards, the isoforms of NOS were determined by immunofluorescence. Results revealed AT rats learned faster, performed less mistakes and were more successful than SC rats in the maze. The nitrergic neurons of the cerebral cortex were larger and they had an increased number of dendrites. The NADPH-d reactivity in the cortex and striatum was upregulated. Colocalization was significant for the neuronal nitric oxide synthase (nNOS), in both groups. In conclusion, moderate and chronic exercise had a positive effect on cognitive performance and anxiety related behavior. An upregulation of the nitrergic system was detected in AT rats and this fact could be involved in this beneficial action on the aged subjects.

  2. Chronic ethanol tolerance as a result of free-choice drinking in alcohol-preferring rats of the WHP line.

    PubMed

    Dyr, Wanda; Taracha, Ewa

    2012-01-01

    The development of tolerance to alcohol with chronic consumption is an important criterion for an animal model of alcoholism and may be an important component of the genetic predisposition to alcoholism. The aim of this study was to determine whether the selectively bred Warsaw High Preferring (WHP) line of alcohol-preferring rats would develop behavioral and metabolic tolerance during the free-choice drinking of ethanol. Chronic tolerance to ethanol-induced sedation was tested. The loss of righting reflex (LRR) paradigm was used to record sleep duration in WHP rats. Ethanol (EtOH)-naive WHP rats received a single intraperitoneal (i.p.) injection of 5.0 g ethanol/kg body weight (b.w.), and sleep duration was measured. Subsequently, rats had access to a 10% ethanol solution under a free-choice condition with water and food for 12 weeks. After 12 weeks of the free-choice intake of ethanol, the rats received another single i.p. injection of 5.0 g ethanol/kg b.w., and sleep duration was reassessed. The blood alcohol content (BAC) for each rat was determined after an i.p. injection of 5 g/kg of ethanol in naive rats and again after chronic alcohol drinking at the time of recovery of the righting reflex (RR). The results showed that the mean ethanol intake was 9.14 g/kg/24 h, and both sleep duration and BAC were decreased after chronic ethanol intake. In conclusion, WHP rats exposed to alcohol by free-choice drinking across 12 weeks exhibited increased alcohol elimination rates. Studies have demonstrated that WHP rats after chronic free-choice drinking (12 weeks) of alcohol develop metabolic tolerance. Behavioral tolerance to ethanol was demonstrated by reduced sleep duration, but this decrease in sleep duration was not significant.

  3. Spatial Reversal Learning in Chronically Sensitized Rats and in Undrugged Sensitized Rats with Dopamine D2-Like Receptor Agonist Quinpirole

    PubMed Central

    Hatalova, Hana; Radostova, Dominika; Pistikova, Adela; Vales, Karel; Stuchlik, Ales

    2014-01-01

    Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP) induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive–compulsive disorder (OCD). Some of these symptoms persist even after QNP discontinuation. In QNP-sensitization, perseverative behavior has often been implicated. To test the effect of QNP-sensitization on reversal learning and its association with perseveration we selected an aversively motivated hippocampus-dependent task, active place avoidance on a Carousel. Performance was measured as the number of entrances into a to-be-avoided sector (errors). We tested separately QNP-sensitized rats in QNP-drugged and QNP-undrugged state in acquisition and reversal tasks on the Carousel. In acquisition learning there were no significant differences between groups and their respective controls. In reversal, QNP-sensitized drugged rats showed a robust but transient increase in number of errors compared to controls. QNP-sensitized rats in an undrugged state were not overtly different from the control animals but displayed an altered learning manifested by more errors at the beginning compensated by quicker learning in the second session compared to control animals. Importantly, performance was not associated with perseveration in neither QNP-sensitized drugged nor QNP-sensitized undrugged animals. The present results show that chronic QNP treatment induces robust reversal learning deficit only when the substance is continuously administered, and suggest that QNP animal model of OCD is also feasible model of cognitive alterations in this disorder. PMID:24782730

  4. Effect of chronic caffeine consumption on changes in locomotor activity of WAG/G and Fischer-344 rats induced by nicotine, ethanol, and morphine.

    PubMed

    Sudakov, S K; Rusakova, I V; Medvedeva, O F

    2003-12-01

    We studied the effect of single treatment with nicotine, ethanol, and morphine on locomotor activity of WAG/G and Fischer-344 rats chronically drinking caffeine solution. In Fischer-344 rats receiving caffeine locomotor activity in the open-field test was much lower than in animals drinking water, while in WAG/G rats no differences in locomotor activity were found. Chronic caffeine intake increased rat sensitivity to the stimulating effect of nicotine and ethanol, but decreased their sensitivity to the depressant effect of morphine. Chronic caffeine treatment most significantly modulated the effects of nicotine, ethanol, and morphine in Fischer-344 rats.

  5. Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats.

    PubMed

    Radahmadi, Maryam; Alaei, Hojjatallah; Sharifi, Mohammad Reza; Hosseini, Nasrin

    2015-04-01

    Previous results indicated that stress impairs learning and memory. In this research, the effects of preventive, therapeutic and regular continually running activity on chronic stress-induced memory deficit in rats were investigated. 70 male rats were randomly divided into seven groups as follows: Control, Sham, Stress-Rest, Rest-Stress, Stress-Exercise, Exercise-Stress and Exercise-Stress & Exercise groups. Chronic restraint stress was applied 6 h/day for 21days and treadmill running 1 h/day. Memory function was evaluated by the passive avoidance test. The results revealed that running activities had therapeutic effect on mid and long-term memory deficit and preventive effects on short and mid-term memory deficit in stressed rats. Regular continually running activity improved mid and long-term memory compared to Exercise-Stress group. The beneficial effects of exercise were time-dependent in stress conditions. Finally, data corresponded to the possibility that treadmill running had a more important role on treatment rather than on prevention on memory impairment induced by stress.

  6. Hypokalemic nephropathy in the rat. Role of ammonia in chronic tubular injury.

    PubMed

    Tolins, J P; Hostetter, M K; Hostetter, T H

    1987-05-01

    Chronic potassium deficiency results in progressive tubulointerstitial injury, associated with augmented renal ammoniagenesis. We investigated the role of elevated renal ammonia levels and the interaction of ammonia with the complement system in this injury. Potassium deficiency was induced in rats by feeding a low potassium diet. Experimental animals received 150 mM NaHCO3 or equimolar NaCl, as drinking water. After 3 wk, NaHCO3 supplemented rats demonstrated decreased ammonia production, less renal hypertrophy, less histologic evidence of injury, and less proteinuria. In in vitro studies on normal cortical tubular fragments, the addition of ammonia to serum in concentrations comparable to renal cortical levels in potassium-deficient animals significantly increased tubular deposition of C3 as quantitated by a radiolabeled antibody binding technique. Thus, alkali supplementation reduced chronic tubulointerstitial disease in a rat model of hypokalemic nephropathy. We propose that increased cortical ammonia levels contribute to hypokalemic nephropathy through ammonia-mediated activation of the alternative complement pathway.

  7. IB4-Saporin Attenuates Acute and Eliminates Chronic Muscle Pain in the Rat

    PubMed Central

    Alvarez, Pedro; Gear, Robert W.; Green, Paul G.; Levine, Jon D.

    2012-01-01

    The function of populations of nociceptors in muscle pain syndromes remain poorly understood. We compared the contribution of two major classes, isolectin B4-positive (IB4(+)) and IB4-negative (IB4(−)) nociceptors, in acute and chronic inflammatory and ergonomic muscle pain. Baseline mechanical nociceptive threshold was assessed in the gastrocnemius muscle of rats treated with IB4-saporin, which selectively destroys IB4(+) nociceptors. Rats were then submitted to models of acute inflammatory (intramuscular carrageenan)- or ergonomic intervention (eccentric exercise or vibration)-induced muscle pain, and each of the three models also evaluated for the transition from acute to chronic pain, manifest as prolongation of prostaglandin E2 (PGE2)-induced hyperalgesia, after recovery from the hyperalgesia induced by acute inflammation or ergonomic interventions. IB4-saporin treatment did not affect baseline mechanical nociceptive threshold. However, compared to controls, IB4-saporin treated rats exhibited shorter duration mechanical hyperalgesia in all three models and attenuated peak hyperalgesia in the ergonomic pain models. And, IB4-saporin treatment completely prevented prolongation of PGE2-induced mechanical hyperalgesia. Thus, IB4(+) and IB4(−) neurons contribute to acute muscle hyperalgesia induced by diverse insults. However, only IB4+ nociceptors participate in the long term consequence of acute hyperalgesia. Finally, using retrograde labelling we found that approximately 70% of sensory neurons innervating the gastrocnemius muscle are IB4(+). PMID:22206923

  8. Evaluation of chronic exposure of the male rat reproductive system to the insecticide methomyl.

    PubMed

    Mahgoub, A A; El-Medany, A H

    2001-08-01

    Carbamate insecticides are widely used in industry, agriculture and for public health purposes. Numerous incidents of acute carbamate poisoning have resulted from inhalation of sprays or contamination of crops or food. This work was conducted to study the effect of chronic exposure to methomyl on hormonal, histopathological and histochemical changes in rat testes. The treated group received methomyl orally (17 mg kg(-1)in saline) daily for 2 months, while the control group received saline. A significant decrease in the level of testosterone was observed in the intoxicated animals, while the levels of FSH, LH and prolactin were significantly increased. Histopathological studies of the intoxicated rat testes revealed variable degrees of degenerative changes in the seminiferous tubules up to total cellular destruction. As regards the histochemical results, it was found that both acid phosphatase and alpha esterase enzyme activity was significantly increased compared to the control group. On the other hand succinic dehydrogenase enzyme activity was significantly reduced. No significant change was observed in alkaline phosphatase enzyme activity. The hormonal changes and testicular damage continued for 30 days after withdrawal of the insecticide indicating a persistent effect. From the above-mentioned findings, it has been concluded that chronic exposure to methomyl insecticide has deleterious effects on rat testes. Therefore application of such insecticide should be limited to a designed program with special care in handling to limit or minimize its hazards.

  9. Environmental enrichment and cafeteria diet attenuate the response to chronic variable stress in rats.

    PubMed

    Zeeni, N; Bassil, M; Fromentin, G; Chaumontet, C; Darcel, N; Tome, D; Daher, C F

    2015-02-01

    Exposure to an enriched environment (EE) or the intake of a highly palatable diet may reduce the response to chronic stress in rodents. To further explore the relationships between EE, dietary intake and stress, male Sprague-Dawley rats were fed one of two diets for 5 weeks: high carbohydrate (HC) or "cafeteria" (CAF) (Standard HC plus a choice of highly palatable cafeteria foods: chocolate, biscuits, and peanut butter). In addition, they were either housed in empty cages or cages with EE. After the first two weeks, half of the animals from each group were stressed daily using a chronic variable stress (CVS) paradigm, while the other half were kept undisturbed. Rats were sacrificed at the end of the 5-week period. The effects of stress, enrichment and dietary intake on animal adiposity, serum lipids, and stress hormones were analyzed. Results showed an increase in intra-abdominal fat associated with the CAF diet and an increase in body weight gain associated with both the CAF diet and EE. Furthermore, the increase in ACTH associated with CVS was attenuated in the presence of EE and the CAF diet independently while the stress-induced increase in corticosterone was reduced by the combination of EE and CAF feeding. The present study provides evidence that the availability of a positive environment combined to a highly palatable diet increases resilience to the effects of CVS in rats. These results highlight the important place of palatable food and supportive environments in reducing central stress responses.

  10. Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction.

    PubMed Central

    Neubauer, S; Horn, M; Naumann, A; Tian, R; Hu, K; Laser, M; Friedrich, J; Gaudron, P; Schnackerz, K; Ingwall, J S

    1995-01-01

    The purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. Hearts were isolated 8 wk later and buffer-perfused isovolumically. MI hearts showed reduced left ventricular developed pressure, but oxygen consumption was unchanged. High-energy phosphate contents were measured chemically and by 31P-NMR spectroscopy. In residual intact left ventricular tissue, ATP was unchanged after MI, while creatine phosphate was reduced by 31%. Total creatine kinase (CK) activity was reduced by 17%, the fetal CK isoenzymes BB and MB increased, while the "adult" mitochondrial CK isoenzyme activity decreased by 44%. Total creatine content decreased by 35%. Phosphoryl exchange between ATP and creatine phosphate, measured by 31P-NMR magnetization transfer, fell by 50% in MI hearts. Thus, energy reserve is substantially impaired in residual intact myocardium of chronically infarcted rats. Because phosphoryl exchange was still five times higher than ATP synthesis rates calculated from oxygen consumption, phosphoryl transfer via CK may not limit baseline contractile performance 2 mo after MI. In contrast, when MI hearts were subjected to acute stress (hypoxia), mechanical recovery during reoxygenation was impaired, suggesting that reduced energy reserve contributes to increased susceptibility of MI hearts to acute metabolic stress. PMID:7883957

  11. Astroglial and cognitive effects of chronic cerebral hypoperfusion in the rat.

    PubMed

    Vicente, Evelin; Degerone, Daniel; Bohn, Liana; Scornavaca, Francisco; Pimentel, Alexandre; Leite, Marina C; Swarowsky, Alessandra; Rodrigues, Letícia; Nardin, Patrícia; de Almeida, Lucia Maria Vieira; Gottfried, Carmem; Souza, Diogo Onofre; Netto, Carlos Alexandre; Gonçalves, Carlos Alberto

    2009-01-28

    The permanent occlusion of common carotid arteries (2VO) causes a significant reduction of cerebral blood flow (hypoperfusion) in rats and constitutes a well established experimental model to investigate neuronal damage and cognitive impairment that occurs in human ageing and Alzheimer's disease. In the present study, we evaluated two astroglial proteins--S100B and glial fibrillary acidic protein (GFAP)--in cerebral cortex and hippocampus tissue, glutamate uptake and glutamine synthetase activity in hippocampus tissue, as well as S100B in cerebrospinal fluid. Cognition, as assessed by reference and working spatial memory protocols, was also investigated. Adult male Wistar rats were submitted to 10 weeks of chronic cerebral hypoperfusion by the 2VO method. A significant increase of S100B and GFAP in hippocampus tissue was observed, as well a significant decrease in glutamate uptake. Interestingly, we observed a decrease in S100B in cerebrospinal fluid. As for the cognitive outcome, there was an impairment of both reference and working spatial memory in the water maze; positive correlation between cognitive impairment and glutamate uptake decrease was evidenced in hypoperfused rats. These data support the hypothesis that astrocytes play a crucial role in the mechanisms of experimental neurodegeneration and that hippocampal pathology arising after chronic hypoperfusion gives rise to memory deficits.

  12. Effect of chronic carbon monoxide exposure on experimental alcoholic liver injury in rats

    SciTech Connect

    Nanji, A.A. ); Jui, L.T.; French, S.W. )

    1989-01-01

    Two groups of experimental animals with pair-fed controls were studied to evaluate the effect of chronic carbon monoxide (CO) exposure on progression of experimental alcoholic liver injury. Eight pairs of male Wistar rats were continuously infused liquid diet and ethanol or isocaloric dextrose for four months. Four pairs were also exposed to CO. Liver damage was followed monthly by serum ALT and morphologic assessment of liver biopsy. Serum levels of ALT were significantly higher in the CO-ethanol group compared to other groups. Electron microscopy revealed a greater degree of cell necrosis in the CO exposed group which explained the significantly higher ALT activity in these animals. Both experimental groups had significantly greater liver damage than controls. Carboxyhemoglobin levels were not different in the ethanol-fed and control group. Our results show that chronic CO exposure enhances liver cell necrosis in ethanol-fed rats thereby lending support to the hypothesis that ethanol and hypoxia enhance cellular disruption in the liver which could be important in the pathogenesis of alcoholic liver disease in rats.

  13. Sensitization and cross-sensitization after chronic treatment with methylphenidate in adolescent Wistar rats.

    PubMed

    Valvassori, Samira S; Frey, Benício N; Martins, Márcio R; Réus, Gislaine Z; Schimidtz, Filipe; Inácio, Cecília G; Kapczinski, Flávio; Quevedo, João

    2007-05-01

    An increasing debate exists about the potential of early exposure to methylphenidate to increase the risk for drug abuse. In addition, little is known about the neurobiological effects of early exposure to methylphenidate. This study was designed to investigate whether chronic treatment with methylphenidate induces behavioral sensitization to subsequent methylphenidate and D-amphetamine challenge in adolescent Wistar rats. Young Wistar rats (P25) were treated with either methylphenidate (1, 2, or 10 mg/kg, intraperitoneally) or saline for 28 days. After 14 days of washout, animals were challenged with methylphenidate 2.5 mg/kg intraperitoneally or D-amphetamine 2 mg/kg intraperitoneally (P67). Locomotor behavior was assessed using the open field test. Rats chronically treated with methylphenidate in the adolescent period showed augmented locomotor sensitization to D-amphetamine but not to methylphenidate in the adult phase. These findings suggest that early exposure do methylphenidate might increase the risk for subsequent D-amphetamine abuse. Further studies focusing on the neurobiological effects of early exposure to methylphenidate are warranted.

  14. Urinary concentrating mechanism and Aquaporin-2 abundance in rats chronically treated with aluminum lactate.

    PubMed

    Mahieu, Stella; Millen, Néstor; Contini, María del Carmen; Gonzalez, Marcela; Molinas, Sara M; Elías, María Mónica

    2006-06-15

    The aim of this work was to study the effects of chronic administration of aluminum (Al) on the urinary concentrating and diluting mechanisms in the distal tubules and collecting ducts. Male Wistar rats were chronically treated with aluminum lactate for 12 weeks (0.575 mg Al/100g of body weight, i.p., three times per week). After 12 weeks, renal function of control and Al-treated rats was evaluated by clearance techniques. To study urinary concentrating mechanisms, renal function was also measured in control and Al-treated rats deprived of water, after the administration of desmopressin (vasopressin agonist) and after the infusion of hypertonic saline at increasing infusion rates. Sodium and water balance were impaired. We found decreased urinary concentrating ability in situations in which endogenous (thirst or infusion of hypertonic saline) or exogenous plasma antidiuretic hormone was increased. Solute-free water formation, measured during the infusion of hypotonic saline showed normal transport in the thick ascending limb. Aquaporin-2 (AQP2) expression was measured by Western blot to evaluate water permeability in collecting ducts. We found that Al produced downregulation of AQP2 in plasma membranes and intracellular vesicles, that could account for the impaired water handling. Administration of desmopressin increased AQP2 in plasma membranes, suggesting that Al did not impair trafficking of this protein, but could interfere with AQP2 synthesis.

  15. Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat.

    PubMed

    Zhang, Yang; Gu, Fenghua; Chen, Jia; Dong, Wenxin

    2010-12-17

    Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, regulates the expression of brain-derived neurotrophic factor (BDNF) in the brain, and mediates mood. Antidepressants alleviate stress and up-regulate BDNF gene expression. In this study, we investigated the effect of chronic unpredictable mild stress (CUMS) and the different kinds of antidepressant treatments on the HPA axis and the BDNF expression in the rat brain. Adult Wistar male rats were exposed to a six-week CUMS procedure and received different antidepressant treatments including venlafaxine, mirtazapine, and fluoxetine. Immunohistochemistry and real-time PCR were used to measure BDNF expression levels in the rat brain, and ELISAs were used to investigate the plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels. CUMS significantly decreased the BDNF protein level in the DG, CA1, and CA3 of the hippocampus and increased plasma CORT level. Chronic antidepressant treatments all significantly increased BDNF protein levels in the hippocampus and the pre-frontal cortex. In addition, venlafaxine and mirtazapine inhibited the increase of plasma CORT level. These results suggested that an increase in the BDNF level in the brain could be a pivotal mechanism of various antidepressants to exert their therapeutic effects.

  16. Sex Differences in the Physiological and Behavioral Effects of Chronic Oral Methylphenidate Treatment in Rats

    PubMed Central

    Robison, Lisa S.; Michaelos, Michalis; Gandhi, Jason; Fricke, Dennis; Miao, Erick; Lam, Chiu-Yim; Mauceri, Anthony; Vitale, Melissa; Lee, Junho; Paeng, Soyeh; Komatsu, David E.; Hadjiargyrou, Michael; Thanos, Panayotis K.

    2017-01-01

    Methylphenidate (MP) is a psychostimulant prescribed for Attention Deficit Hyperactivity Disorder. Previously, we developed a dual bottle 8-h-limited-access-drinking-paradigm for oral MP treatment of rats that mimics the pharmacokinetic profile of treated patients. This study assessed sex differences in response to this treatment. Male and female Sprague Dawley rats were assigned to one of three treatment groups at 4 weeks of age (n = 12/group): Control (water), low dose (LD) MP, and high dose (HD) MP. Rats drank 4 mg/kg MP (LD) or 30 mg/kg MP (HD) during the first hour, and 10 mg/kg (LD) or 60 mg/kg MP (HD) for the remaining 7 h each day. Throughout 3 months of treatment, rats were monitored for body weight, food intake, and fluid intake; as well as tested for open field behavior, circadian activity, novel object recognition, and social interaction. Chronic MP treated rats exhibited reduced fluid intake during distinct treatment weeks to a greater extent in males, and reduced total fluid intake in males only. HD MP treatment decreased body weight in both sexes, while HD MP increased total food intake in females only, likely to offset energy deficits resulting from MP-induced hyperactivity. LD and HD MP increased locomotor activity in the open field, particularly in females and during later treatment weeks. MP dose-dependently increased activity during the dark cycle of circadian testing in females, while in males hyperactivity was only exhibited by HD rats. HD MP increased center activity to a greater extent in males, while MP increased rearing behavior in females only. MP had no effect on social behavior or novel object recognition in either sex. This study concludes that chronic oral MP treatment at clinically-relevant dosages has significant effects on food intake, body weight, open field behavior, and wake cycle activity. Particularly marked sex differences were apparent for locomotor activity, with females being significantly more sensitive to the

  17. Investigation of redox status in chronic cerebral hypoperfusion-induced neurodegeneration in rats

    PubMed Central

    Saxena, Anil Kumar; Abdul-Majeed, Saif Saad; Gurtu, Sunil; Mohamed, Wael M.Y.

    2015-01-01

    Aging related reduction in cerebral blood flow (CBF) has been linked with neurodegenerative disorders including Alzheimer's disease and dementia. Experimentally, a condition of chronic cerebral hypoperfusion due to reduced CBF can be induced by permanent bilateral occlusion of common carotid arteries (2-vessel occlusion, 2VO) in rats. Since oxidative stress, leading to neuronal apoptosis and death, is one of the mechanisms, which is thought to play a significant role in chronic degenerative neurological disorders, the present study was planned to assess the ROS status by measuring the levels of anti-oxidant enzymes that might occur during chronic cerebral hypoperfusion. Antioxidant enzymes namely glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase were measured in the brain tissue at eight weeks of 2VO induction in rats. Results show significantly elevated levels of GPx, SOD, and catalase enzymes as compared with the control group. It is possible that compensatory rise in antioxidant enzymes occurs in response to increased oxidative stress following ischemic insult. PMID:26937356

  18. [Chronic renal insufficiency and secondary hyperparathyroidism in rats. Biochemical and histological evaluation].

    PubMed

    Virgós, M J; Menéndez-Rodríguez, P; Serrano, M; González-Carcedo, A; Braga, S; Cannata, J B

    1993-12-01

    Chronic renal failure (CRF) in rats (surgical nephrectomy, 5/6) as well as its derived bone lesions have been studied. Eighty-five male Wistar rats were used, to which chronic renal failure was induced in 1 or 2 surgical times, the parameters of renal function in basal conditions and at different times after surgery being determined. With the method used chronic renal failure is induced with values of creatinine clearance 2/3 times lower than the initial ones (p < 0.05), which stabilize at the 7th week. On the other hand the parathyroid hormone levels (PTH) in serum triple (from 125 +/- 49 to 395 +/- 191, p < 0.05), and a decrease in the tubular phosphate reabsorption is produced (p < 0.001). In bone histology an increase in resorption and bone formation is observed as well as paratrabecular fibrosis, all of which is compatible with the histological diagnosis of hyperparathyroidism. The model of surgical renal insufficiency with ablation of 5/6 of the renal mass, reduces renal function to 1/3 of the initial values after 7 weeks, this procedure having a 20% global mortality without differences being observed between the carrying out of nephrectomies in 1 or 2 surgical times. This degree of CRF was accompanied by secondary hyperparathyroidism both at the biochemical and histological levels, findings which are of great usefulness for future experimental studies.

  19. [COMPOSITION OF GASTRIC JUICE AND BILE IN RATS AT THE EXPERIMENTAL CHRONIC PANCREATITIS].

    PubMed

    Gorenko, Z A; Grinchenko, O A; Veselsky, S P; Baban, V M

    2015-01-01

    Chronic pancreatitis is an inflammatory disease of the pancreas, which is characterized by destruction of pancreatic secretory parenchyma and progressing exocrine and endocrine insufficiency. Usually these patients have complications as cardiovascular, renal, respiratory and liver failure, and various gastric dysfunctions. The data of clinical observations do not reveal fully the functional state of the stomach and liver in chronic pancreatitis also remains an open question about the quality of the gastric juices and bile by this pathology. Therefore our aim was to investigate the secretory functions of the stomach and liver features in rats at the experimental chronic pancreatitis. This pathology modeled using L-arginine. Basal gastric secretion was investigated in chronic experiment by aspiration method for 10th and 63rd days, and pancreas and liver--in acute experiments at 13th and 68th days after the last administration of L-arginine. It was established that the character of the secretory response of the digestive tract depends on the duration of the pathology course. On the 10th day the functional state of the gastric secretory glands in rats with chronic pancreatitis characterized by twice increase of gastric acid production but decrease the level of hexosamines on 23.8% (P < 0.001) that indicate a increase of gastric content aggressiveness and mucus producing cells secretory insufficiency. In these animals the rate of total protein decreased on 61.7% (P < 0.05). On the 13th day observed the increase of pancreatic juice on 332% (P < 0.01), hepatic secret volume on 74.9% (P < 0.001) and redistribution in the cholates spectrum: glycocholates level increased but tauro-, free and total dehydroxylated bile acids decreased. These changes suggest deterioration of bile detergent properties, inhibition of acidic pathway of bile acids biosynthesis and conjugation of cholates with taurine. In two months total deficit of amino acids in gastric juice correlated with

  20. Blackberry pigment (whitlockite) gallstones in uremic patient.

    PubMed

    Cariati, Andrea

    2013-04-01

    Black pigment gallstones represent nearly the 15% of all gallstones and are usually related with the typical "hyperbilirubinbilia" factors as hemolysis, ineffective erythropoiesis, pathologic enterohepatic cycling of unconjugated bilirubin, cirrhosis and with gallbladder mucosa (parietal) factors as adenomyomatosis. During a prospective study on 179 patients who underwent cholecystectomy for gallstone disease a 69-year-old female with predialysis chronic kidney disease was operated for symptomatic gallstone. The removed gallstones were black pigment gallstones, with an irregular (as small blackberry) surface. Analysis of the stones revealed a great amount of whitlockite (Ca Mg)3 (PO4)2. Recent studies on chronic renal failure patients found that chronic uremia is associated with an increased risk of gallstones formation (22%) as it seems in women affected by primary hyperparathyroidism (30%). The presence of calcium phosphate gallstones in these patients have been never described. In conclusion, further studies could be necessary to establish the role of chronic renal failure and of primary and secondary hyperparathyroidism in gallstones formation and, in particular, if dialysis and predialysis patients have an higher risk to develop cholesterol and black pigment gallstones in particular of the "blackberry" (whitlockite) subtype.

  1. Acquisition of nicotine discrimination and discriminative stimulus effects of nicotine in rats chronically exposed to caffeine.

    PubMed

    Gasior, M; Shoaib, M; Yasar, S; Jaszyna, M; Goldberg, S R

    1999-03-01

    Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, with a high frequency of concurrent use in humans. This study examined the effects of chronic caffeine exposure on 1) rates of acquisition of a nicotine discrimination (0.1 or 0.4 mg/kg, s.c., training doses) and 2) the pharmacological characteristics of the established nicotine discrimination in male Sprague-Dawley rats. Once rats learned to lever-press reliably under a fixed ratio of 10 schedule for food pellets, they were randomly divided into two groups; 12 animals were maintained continuously on caffeine added to the drinking water (3 mg/ml) and another 12 control rats continued to drink tap water. In each group of water- and caffeine-drinking rats, there were six rats trained to discriminate 0.1 mg/kg of nicotine from saline and six rats trained to discriminate 0.4 mg/kg of nicotine from saline. Regardless of the training dose of nicotine, both water- and caffeine-drinking groups required a comparable number of training sessions to attain reliable stimulus control, although there was a trend for a slower acquisition in the caffeine-drinking group trained with 0.1 mg/kg of nicotine. Tests for generalization to different doses of nicotine revealed no significant differences in potency of nicotine between water- and caffeine-drinking groups. The nicotinic-receptor antagonist mecamylamine blocked the discriminative effects of 0.1 and 0.4 mg/kg nicotine with comparable potency and efficacy in water- and caffeine-drinking groups. There was a dose-related generalization to both the 0.1 and 0.4 mg/kg nicotine cue (maximum average of 51-83%) in water-drinking rats after i.p. treatment with d-amphetamine, cocaine, the selective dopamine uptake inhibitor GBR-12909, apomorphine, and the selective dopamine D1 receptor agonist SKF-82958, but not in caffeine-drinking rats (0-22%). There was no generalization to the nicotine cues after i.p. treatment with caffeine or the selective D2 (NPA) and

  2. Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats.

    PubMed

    Ghiassy, Bentolhoda; Rahimi, Nastaran; Javadi-Paydar, Mehrak; Gharedaghi, Mohammad Hadi; Norouzi-Javidan, Abbas; Dehpour, Ahmad R

    2017-01-01

    Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.

  3. Possible cause for altered spatial cognition of prepubescent rats exposed to chronic radiofrequency electromagnetic radiation.

    PubMed

    Narayanan, Sareesh Naduvil; Kumar, Raju Suresh; Karun, Kalesh M; Nayak, Satheesha B; Bhat, P Gopalakrishna

    2015-10-01

    The effects of chronic and repeated radiofrequency electromagnetic radiation (RFEMR) exposure on spatial cognition and hippocampal architecture were investigated in prepubescent rats. Four weeks old male Wistar rats were exposed to RF-EMR (900 MHz; SAR-1.15 W/kg with peak power density of 146.60 μW/cm(2)) for 1 h/day, for 28 days. Followed by this, spatial cognition was evaluated by Morris water maze test. To evaluate the hippocampal morphology; H&E staining, cresyl violet staining, and Golgi-Cox staining were performed on hippocampal sections. CA3 pyramidal neuron morphology and surviving neuron count (in CA3 region) were studied using H&E and cresyl violet stained sections. Dendritic arborization pattern of CA3 pyramidal neuron was investigated by concentric circle method. Progressive learning abilities were found to be decreased in RF-EMR exposed rats. Memory retention test performed 24 h after the last training revealed minor spatial memory deficit in RF-EMR exposed group. However, RF-EMR exposed rats exhibited poor spatial memory retention when tested 48 h after the final trial. Hirano bodies and Granulovacuolar bodies were absent in the CA3 pyramidal neurons of different groups studied. Nevertheless, RF-EMR exposure affected the viable cell count in dorsal hippocampal CA3 region. RF-EMR exposure influenced dendritic arborization pattern of both apical and basal dendritic trees in RF-EMR exposed rats. Structural changes found in the hippocampus of RF-EMR exposed rats could be one of the possible reasons for altered cognition.

  4. Abnormal DNA methylation in the lumbar spinal cord following chronic constriction injury in rats.

    PubMed

    Wang, Ying; Lin, Zhi-Ping; Zheng, Hui-Zhe; Zhang, Shuang; Zhang, Zong-Luan; Chen, Yan; You, Yi-Sheng; Yang, Ming-Hua

    2016-01-01

    Pathogenesis of neuropathic pain is complex and not clearly understood. Glutamate decarboxylase 67 (GAD 67) is a key synthetic enzyme for the main inhibitory transmitter gamma-aminobutyric acid (GABA), and diminishes in the spinal dorsal horn in rats following chronic constriction injury (CCI). GAD 67 is coded by gene GAD 1. DNA methylation can regulate the expression of GAD 67 by regulating the methylation of GAD 1 promoter in the psychotic brain. DNA methylation is primarily mediated by DNA methyltransferases (DNMTs) and methyl-DNA binding domain proteins (MBDs). In this study, in order to discover whether DNA methylation regulates GAD 67 expression in the spinal cord in CCI rats and is involved in neuropathic pain, we examined mRNA levels of DNMTs, MBDs and GAD 67 with real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), and methylation of GAD 1 promoter with Pyromark CpG Assays in the lumbar spinal cord in CCI rats on day 14 after surgery. Our results showed that DNMT3a, DNMT3b and methyl-CpG binding protein 2 (MeCP2) expression increased, MBD2 expression decreased, and DNMT1, MBD1 and MBD3 expression hardly changed in the lumbar spinal cord in CCI rats on day 14 after surgery. GAD 67 expression decreased, and methylation of GAD 1 promoter increased in the lumbar spinal cord in CCI rats on day 14 after surgery. These results indicate that decreased GAD 67 may be associated with increased GAD 1 promoter methylation, which may be mediated by DNMT3a, DNMT3b, MeCP2 and MBD2 in CCI rats. These indicate that abnormal DNA methylation may be highly involved in CCI-induced neuropathic pain.

  5. Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats

    SciTech Connect

    Minor, Robin K.; Smith, Daniel L.; Sossong, Alex M.; Kaushik, Susmita; Poosala, Suresh; Spangler, Edward L.; Roth, George S.; Lane, Mark; Allison, David B.; Cabo, Rafael de; Ingram, Donald K.; Mattison, Julie A.

    2010-03-15

    Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway rats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound.

  6. Therapy effect of antiulcer agents on new chronic cysteamine colon lesion in rat.

    PubMed

    Sikiric, P; Seiwerth, S; Aralica, G; Perovic, D; Staresinic, M; Anic, T; Gjurasin, M; Prkacin, I; Separovic, J; Stancic-Rokotov, D; Lovric-Bencic, M; Mikus, D; Turkovic, B; Rotkvic, I; Mise, S; Rucman, R; Petek, M; Ziger, T; Sebecic, B; Ivasovic, Z; Jagic, V; Komericki, L; Balen, I; Boban-Blagaic, A; Sjekavica, I

    2001-01-01

    After demonstration that cysteamine induced duodenal lesions in gastrectomized rats, while a number of antiulcer drugs mitigated these lesions, it was shown that one single intrarectal (i.r.) cysteamine application produced severe colon lesions in acute studies in rats. Thus, the further focus was on the protracted effect of cysteamine challenge (400 mg/kg b.w. i.r.) and therapy influence in chronic experiments in female rats. Regularly, cysteamine colon lesions were markedly mitigated by ranitidine (10), omeprazole (10), atropine (10), methylprednisolone (1), sulphasalazine (50; mg/kg), pentadecapeptide BPC 157 (PL-10, PLD-116; 10 microg or 10 ng/kg). Specifically, after 1 or 3 months following initial challenge (cysteamine 400 mg/kg i.r.) in female rat, the therapy [BPC 157 (PL-10, PLD-116 (10.0 microg or 10.0 ng/kg; i.g., i.p., i.r.), ranitidine, omeprazole, atropine, methylprednisolone, sulphasalazine (i.p.)] reversed the protracted cysteamine colon injury: the 1 week-regimen (once daily application) started after 1 month post-cysteamine, as well as the 2 weeks-regimen (once daily application), which started after 3 months. The effect on recidive lesion was also tested. These cysteamine lesions may reappear after stopping therapy (after stopping therapy for 3 weeks at the end of 2-weeks regimen started in 3 months-cysteamine female rats) in sulphasalazine group, while this reappearance is markedly antagonized in pentadecapeptide BPC 157 (PL-10, PLD-116)-rats (cysteamine-colon lesion still substantially low).

  7. Chronic intermittent hypoxia promotes expression of 3-mercaptopyruvate sulfurtransferase in adult rat medulla oblongata.

    PubMed

    Li, Mingqiang; Nie, Lihong; Hu, Yajie; Yan, Xiang; Xue, Lian; Chen, Li; Zhou, Hua; Zheng, Yu

    2013-12-01

    The present experiments were carried out to investigate the expression of 3-mercaptopyruvate sulfurtransferase (3MST) in medulla oblongata of rats and effects of chronic intermittent hypoxia (CIH) on its expression. Sprague Dawley adult rats were randomly divided into two groups, including control (Con) group and CIH group. The endogenous production of hydrogen sulfide (H2S) in medulla oblongata tissue homogenates was measured using the methylene blue assay method, 3MST mRNA and protein expression were analyzed by RT-PCR and Western blotting, respectively, and the expression of 3MST in the neurons of respiratory-related nuclei in medulla oblongata of rats was investigated with immunohistochemical technique. CIH elevated the endogenous H2S production in rat medulla oblongata (P<0.01). The RT-PCR and Western blotting analyses showed that 3MST mRNA and protein were expressed in the medulla oblongata of rats and CIH promoted their expression (P<0.01). Immunohistochemical staining indicated that 3MST existed in the neurons of pre-Bötzinger complex (pre-BötC), hypoglossal nucleus (12N), ambiguous nucleus (Amb), facial nucleus (FN) and nucleus tractus solitarius (NTS) in the animals and the mean optical densities of 3MST-positive neurons in the pre-BötC, 12N and Amb, but not in FN and NTS, were significantly increased in CIH group (P<0.05). In conclusion, 3MST exists in the neurons of medullary respiratory nuclei and its expression can be up-regulated by CIH in adult rat, suggesting that 3MST-H2S pathway may be involved in regulation of respiration and protection on medullary respiratory centers from injury induced by CIH.

  8. Food deprivation does not potentiate glucose taste reactivity responses of chronic decerebrate rats.

    PubMed

    Kaplan, J M; Roitman, M; Grill, H J

    2000-07-07

    The chronic supracollicular decerebrate (CD) rat fails to increase meal size in response to systemic/metabolic aspects of food deprivation. Here we asked whether or not deprivation increases immediate oral motor responding to taste stimuli (taste reactivity) in CD rats, as it does in neurologically intact controls. The responses of CD rats were evaluated as functions of glucose concentration and deprivation state, with taste reactivity responses recorded myographically during 15-s intraoral infusions and during 45-s post-infusion periods. Five glucose concentrations (0, 3.2, 6. 25, 12.5, 25%) were each presented three times during each test session. The rats were tested when not-deprived (i.e. receiving their full complement of gavage feedings), deprived (23.5 h) of food and water, and deprived of food but not water. The number of oral motor responses emitted increased monotonically with stimulus concentration; during oral infusions the increase was greatest over the lower half of the concentration range, whereas responding increased linearly with concentration in the post-infusion period. This CD response profile resembled that obtained previously with neurologically intact rats tested according to the same protocols. In contrast to results obtained in intact rats, deprivation did not influence the CD's response to glucose at any concentration or for any observation period. Although the caudal brainstem may receive and process information associated with deprivation state, neural interactions between forebrain and brainstem structures appear necessary for the behavioral expression of deprivation effects on meal size or, as we can now conclude, on immediate oral motor responses to taste stimuli.

  9. Regression of Fibrosis after Chronic Stimulation of Cannabinoid CB2 Receptor in Cirrhotic Rats

    PubMed Central

    Muñoz-Luque, Javier; Ros, Josefa; Fernández-Varo, Guillermo; Tugues, Sònia; Morales-Ruiz, Manuel; Alvarez, Carlos E.; Friedman, Scott L.; Arroyo, Vicente; Jiménez, Wladimiro

    2010-01-01

    Two cannabinoid (CB) receptor subtypes, CB1 and CB2, have been cloned and characterized. Among other activities, receptor activation by cannabinoid ligands may result in pro- or antifibrogenic effects depending on their interaction with CB1 or CB2, respectively. In the current study, we investigated whether selective activation of hepatic CB2 modifies collagen abundance in cirrhotic rats with ascites. mRNA and protein expression of CB receptors in the liver of control and cirrhotic rats was assessed by reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry. The effect of chronically activating the CB2 receptor was investigated in cirrhotic rats with ascites treated daily (9 days) with the CB2 receptor-selective agonist 3-(1,1-dimethylbutyl)-1-deoxy-Δ8-tetrahydrocannabinol (JWH-133). At the end of treatment, mean arterial pressure and portal pressure were measured, and liver samples were obtained to evaluate infiltrate of mononuclear cells, hepatic apoptosis, α-smooth muscle actin (SMA) expression, collagen content, and matrix metalloproteinase (MMP)-2 abundance in all animals. JWH-133 improved arterial pressure, decreased the inflammatory infiltrate, reduced the number of activated stellate cells, increased apoptosis in nonparenchymal cells located in the margin of the septa, and decreased fibrosis compared with cirrhotic rats treated with vehicle. This was associated with decreased α-SMA and collagen I and increased MMP-2 in the hepatic tissue of cirrhotic rats treated with the CB2 agonist compared with untreated cirrhotic animals. Therefore, selective activation of hepatic CB2 receptors significantly reduces hepatic collagen content in rats with pre-existing cirrhosis, thus raising the possibility of using selective CB2 agonists for the treatment of hepatic fibrosis in human cirrhosis. PMID:18029545

  10. Chronic Alcohol Intoxication Is Not Accompanied by an Increase in Calpain Proteolytic Activity in Cardiac Muscle of Rats.

    PubMed

    Gritsyna, Yu V; Salmov, N N; Bobylev, A G; Fadeeva, I S; Fesenko, N I; Sadikova, D G; Kukushkin, N I; Podlubnaya, Z A; Vikhlyantsev, I M

    2017-02-01

    Enzymatic activity of Ca2+-dependent calpain proteases as well as the content and gene expression of μ-calpain (activated by micromolar calcium ion concentrations), calpastatin (inhibitor of calpains), and titin (substrate for calpains) were investigated in cardiac muscles of rats subjected to chronic alcoholization for 3 and 6 months. There was no increase in the "heart weight/body weight" parameter indicating development of heart hypertrophy in the alcoholized rats, while a decreasing trend was observed for this parameter in the rats after 6-month modeling of alcoholic cardiomyopathy, which indicated development of atrophic changes in the myocardium. Fluorometric measurements conducted using the Calpain Activity Assay Kit did not reveal any changes in total calpain activity in protein extracts of cardiac muscles of the rats alcoholized for 3 and 6 months. Western blot analysis did not show reliable changes in the contents of μ-calpain and calpastatin, and SDS-PAGE did not reveal any decrease in the titin content in the myocardium of rats after the chronic alcohol intoxication. Autolysis of μ-calpain was also not verified, which could indicate that proteolytic activity of this enzyme in myocardium of chronically alcoholized rats is not enhanced. Using Pro-Q Diamond staining, changes in phosphorylation level of titin were not detected in cardiac muscle of rats after chronic alcoholization during three and six months. A decrease in µ-calpain and calpastatin mRNA content (~1.3-fold, p ≤ 0.01 and ~1.9-fold, p ≤ 0.01, respectively) in the myocardium of rats alcoholized for 3 months and decrease in calpastatin mRNA (~1.4-fold, p ≤ 0.01) in animals alcoholized for 6 months was demonstrated using real-time PCR. These results indicate negative effect of chronic alcohol intoxication on expression of the abovementioned genes.

  11. Critical appraisal of eculizumab for atypical hemolytic uremic syndrome

    PubMed Central

    Palma, Lilian M Pereira; Langman, Craig B

    2016-01-01

    The biology of atypical hemolytic uremic syndrome has been shown to involve inability to limit activation of the alternative complement pathway, with subsequent damage to systemic endothelial beds and the vasculature, resulting in the prototypic findings of a thrombotic microangiopathy. Central to this process is the formation of the terminal membrane attack complex C5b-9. Recently, application of a monoclonal antibody that specifically binds to C5, eculizumab, became available to treat patients with atypical hemolytic uremic syndrome, replacing plasma exchange or infusion as primary therapy. This review focuses on the evidence, based on published clinical trials, case series, and case reports, on the efficacy and safety of this approach. PMID:27110144

  12. Adipose Tissue Deficiency and Chronic Inflammation in Diabetic Goto-Kakizaki Rats

    PubMed Central

    Xue, Bai; Sukumaran, Siddharth; Nie, Jing; Jusko, William J.; DuBois, Debra C.; Almon, Richard R.

    2011-01-01

    Type 2 diabetes (T2DM) is a heterogeneous group of diseases that is progressive and involves multiple tissues. Goto-Kakizaki (GK) rats are a polygenic model with elevated blood glucose, peripheral insulin resistance, a non-obese phenotype, and exhibit many degenerative changes observed in human T2DM. As part of a systems analysis of disease progression in this animal model, this study characterized the contribution of adipose tissue to pathophysiology of the disease. We sacrificed subgroups of GK rats and appropriate controls at 4, 8, 12, 16 and 20 weeks of age and carried out a gene array analysis of white adipose tissue. We expanded our physiological analysis of the animals that accompanied our initial gene array study on the livers from these animals. The expanded analysis included adipose tissue weights, HbA1c, additional hormonal profiles, lipid profiles, differential blood cell counts, and food consumption. HbA1c progressively increased in the GK animals. Altered corticosterone, leptin, and adiponectin profiles were also documented in GK animals. Gene array analysis identified 412 genes that were differentially expressed in adipose tissue of GKs relative to controls. The GK animals exhibited an age-specific failure to accumulate body fat despite their relatively higher calorie consumption which was well supported by the altered expression of genes involved in adipogenesis and lipogenesis in the white adipose tissue of these animals, including Fasn, Acly, Kklf9, and Stat3. Systemic inflammation was reflected by chronically elevated white blood cell counts. Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes. This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose

  13. A modified chronic ocular hypertension rat model for retinal ganglion cell neuroprotection.

    PubMed

    Zhong, Lichun

    2013-09-01

    This study aimed to modify a chronic ocular hypertension (OHT) rat model to screen for potential compounds to protect retinal ganglion cells (RGCs) from responding to increased intraocular pressure (IOP). A total of 266 rats were prepared and randomly grouped according to different time-points, namely, weeks 3, 8, 16, and 24. Rats were sedated and eye examination was performed to score as the corneal damage on a scale of 1 to 4. The OHT rat model was created via the injection of a hypertonic saline solution into the episcleral veins once weekly for two weeks. OHT was identified when the IOP at week 0 was [Symbol: see text] 6 mmHg than that at week -2 for the same eye. Viable RGCs were labeled by injecting 4% FluoroGold. Rats were sacrificed, and the eyes were enucleated and fixed. The fixed retinas were dissected to prepare flat whole-mounts. The viable RGCs were visualized and imaged. The IOP (mean ± SD) was calculated, and data were analyzed by the paired t-test and one-way ANOVA. The OHT model was created in 234 of 266 rats (87.97%), whereas 32 rats (12.03%) were removed from the study because of the absence of IOP elevation (11.28%) and/or corneal damage scores over 4 (0.75%). IOP was elevated by as much as 81.35% for 24 weeks. The average IOP was (16.68 ± 0.98) mmHg in non-OHT eyes (n = 234), but was (27.95 ± 0.97) mmHg in OHTeyes (n = 234). Viable RGCs in the OHT eyes were significantly decreased in a time-dependent manner by 29.41%, 38.24%, 55.32%, and 59.30% at weeks 3, 8, 16, and 24, respectively, as compared to viable RGCs in the non-OHT eyes (P < 0.05). The OHT model was successfully created in 88% of the rats. The IOP in the OHT eyes was elevated by approximately 81% for 24 weeks. The number of viable RGCs was decreased by 59% of the rats in a time-dependent manner. The modified OHT model may provide an effective and reliable method for screening drugs to protect RGCs from glaucoma.

  14. (-)-SCR1693 Protects against Memory Impairment and Hippocampal Damage in a Chronic Cerebral Hypoperfusion Rat Model

    PubMed Central

    Zhu, Xiaoyin; Tian, Jingwei; Sun, Songmei; Dong, Qiuju; Zhang, Fangxi; Zhang, Xiumei

    2016-01-01

    Chronic cerebral hypoperfusion (CCH) is one of the most common causes of vascular dementia (VaD) and is recognised as an etiological factor in the development of Alzheimer’s disease (AD). CCH can induce severe cognitive deficits, as assessed by the water maze task, along with neuronal loss in the hippocampus. However, there are currently no effective, approved pharmacological treatments available for VaD. In the present study, we created a rat model of CCH using bilateral common carotid artery occlusion and found that (-)-SCR1693, a novel compound, prevented rats from developing memory deficits and neuronal damage in the hippocampus by rectifying cholinergic dysfunction and decreasing the accumulation of the phospho-tau protein. These results strongly suggest that (-)-SCR1693 has therapeutic potential for the treatment of CCH-induced VaD. PMID:27349344

  15. Anemia and genotoxicity induced by sub-chronic intragastric treatment of rats with titanium dioxide nanoparticles.

    PubMed

    Grissa, Intissar; Elghoul, Jaber; Ezzi, Lobna; Chakroun, Sana; Kerkeni, Emna; Hassine, Mohsen; El Mir, Lassaad; Mehdi, Meriem; Ben Cheikh, Hassen; Haouas, Zohra

    2015-12-01

    Titanium dioxide nanoparticles (TiO2 NPs) are widely used for their whiteness and opacity. We investigated the hematological effects and genotoxicity of anatase TiO2 NPs following sub-chronic oral gavage treatment. TiO2-NPs were characterized by X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). Wistar rats were treated with anatase TiO2 NPs by intragastric administration for 60 days. Hematological analysis showed a significant decrease in RBC and HCT and a significant increase in MCV, PLT, MPV and WBC at higher doses. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, and hyper-segmented neutrophil nuclei were observed with TiO2 NPs treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow at 100 and 200mg/kg bw; the comet assay showed significant DNA damage at the same doses.

  16. Biodegradable Magnesium (Mg) Implantation Does Not Impose Related Metabolic Disorders in Rats with Chronic Renal Failure

    PubMed Central

    Wang, Jiali; Xu, Jiankun; Liu, Waiching; Li, Yangde; Qin, Ling

    2016-01-01

    Mg and its alloys have been considered as one of the most promising biodegradable medical devices, but it was still unclear whether hypermagnesemia involved health risks would occur in persons with kidney disease due to their deteriorated kidney function for Mg ions excretion from their body. In this study, we established a chronic renal failure (CRF) model in rats induced by adenine administration prior to Mg implantation, aiming to predict if CRF patients are suitable for the use of Mg implants. The results showed that Mg levels in serum, urine, feces and internal organs had no significant changes after Mg implantation for both normal and CRF rats. Biochemical indices detection and histopathological analysis in kidney, liver and heart tissue confirmed that Mg implants did not induce any extra damage in animals even with renal failure. Our study indicates that Mg based orthopaedic medical device may be considered for use in CRF patients without biosafety concerns. PMID:27210744

  17. Morphology of Pyramidal Neurons in the Rat Prefrontal Cortex: Lateralized Dendritic Remodeling by Chronic Stress

    PubMed Central

    Perez-Cruz, Claudia; Müller-Keuker, Jeanine I. H.; Heilbronner, Urs; Fuchs, Eberhard; Flügge, Gabriele

    2007-01-01

    The prefrontal cortex (PFC) plays an important role in the stress response. We filled pyramidal neurons in PFC layer III with neurobiotin and analyzed dendrites in rats submitted to chronic restraint stress and in controls. In the right prelimbic cortex (PL) of controls, apical and distal dendrites were longer than in the left PL. Stress reduced the total length of apical dendrites in right PL and abolished the hemispheric difference. In right infralimbic cortex (IL) of controls, proximal apical dendrites were longer than in left IL, and stress eliminated this hemispheric difference. No hemispheric difference was detected in anterior cingulate cortex (ACx) of controls, but stress reduced apical dendritic length in left ACx. These data demonstrate interhemispheric differences in the morphology of pyramidal neurons in PL and IL of control rats and selective effects of stress on the right hemisphere. In contrast, stress reduced dendritic length in the left ACx. PMID:18253468

  18. Chronic exercise dampens hippocampal glutamate overflow induced by kainic acid in rats.

    PubMed

    Holmes, Philip V; Reiss, Jenny I; Murray, Patrick S; Dishman, Rod K; Spradley, Jessica M

    2015-05-01

    Our laboratory has previously reported that chronic, voluntary exercise diminishes seizure-related behaviors induced by convulsant doses of kainic acid. The present experiments tested the hypothesis that exercise exerts this protective effect through a mechanism involving suppression of glutamate release in the hippocampal formation. Following three weeks of voluntary wheel running or sedentary conditions, rats were injected with 10 mg/kg of kainic acid, and hippocampal glutamate was measured in real time using a telemetric, in vivo voltammetry system. A separate experiment measured electroencephalographic (EEG) activity following kainic acid treatment. Results of the voltammetry experiment revealed that the rise in hippocampal glutamate induced by kainic acid is attenuated in exercising rats compared to sedentary controls, indicating that the exercise-induced protection against seizures involves regulation of hippocampal glutamate release. The findings reveal the potential benefit of regular exercise in the treatment and prevention of seizure disorders and suggest a possible neurobiological mechanism underlying this effect.

  19. Adolescent and adult male spontaneous hyperactive rats (SHR) respond differently to acute and chronic methylphenidate (Ritalin).

    PubMed

    Barron, Elyssa; Yang, Pamela B; Swann, Alan C; Dafny, Nachum

    2009-01-01

    Eight groups of male adolescent and adult spontaneous hyperactive rats (SHR) were used in a dose response (saline, 0.6, 2.5, and 10 mg/kg) experiment of methylphenidate (MPD). Four different locomotor indices were recorded for 2 hours postinjection using a computerized monitoring system. Acutely, the 0.6 mg/kg dose of MPD did not elicit an increase in locomotor activity in either the adolescent or in the adult male SHR. The 2.5 and the 10.0 mg/kg doses increased activity in the adolescent and the adult rats. Chronically, MPD treatment when comparing adolescent and adult gave the following results: the 0.6 mg/kg dose of MPD failed to cause sensitization in the adolescent group but caused sensitization in the adult group, while the 2.5 and 10 mg/kg both caused sensitization in the adolescent and adult groups.

  20. Biodegradable Magnesium (Mg) Implantation Does Not Impose Related Metabolic Disorders in Rats with Chronic Renal Failure

    NASA Astrophysics Data System (ADS)

    Wang, Jiali; Xu, Jiankun; Liu, Waiching; Li, Yangde; Qin, Ling

    2016-05-01

    Mg and its alloys have been considered as one of the most promising biodegradable medical devices, but it was still unclear whether hypermagnesemia involved health risks would occur in persons with kidney disease due to their deteriorated kidney function for Mg ions excretion from their body. In this study, we established a chronic renal failure (CRF) model in rats induced by adenine administration prior to Mg implantation, aiming to predict if CRF patients are suitable for the use of Mg implants. The results showed that Mg levels in serum, urine, feces and internal organs had no significant changes after Mg implantation for both normal and CRF rats. Biochemical indices detection and histopathological analysis in kidney, liver and heart tissue confirmed that Mg implants did not induce any extra damage in animals even with renal failure. Our study indicates that Mg based orthopaedic medical device may be considered for use in CRF patients without biosafety concerns.

  1. Aliskiren Prevents the Toxic Effects of Peritoneal Dialysis Fluids during Chronic Dialysis in Rats

    PubMed Central

    Pérez-Martínez, Juan; Pérez-Martínez, Francisco C.; Carrión, Blanca; Masiá, Jesús; Ortega, Agustín; Simarro, Esther; Nam-Cha, Syong H.; Ceña, Valentín

    2012-01-01

    The benefits of long-term peritoneal dialysis (PD) in patients with end-stage renal failure are short-lived due to structural and functional changes in the peritoneal membrane. In this report, we provide evidence for the in vitro and in vivo participation of the renin-angiotensin-aldosterone system (RAAS) in the signaling pathway leading to peritoneal fibrosis during PD. Exposure to high-glucose PD fluids (PDFs) increases damage and fibrosis markers in both isolated rat peritoneal mesothelial cells and in the peritoneum of rats after chronic dialysis. In both cases, the addition of the RAAS inhibitor aliskiren markedly improved damage and fibrosis markers, and prevented functional modifications in the peritoneal transport, as measured by the peritoneal equilibrium test. These data suggest that inhibition of the RAAS may be a novel way to improve the efficacy of PD by preventing inflammation and fibrosis following peritoneal exposure to high-glucose PDFs. PMID:22558414

  2. Effects of combined exposure of F344 rats to radiation and chronically inhaled cigarette smoke

    SciTech Connect

    Finch, G.L.; Nikula, K.J.; Barr, E.B.

    1995-12-01

    Nuclear workers may be exposed to radiation in various forms, such as low-LET {gamma}-irradiation or {alpha}-irradiation from inhaled {sup 239}PuO{sub 2} particles. These workers may then have increased risk for lung cancer compared to the general population. Of additional concern is the possibility that interactions between radiation and other carcinogens may increase the risk of cancer induction, compared to the risks from either type of agent alone. An important and common lung carcinogen is cigarette smoke. The purpose of this project is to better determine the combined effects of chronically inhaled cigarette smoke and either inhaled {sup 239}PuO{sub 2} or external, thoracic X-irradiation on the induction of lung cancer in rats. Histologic and dosimetric evaluations of rats in the CS + {sup 239}PuO{sub 2} study continue, and the study of CS + X rays is beginning.

  3. Hepcidin as a Biomarker of Impaired Renal Function in Rat Models for Chronic Allograft Nephropathy.

    PubMed

    Xue, Dong; Zhou, Cuixing; Shi, Yunbo; Lu, Hao; He, Xiaozhou

    2016-02-23

    BACKGROUND To explore the use of hepcidin as a marker of impaired renal function in a rat model for chronic allograft nephropathy (CAN). MATERIAL AND METHODS Twenty-four models were developed and 20 models were included in this study, using Fisher (F344) rats (donors) and Lewis rats (recipients). Renal function tests were performed preoperatively and postoperatively. Hepcidin, interleukin-6 (IL-6), and erythropoietin levels in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). To observe pathological changes in the kidneys, 10 rats each were sacrificed at 2 months and 4 months after surgery. RESULTS After transplantation, the serum hepcidin and IL-6 levels increased, while urine hepcidin levels decreased. Erythropoietin levels showed a similar trend; all P<0.05. Serum creatinine (SCr) and blood urea nitrogen significantly increased post-operatively, with SCr positively correlating with serum hepcidin. Serum hepcidin positively correlated with IL-6 and negatively correlated with EPO. Histopathological results were consistent with CAN, after transplantation. CONCLUSIONS Hepcidin may be considered as a potential marker of impaired renal function.

  4. Chronic Toxicity of Aluminium in Rats and Mice and its Effects on Phosphorous Metabolism

    PubMed Central

    Ondreička, R.; Ginter, E.; Kortus, J.

    1966-01-01

    In mice the oral LD50 values of aluminium chloride and aluminium sulphate were 0·77 ± 0·12 and 0·98 ± 0·09 g. Al/kg. (± S.E.) respectively. Mice and rats were fed on a normal diet containing about 170 p.p.m. of aluminium. Doubling this concentration caused a decrease in growth in the second and third generations of mice. A high intake of aluminium sulphate (2,835 p.p.m.) caused a 20-fold increase of aluminium retention in white rats. Aluminium accumulated in various tissues, especially in the skeleton, liver, and testes. A high rate of intake (2,665 p.p.m.) caused a negative phosphorus balance in the rat, with an increased output of phosphorus in the faeces. The lower absorption of phosphorus was also demonstrated with Na2H32PO4. Chronic and acute poisoning by aluminium chloride caused, after intraperitoneal Na2H32PO4, decreased incorporation of 32P into the phospholipids and nucleic acids of various tissues in the rat. It also caused a fall in the adenosinetriphosphate acid-levels in plasma, and a rise in the adenosine diphosphate level. The results suggest that the toxic effects of aluminium salts result both from decreased absorption of phosphorus and from interference with phosphorylation processes in the tissues. PMID:5926895

  5. Effect of diesel exhaust particles on renal vascular responses in rats with chronic kidney disease.

    PubMed

    Al Suleimani, Y M; Al Mahruqi, A S; Al Za'abi, M; Shalaby, A; Ashique, M; Nemmar, A; Ali, B H

    2017-02-01

    Several recent studies have indicated the possible association between exposure to particulate air pollution and the increased rate of morbidity and mortality in patients with kidney diseases. The link of this observation to vascular damage has not been adequately addressed. Therefore, this study aims to investigate possible vascular damage that might be associated with exposure to diesel exhaust particles (DP) in adenine (AD)-induced chronic kidney disease (CKD) in rats, and the possible ameliorative effect of gum acacia (GA). CKD was induced by feeding AD (0.75%, w/w), and DP (0.5 mg/kg) was instilled intratracheally every second day and GA was given concomitantly in the drinking water at a dose of 15% w/v. All treatments were given concomitantly for 28 days. Changes in renal blood flow (RBF) and systolic and diastolic blood pressure were monitored in these animals after anesthesia, together with several other endpoints. Exposure to DP significantly reduced RBF and this was significantly potentiated in AD-treated rats. Phenylephrine-induced decreases in RBF and increases in systolic and diastolic blood pressure were severely potentiated in rats exposed to DP, and these actions were significantly augmented in AD-treated rats. GA did not significantly affect the vascular impairment induced by AD and DP given together. This study provides experimental evidence that exposure to particulate air pollution can exacerbate the vascular damage seen in patients with CKD. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 541-549, 2017.

  6. Hepatic cholesterol metabolism following a chronic ingestion of cesium-137 starting at fetal stage in rats.

    PubMed

    Racine, Radjini; Grandcolas, Line; Blanchardon, Eric; Gourmelon, Patrick; Veyssiere, Georges; Souidi, Maamar

    2010-01-01

    The Chernobyl accident released many radionuclides in the environment. Some are still contaminating the ground and thus the people through dietary intake. The long-term sanitary consequences of this disaster are still unclear and several biological systems remain to be investigated. Cholesterol metabolism is of particular interest, with regard to the link established between atherosclerosis and exposure to high-dose ionizing radiations. This study assesses the effect of cesium-137 on cholesterol metabolism in rats, after a chronic exposure since fetal life. To achieve this, rat dams were contaminated with cesium-137-supplemented water from two weeks before mating until the weaning of the pups. Thereafter, the weaned rats were given direct access to the contaminated drinking water until the age of 9 months. After the sacrifice, cholesterol metabolism was investigated in the liver at gene expression and protein level. The cholesterolemia was preserved, as well as the cholesterol concentration in the liver. At molecular level, the gene expressions of ACAT 2 (a cholesterol storage enzyme), of Apolipoprotein A-I and of RXR (a nuclear receptor involved in cholesterol metabolism) were significantly decreased. In addition, the enzymatic activity of CYP27A1, which catabolizes cholesterol, was increased. The results indicate that the rats seem to adapt to the cesium-137 contamination and display modifications of hepatic cholesterol metabolism only at molecular level and within physiological range.

  7. Chronic consumption of fructose rich soft drinks alters tissue lipids of rats

    PubMed Central

    2010-01-01

    Background Fructose-based diets are apparently related to the occurrence of several metabolic dysfunctions, but the effects of the consumption of high amounts of fructose on body tissues have not been well described. The aim of this study was to analyze the general characteristics and the lipid content of different tissues of rats after chronic ingestion of a fructose rich soft drink. Methods Forty-five Wistar rats were used. The rats were divided into three groups (n = 15) and allowed to consume water (C), light Coca Cola ® (L) or regular Coca Cola® (R) as the sole source of liquids for eight weeks. Results The R group presented significantly higher daily liquid intake and significantly lower food intake than the C and L groups. Moreover, relative to the C and L groups, the R group showed higher triglyceride concentrations in the serum and liver. However, the L group animals presented lower values of serum triglycerides and cholesterol than controls. Conclusions Based on the results, it can be concluded that daily ingestion of a large amount of fructose- rich soft drink resulted in unfavorable alterations to the lipid profile of the rats. PMID:20573247

  8. Chronic Oral Pelargonidin Alleviates Streptozotocin-Induced Diabetic Neuropathic Hyperalgesia in Rat: Involvement of Oxidative Stress

    PubMed Central

    Mirshekar, Mohammadali; Roghani, Mehrdad; Khalili, Mohsen; Baluchnejadmojarad, Tourandokht; Arab Moazzen, Saiedeh

    2010-01-01

    Background: Diabetes mellitus in some clinical cases is accompanied with hyperalgesia. In this study, we evaluated the possible beneficial effect of chronic pelargonidin (PG) treatment on hyperalgesia in streptozotocin (STZ)-diabetic neuropathic rat. Methods: Male Wistar rats (n = 56) were divided into seven groups, i.e. control, diabetic, PG-treated control, PG (single- and multiple-dose)-treated diabetic, and sodium salicylate-treated control and diabetics. For induction of diabetes, STZ was injected i.p. at a single dose of 60 mg/kg. PG was orally administered at a dose of 10 mg/kg once and/or on alternate days for 8 weeks; 1 week after diabetes induction. After two months, hyperalgesia was assessed using standard formalin and hot tail immersion tests. Meanwhile, markers of oxidative stress in brain were measured. One-way analysis of variance was used for statistical analysis of the data. Results: Diabetic rats showed a marked chemical and thermal hyperalgesia, indicating that development of diabetic neuropathy and PG treatment (especially multiple-doses) significantly ameliorated the alteration in hyperalgesia (P<0.05-0.01) in diabetic rats as compared to untreated diabetics. PG (multiple doses) also significantly decreased diabetes-induced thiobarbituric acid reactive substances formation and non-significantly reversed elevation of nitrite level and reduction of antioxidant defensive enzyme superoxide dismutase. Conclusion: These results clearly suggest that PG prevents diabetic neuropathic hyperalgesia through attenuation of oxidative stress. PMID:20683496

  9. Protective effects of chronic mild stress during adolescence in the low-novelty responder rat.

    PubMed

    Rana, Samir; Nam, Hyungwoo; Glover, Matthew E; Akil, Huda; Watson, Stanley J; Clinton, Sarah M; Kerman, Ilan A

    2016-01-01

    Stress-elicited behavioral and physiologic responses vary widely across individuals and depend on a combination of environmental and genetic factors. Adolescence is an important developmental period when neural circuits that guide emotional behavior and stress reactivity are still maturing. A critical question is whether stress exposure elicits contrasting effects when it occurs during adolescence versus adulthood. We previously found that Sprague-Dawley rats selectively bred for low-behavioral response to novelty (bred Low Responders; bLRs) are particularly sensitive to chronic unpredictable mild stress (CMS) exposure in adulthood, which exacerbates their typically high levels of spontaneous depressive- and anxiety-like behavior. Given developmental processes known to occur during adolescence, we sought to determine whether the impact of CMS on bLR rats is equivalent when they are exposed to it during adolescence as compared with adulthood. Young bLR rats were either exposed to CMS or control condition from postnatal days 35-60. As adults, we found that CMS-exposed bLRs maintained high levels of sucrose preference and exhibited increased social exploration along with decreased immobility on the forced swim test compared with bLR controls. These data indicate a protective effect of CMS exposure during adolescence in bLR rats.

  10. Metabolic consequences of chronic sleep restriction in rats: changes in body weight regulation and energy expenditure.

    PubMed

    Barf, R P; Van Dijk, G; Scheurink, A J W; Hoffmann, K; Novati, A; Hulshof, H J; Fuchs, E; Meerlo, P

    2012-10-10

    Epidemiological studies have shown an association between short or disrupted sleep and an increased risk to develop obesity. In animal studies, however, sleep restriction leads to an attenuation of weight gain that cannot be explained by changes in energy intake. In the present study, we assessed whether the attenuated weight gain under conditions of restricted sleep is a consequence of an overall increase in energy expenditure. Adult male rats were subjected to a schedule of chronic sleep restriction (SR) for 8 days with a 4h window of unrestricted rest per day. Electroencephalogram and electromyogram recordings were performed to quantify the effect of the sleep restriction schedule on sleep-wake patterns. In a separate experiment, we measured sleep restriction-induced changes in body weight, food intake, and regulatory hormones such as glucose, insulin, leptin and corticosterone. To investigate whether a change in energy expenditure underlies the attenuation of weight gain, energy expenditure was measured by the doubly labeled water method from day 5 until day 8 of the SR protocol. Results show a clear attenuation of weight gain during sleep restriction but no change in food intake. Baseline plasma glucose, insulin and leptin levels are decreased after sleep restriction which presumably reflects the nutritional status of the rats. The daily energy expenditure during SR was significantly increased compared to control rats. Together, we conclude that the attenuation of body weight gain in sleep restricted rats is explained by an overall increase in energy expenditure together with an unaltered energy intake.

  11. Chronic Fluoride Toxicity and Myocardial Damage: Antioxidant Offered Protection in Second Generation Rats

    PubMed Central

    Basha, Mahaboob P.; Sujitha, N. S.

    2011-01-01

    This experiment was designed to investigate the extent of peroxidative changes and histological alterations in the myocardium of rats exposed to high fluoride for two generations, in addition to ameliorative role of selenium and vitamin E on the above indices. Adult albino Wistar rats were given fluoride through drinking water (200 ppm F) and maintained subsequently for two generations, while they were exposed to fluoride throughout the experiment. Fluoride treatment significantly increased the lipid peroxidation and decreased the activity of antioxidant enzymes, viz., catalase, superoxide dismutase, and glutathione level in auricle and ventricle regions of the heart. Decreased feed and water consumption, organ somatic index and marginal drop in body growth rate were observed. Decreased antioxidant enzymes and increased malondialdehyde levels might be related to oxidative damage that occurs variably in the myocardium of rats. Biochemical changes were supported by the histological observations, which also revealed that chronic exposure to fluoride causes damage to the myocardium. Results of this study can be taken as an index of cardio-toxicity in rats exposed to water fluoridation. Further, oral supplementation of selenium and vitamin E not only inhibited oxidative stress but also enhanced the activities of antioxidant enzymes. Administration of antioxidants during fluoride exposure significantly overcame cardiac fluoride toxicity and therefore may be a therapeutic strategy for fluorotic victims. PMID:21976813

  12. Behavioural effects of chronic manipulations of dietary choline in senescent rats.

    PubMed

    Fundaro, A; Paschero, A

    1990-01-01

    1. Senescent rats were maintained on choline-deficient and choline-enriched diets. The modifications in rat behaviour caused by the chronic manipulations of dietary choline were studied in two schedules of operant conditioning. 2. In the "periodic conditioning" test, the schedule of reinforcement, in a 100 min trial, was changed from a fixed ratio to a fixed interval schedule. In the "reversal" test the contingency for food delivery was switched four times from one lever to the other in a two lever Skinner box. 3. In the "periodic conditioning" test, the choline enriched group (430 mg/Kg/day) showed the same reduction of responses/reinforcement as controls, from the beginning to the end of trial; in the same group the time course reduction of responses/reinforcement became significant earlier than in the control group. The deficient-choline group in the last 40 min of "periodic conditioning" trial gave a reduction of responses/reinforcement greater than controls and one rat in the group did not learn the change of experimental schedule and extinguished its operant behaviour. 4. In the "reversal" test, the choline-enriched diet (320 mg/Kg/day) improved the reinforced responses in the IV reversal; one rat of the deficient-choline group could not learn the new operant schedule since the first reversal and continued to respond on the same lever during the whole of the test.

  13. Beneficial effect of testosterone in the treatment of chronic autoimmune thyroiditis in rats

    SciTech Connect

    Ahmed, S.A.; Young, P.R.; Penhale, W.J.

    1986-01-01

    Early thymectomy and sublethal irradiation of normal rats consistently induces a sex-dependent chronic autoimmune thyroiditis. Females are much more susceptible to this autoimmune disorder than are males. The possible therapeutic effects of testosterone (Te) on established autoimmune thyroiditis has been investigated in this model. The pathologic condition of the gland before treatment was monitored by a thyroid grafting and extirpation techniques. Te administration by either parenteral injection or implantation caused significant regression of established thyroiditis. Repeated doses of Te ester in oil were found to be more effective than powdered free-Te given by implantation, and frequently produced complete resolution of chronic lesions involving the entire gland. In these thyroids, there was reappearance of normal thyroid architecture and complete absence of mononuclear cellular infiltration. However, no inhibitory effect on serum autoantibody production to thyroglobulin was noted with any form of Te treatment. These observations strengthen the concept that cellular rather than humoral mechanisms are involved in the pathogenesis of thyroiditis.

  14. DNA damage after chronic oxytocin administration in rats: a safety yellow light?

    PubMed

    Leffa, Daniela D; Daumann, Francine; Damiani, Adriani P; Afonso, Arlindo C; Santos, Maria A; Pedro, Thayara H; Souza, Renan P; Andrade, Vanessa M

    2017-02-01

    Adjuvant therapy is a common therapeutic strategy used for schizophrenia management. Oxytocin has shown promising results as antipsychotic adjuvant in patients with schizophrenia. Although short-term clinical studies have indicated tolerability and no major side-effect manifestation, long-term studies remain needed. In this study, we investigated whether oxytocin chronic administration in rats may lead to brain DNA damage by comet assay. Our results suggest that 21 and 56-day treatment with once daily intraperitoneal oxytocin (0.1, 1.0 and 10.0 mg/kg) may cause substantial DNA damage in hippocampus. We have not found differences on body weight gain. Our findings also point that further clinical and preclinical studies evaluating oxytocin safety after chronic exposure are necessary.

  15. [Mesenchymal stromal cells transplantation in acute and chronic pancreatitis in rats].

    PubMed

    Lazebnik, L B; Trubitsyna, I E; Agafonov, M A; Kniazev, O V; Liundup, A V

    2011-01-01

    Before using MSC transplantation in the clinic to conduct preclinical studies MSCs to animals with acute and chronic pancreatitis. Work out the timing and dose of MSCs. The rationale of MSCs transplantation for the regeneration of damaged pancreatic tissue. The essence of the experiments is to establish the existence of common pathogenetic mechanisms for the development of pathological processes and sanogenesis toxic damage of pancreatic tissue. The study was work out in the rat model of acute and chronic pancreatitis, to explore beneficial and adverse effects of allogeneic stem cells for regenerative-reduction processes. For cell transplantation using allogenic stromal cell fraction of bone marrow, the cell suspension was injected at a dose of 2 x 10(6) and 5 x 10(6) cells.

  16. Evaluation of depression in rats exposed to chronic (unpredictable) electric shock.

    PubMed

    Naruo, T; Hara, C; Nozoe, S; Tanaka, H; Ogawa, N

    1993-11-01

    The present study was undertaken to evaluate the applicability of a proposed behavioral stress paradigm as an animal model for depression. Rats were trained to press a lever under a fixed ratio (FR) 5 schedule in a Skinner box for 10 days and were subsequently exposed to a daily regimen of 20 cycles of FR 5 and 10 cycles of variable ratio (VR) 10 for about a week. This exposure resulted in a reduction of the number of lever presses and successful escapes compared to the level achieved after training. In addition, weight gain was significantly suppressed compared with other treatments. Acute and chronic administration of psychotropic drugs (imipramine and chlordiazepoxide) showed that treatment with imipramine increased both the number of lever presses and successful escapes while chlordiazepoxide increased only the number of lever presses. The results suggest that this simplified animal model utilizing chronic unpredictable electric shock may be useful in the study of human depression.

  17. Lipoprotein(a) accelerates atherosclerosis in uremic mice[S

    PubMed Central

    Pedersen, Tanja X.; McCormick, Sally P.; Tsimikas, Sotirios; Bro, Susanne; Nielsen, Lars B.

    2010-01-01

    Uremic patients have increased plasma lipoprotein(a) [Lp(a)] levels and elevated risk of cardiovascular disease. Lp(a) is a subfraction of LDL, where apolipoprotein(a) [apo(a)] is disulfide bound to apolipoprotein B-100 (apoB). Lp(a) binds oxidized phospholipids (OxPL), and uremia increases lipoprotein-associated OxPL. Thus, Lp(a) may be particularly atherogenic in a uremic setting. We therefore investigated whether transgenic (Tg) expression of human Lp(a) increases atherosclerosis in uremic mice. Moderate uremia was induced by 5/6 nephrectomy (NX) in Tg mice with expression of human apo(a) (n = 19), human apoB-100 (n = 20), or human apo(a) + human apoB [Lp(a)] (n = 15), and in wild-type (WT) controls (n = 21). The uremic mice received a high-fat diet, and aortic atherosclerosis was examined 35 weeks later. LDL-cholesterol was increased in apoB-Tg and Lp(a)-Tg mice, but it was normal in apo(a)-Tg and WT mice. Uremia did not result in increased plasma apo(a) or Lp(a). Mean atherosclerotic plaque area in the aortic root was increased 1.8-fold in apo(a)-Tg (P = 0.025) and 3.3-fold (P = 0.0001) in Lp(a)-Tg mice compared with WT mice. Plasma OxPL, as detected with the E06 antibody, was associated with both apo(a) and Lp(a). In conclusion, expression of apo(a) or Lp(a) increased uremia-induced atherosclerosis. Binding of OxPL on apo(a) and Lp(a) may contribute to the atherogenicity of Lp(a) in uremia. PMID:20584868

  18. Effect of chronic psychogenic stress on some behavioral and neurochemical characteristics of rats

    SciTech Connect

    Danchev, N.D.; Rozhanets, V.V.; Val'dman, A.V.

    1986-06-01

    This paper studies the behavioral, somatic, and certain neurochemical parameters in rats under conditions of unavoidable chronic stress, according to Hecht et al. in a situation of possible avoidance, with the same total number of aversive stimuli. Specific binding of tritium-flunitrazepam and tritium-dihydroalprenolol was studied. The dissociatin constant and the maximal concentration of ligand-receptor complexes were determined in Scatchard plots by means of an HP-33E computer. The protein concentration in the samples was determined by Peterson's method.

  19. Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption

    PubMed Central

    Bell, Richard L.; Kimpel, Mark W.; McClintick, Jeanette N.; Strother, Wendy N.; Carr, Lucinda G.; Liang, Tiebing; Rodd, Zachary A.; Mayfield, R. Dayne; Edenberg, Howard J.; McBride, William J.

    2009-01-01

    The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-hr dark-cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24 hr/day). A third group was ethanol-naïve (W group). Average ethanol intakes for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hr after the last drinking episode, rats were euthanized, the brains extracted, and the ACB dissected. RNA was extracted and purified for microarray analysis. The only significant differences were between the CA and W groups (p < 0.01; Storey false discovery rate = 0.15); there were 374 differences in named genes between these 2 groups. There were 20 significant Gene Ontology (GO) categories, which included negative regulation of protein kinase activity, anti-apoptosis, and regulation of G-protein-coupled receptor signaling. Ingenuity® analysis indicated a network of transcription factors, involving oncogenes (Fos, Jun, Junb had higher expression in the ACB of the CA group), suggesting increased neuronal activity. There were 43 genes located within rat QTLs for alcohol consumption and preference; 4 of these genes (Tgfa, Hspa5, Mtus1 and Creb3l2) are involved in anti-apoptosis and increased transcription, suggesting that they may be contributing to cellular protection and maintaining high alcohol intakes. Overall, these findings suggest that chronic CA drinking results in genomic changes that can be observed during the early acute phase of ethanol withdrawal. Conversely, chronic MSA drinking, with its associated protracted withdrawal periods, results in genomic changes that may be masked by tight regulation of these genes following repeated experiences of ethanol withdrawal. PMID:19666046

  20. Soymilk products affect ethanol absorption and metabolism in rats during acute and chronic ethanol intake.

    PubMed

    Kano, M; Ishikawa, F; Matsubara, S; Kikuchi-Hayakawa, H; Shimakawa, Y

    2002-02-01

    In this study we evaluated the effects of soy products on ethanol metabolism during periods of acute and chronic consumption in rats. Gastric ethanol content and blood ethanol and acetaldehyde concentrations were investigated after the oral administration of ethanol (34 mmol/kg) plus soy products such as soymilk (SM) or fermented soymilk (FSM). The gastric ethanol concentration of the FSM group was greater than that of the control group, whereas portal and aortal blood ethanol concentrations of the FSM group were lower than in controls. The aortal acetaldehyde concentration in the FSM group was lower than that of the control group. The direct effect of isoflavones on liver function was investigated by using hepatocytes isolated from untreated rats. Genistein (5 micromol/L) decreased ethanol (P = 0.045) and tended to decrease acetaldehyde (P = 0.10) concentrations in the culture filtrate. Some variables of ethanol metabolism in the liver were investigated after chronic ethanol exposure for 25 d. Rats consumed a 5% ethanol fluid plus the SM diet, the FSM diet or a control diet. Microsomal ethanol oxidizing activity was significantly lower in the FSM group than the control group. Furthermore, cytosolic glutathione S-transferase activity was higher in the SM and FSM groups than in the control group. Acetaldehyde dehydrogenase activity (low K(m)) in the FSM group (P = 0.15), but not in the SM group (P = 0.31), tended to be greater than in the control group. The amount of thiobarbituric acid reacting substances in the liver of the SM and FSM groups tended to be less than that of the control group (P = 0.18 and 0.10, respectively). These results demonstrate that soymilk products inhibit ethanol absorption and enhance ethanol metabolism in rats.

  1. Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats

    PubMed Central

    Godfrey, Jessica; Jeanguenin, Lisa; Castro, Norma; Olney, Jeffrey J.; Dudley, Jason; Pipkin, Joseph; Walls, Stanley M.; Wang, Wei; Herr, Deron R.; Harris, Greg L.; Brasser, Susan M.

    2015-01-01

    Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P) rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total) or were given access only to water (control). Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4)-desaturase (Degs2), an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels achieved by

  2. Effects of Anterior Thalamic Nucleus Deep Brain Stimulation in Chronic Epileptic Rats

    PubMed Central

    Amorim, Beatriz; Cavarsan, Clarissa; Miranda, Maisa Ferreira; Aarão, Mayra C.; Madureira, Ana Paula; Rodrigues, Antônio M.; Nobrega, José N.; Mello, Luiz E.; Hamani, Clement

    2014-01-01

    Deep brain stimulation (DBS) has been investigated for the treatment of epilepsy. In rodents, an increase in the latency for the development of seizures and status epilepticus (SE) has been reported in different animal models but the consequences of delivering stimulation to chronic epileptic animals have not been extensively addressed. We study the effects of anterior thalamic nucleus (AN) stimulation at different current intensities in rats rendered epileptic following pilocarpine (Pilo) administration. Four months after Pilo-induced SE, chronic epileptic rats were bilaterally implanted with AN electrodes or had sham-surgery. Stimulation was delivered for 6 h/day, 5 days/week at 130 Hz, 90 µsec. and either 100 µA or 500 µA. The frequency of spontaneous recurrent seizures in animals receiving stimulation was compared to that recorded in the preoperative period and in rats given sham treatment. To investigate the effects of DBS on hippocampal excitability, brain slices from animals receiving AN DBS or sham surgery were studied with electrophysiology. We found that rats treated with AN DBS at 100 µA had a 52% non-significant reduction in the frequency of seizures as compared to sham-treated controls and 61% less seizures than at baseline. Animals given DBS at 500 µA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values. In non-stimulated controls, the average frequency of seizures before and after surgery remained unaltered. In vitro recordings have shown that slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude compared to non-stimulated controls. In contrast, a higher spike amplitude was recorded in slices from animals given AN DBS at 500 µA. PMID:24892420

  3. A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats.

    PubMed

    Neven, Ellen; De Schutter, Tineke M; Dams, Geert; Gundlach, Kristina; Steppan, Sonja; Büchel, Janine; Passlick-Deetjen, Jutta; D'Haese, Patrick C; Behets, Geert J

    2014-01-01

    The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.

  4. Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.

    PubMed

    Bell, Richard L; Kimpel, Mark W; McClintick, Jeanette N; Strother, Wendy N; Carr, Lucinda G; Liang, Tiebing; Rodd, Zachary A; Mayfield, R Dayne; Edenberg, Howard J; McBride, William J

    2009-11-01

    The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-h dark cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24h/day). A third group was ethanol-naïve (W group). Average ethanol intakes for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hours after the last drinking episode, rats were euthanized, the brains extracted, and the ACB dissected. RNA was extracted and purified for microarray analysis. The only significant differences were between the CA and W groups (p<0.01; Storey false discovery rate=0.15); there were 374 differences in named genes between these 2 groups. There were 20 significant Gene Ontology (GO) categories, which included negative regulation of protein kinase activity, anti-apoptosis, and regulation of G-protein coupled receptor signaling. Ingenuity analysis indicated a network of transcription factors, involving oncogenes (Fos, Jun, Junb had higher expression in the ACB of the CA group), suggesting increased neuronal activity. There were 43 genes located within rat QTLs for alcohol consumption and preference; 4 of these genes (Tgfa, Hspa5, Mtus1 and Creb3l2) are involved in anti-apoptosis and increased transcription, suggesting that they may be contributing to cellular protection and maintaining high alcohol intakes. Overall, these findings suggest that chronic CA drinking results in genomic changes that can be observed during the early acute phase of ethanol withdrawal. Conversely, chronic MSA drinking, with its associated protracted withdrawal periods, results in genomic changes that may be masked by tight regulation of these genes following repeated experiences of ethanol withdrawal.

  5. Sub-chronic iron overload triggers oxidative stress development in rat brain: implications for cell protection.

    PubMed

    Piloni, Natacha E; Perazzo, Juan C; Fernandez, Virginia; Videla, Luis A; Puntarulo, Susana

    2016-02-01

    This work was aimed to test the hypothesis that sub-chronic administration of iron-dextran (Fe-dextran) (six doses of 50 mg Fe-dextran/kg) to rats triggers a transient oxidative stress in brain and mechanisms of cellular antioxidant defence. After 2 h of administration of the 6th dose, a significant increase of total Fe, the labile Fe pool (LIP), the lipid radical (LR(•))/α-tocopherol (α-T) content ratio were observed, as compared to values in control brain homogenates. The ascorbyl radical (A(•))/ascorbate (AH(-)) content ratio and the oxidation rate of 2',7'-dichlorodihidrofluorescein (DCFH-DA) were significantly higher in Fe-dextran treated rats, as compared to values in brain from control rats after 4 h treatment. An increase in both catalase (CAT) and superoxide dismutase (SOD) activity was observed at 8 and 1-2 h, respectively. No significant changes were detected in the nuclear factor-κB (NF-κB) levels in nuclear extracts from rat brains after 1-8 h of Fe-dextran administration. After 2 h of Fe administration Fe concentration in cortex, striatum and hippocampus was significantly increased as compared to the same areas from control animals. Both, CAT and SOD activities were significantly increased in cortex after Fe administration over control values, without changes in striatum and hippocampus. Taken as a whole, sub-chronic Fe administration enhances the steady state concentration of Fe in the brain LIP that favors the settlement of an initial oxidative stress condition, both at hydrophilic and lipophilic compartments, resulting in cellular protection evidenced by antioxidant enzyme upregulation.

  6. Protection of chronic intermittent hypobaric hypoxia against collagen-induced arthritis in rat through increasing apoptosis.

    PubMed

    Shi, Min; Cui, Fang; Liu, Ai-Jing; Li, Jiao; Ma, Hui-Juan; Cheng, Ming; Yang, Jing; Zhang, Yi

    2011-04-25

    The aim of present study was to investigate the effect of chronic intermittent hypobaric hypoxia (CIHH) on collagen-induced arthritis (CIA) in rat. Fifty male adult Sprague-Dawley rats were randomly divided into 5 groups: CIHH pre-treatment group (Pre-T), pre-control group (Pre-C), CIHH post-treatment group (Post-T), post-control group (Post-C) and blank control group (Con). The rats in Pre-T and Post-T groups were exposed to 28 d of hypobaric hypoxia (simulated 3 000 m altitude, 5 h per day, pO2 = 108.8 mmHg, 14% O2) in a hypobaric chamber before and 12 days after CIA induction, respectively. The rats in Pre-C and Post-C groups were only experienced CIA induction, being control groups for Pre-T and Post-T groups, respectively. The rats in Con group were not given any treatment. The thickness of two-hind paw of rat was measured with spiral micrometer and the degree of arthritis was evaluated by arthritis index (AI). Morphological changes of ankle joint were observed through HE staining. The apoptotic rate in synovial tissue was measured by terminal dUTP nick end labeling (TUNEL) and the apoptotic rate of CD3(+) T lymphocyte in spleen was measured by flow cytometry technique. The protein expressions of Bcl-2 and Bax were measured using immunohistochemistry SP method. The results showed that incidence rate of CIA in Pre-T rats was lower than that in Pre-C rats (P < 0.05). AI in Pre-T and Post-T rats were smaller than those in Pre-C and Post-C, respectively (P < 0.05). In Pre-C and Post-C rats, there were hyperplasia of synovial cell, pannus forming, infiltration with inflammatory cell, and destroyed cartilage and bone in ankle joint. On the contrary, pathological changes of ankle joint were alleviated significantly in Pre-T and Post-T rats. Compared with Pre-C and Post-C rats, apoptotic rates of synovial cell and T lymphocyte in Pre-T and Post-T rats were increased (P < 0.05). As to the possible anti-apoptosis mechanism, CIHH, no matter before and after CIA induction

  7. Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats.

    PubMed

    Wallace, Ashley; Pehrson, Alan L; Sánchez, Connie; Morilak, David A

    2014-10-01

    Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.

  8. Gene expression in the rat supraoptic nucleus induced by chronic hyperosmolality versus hyposmolality.

    PubMed

    Glasgow, E; Murase, T; Zhang, B; Verbalis, J G; Gainer, H

    2000-10-01

    Magnocellular neurons of the hypothalamo-neurohypophysial system play a fundamental role in the maintenance of body homeostasis by secreting vasopressin and oxytocin in response to systemic osmotic perturbations. During chronic hyperosmolality, vasopressin and oxytocin mRNA levels increase twofold, whereas, during chronic hyposmolality, these mRNA levels decrease to 10-20% of that of normoosmolar control animals. To determine what other genes respond to these osmotic perturbations, we have analyzed gene expression during chronic hyper- versus hyponatremia. Thirty-seven cDNA clones were isolated by differentially screening cDNA libraries that were generated from supraoptic nucleus tissue punches from hyper- or hyponatremic rats. Further analysis of 12 of these cDNAs by in situ hybridization histochemistry confirmed that they are osmotically regulated. These cDNAs represent a variety of functional classes and include cytochrome oxidase, tubulin, Na(+)-K(+)-ATPase, spectrin, PEP-19, calmodulin, GTPase, DnaJ-like, clathrin-associated, synaptic glycoprotein, regulator of GTPase stimulation, and gene for oligodendrocyte lineage-myelin basic proteins. This analysis therefore suggests that adaptation to chronic osmotic stress results in global changes in gene expression in the magnocellular neurons of the supraoptic nucleus.

  9. Antioxidant Effect of Spirulina (Arthrospira) maxima on Chronic Inflammation Induced by Freund's Complete Adjuvant in Rats

    PubMed Central

    Gutiérrez-Rebolledo, Gabriel Alfonso; Galar-Martínez, Marcela; García-Rodríguez, Rosa Virginia; Chamorro-Cevallos, Germán A.; Hernández-Reyes, Ana Gabriela

    2015-01-01

    Abstract One of the major mechanisms in the pathogenesis of chronic inflammation is the excessive production of reactive oxygen and reactive nitrogen species, and therefore, oxidative stress. Spirulina (Arthrospira) maxima has marked antioxidant activity in vivo and in vitro, as well as anti-inflammatory activity in certain experimental models, the latter activity being mediated probably by the antioxidant activity of this cyanobacterium. In the present study, chronic inflammation was induced through injection of Freund's complete adjuvant (CFA) in rats treated daily with Spirulina (Arthrospira) maxima for 2 weeks beginning on day 14. Joint diameter, body temperature, and motor capacity were assessed each week. On days 0 and 28, total and differential leukocyte counts and serum oxidative damage were determined, the latter by assessing lipid peroxidation and protein carbonyl content. At the end of the study, oxidative damage to joints was likewise evaluated. Results show that S. maxima favors increased mobility, as well as body temperature regulation, and a number of circulating leukocytes, lymphocytes, and monocytes in specimens with CFA-induced chronic inflammation and also protects against oxidative damage in joint tissue as well as serum. In conclusion, the protection afforded by S. maxima against development of chronic inflammation is due to its antioxidant activity. PMID:25599112

  10. Acute and chronic antiinflammatory profile of the ivy plant, Hedera helix, in rats.

    PubMed

    Süleyman, H; Mshvildadze, V; Gepdiremen, A; Elias, R

    2003-01-01

    Hedera helix is a plant well-known as ivy or English ivy, and a member of the Araliaceae family. In the present study, we tested the possible antiinflammatory effects of a crude saponin extract (CSE) and a saponin's purified extracts (SPE) of Hedera helix in carrageenan- and cotton-pellet-induced acute and chronic inflammation models in rats. Both the CSE and SPE of Hedera helix were found to have antiinflammatory effects. The most potent drug screened was indomethacin (89.2% acute antiinflammatory effect), while the most potent extract screened was the CSE of Hedera helix at 100 and 200 mg/kg body wt. doses with 77% acute antiinflammatory effects. For testing chronic antiinflammatory (antiproliferative) effects, the cotton-pellet-granuloma test was conducted. Indomethacin was found to be the most potent drug in the chronic phase of inflammation, with 66% effect. The SPE of Hedera helix was more potent than the CSE in its chronic antiinflammatory effect (60% and 49%, respectively).

  11. Antioxidant Effect of Spirulina (Arthrospira) maxima on Chronic Inflammation Induced by Freund's Complete Adjuvant in Rats.

    PubMed

    Gutiérrez-Rebolledo, Gabriel Alfonso; Galar-Martínez, Marcela; García-Rodríguez, Rosa Virginia; Chamorro-Cevallos, Germán A; Hernández-Reyes, Ana Gabriela; Martínez-Galero, Elizdath

    2015-08-01

    One of the major mechanisms in the pathogenesis of chronic inflammation is the excessive production of reactive oxygen and reactive nitrogen species, and therefore, oxidative stress. Spirulina (Arthrospira) maxima has marked antioxidant activity in vivo and in vitro, as well as anti-inflammatory activity in certain experimental models, the latter activity being mediated probably by the antioxidant activity of this cyanobacterium. In the present study, chronic inflammation was induced through injection of Freund's complete adjuvant (CFA) in rats treated daily with Spirulina (Arthrospira) maxima for 2 weeks beginning on day 14. Joint diameter, body temperature, and motor capacity were assessed each week. On days 0 and 28, total and differential leukocyte counts and serum oxidative damage were determined, the latter by assessing lipid peroxidation and protein carbonyl content. At the end of the study, oxidative damage to joints was likewise evaluated. Results show that S. maxima favors increased mobility, as well as body temperature regulation, and a number of circulating leukocytes, lymphocytes, and monocytes in specimens with CFA-induced chronic inflammation and also protects against oxidative damage in joint tissue as well as serum. In conclusion, the protection afforded by S. maxima against development of chronic inflammation is due to its antioxidant activity.

  12. Dietary restriction protects against chronic-ethanol-induced changes in exploratory behavior in Wistar rats.

    PubMed

    Pinto, Lucas S N M; Gualberto, Felipe A S; Pereira, Silvia R C; Barros, Paula A; Franco, Glaura C; Ribeiro, Angela M

    2006-03-17

    Chronic ethanol intake causes various types of neural damage and behavioral impairments, probably acting through oxidative stress and excitotoxicity, while dietary restriction is considered by some authors to protect the central nervous system from these kinds of damage. In the present study, a factorial experimental design was used to investigate the effects of chronic ethanol and dietary restriction treatments, associated or not, on Wistar rats' exploratory behavior, spatial memory aspects and cortical and hippocampal acetylcholinesterase (AChE) activity. Dietary restriction lasted for the whole experiment, while ethanol treatment lasted for only 3 weeks. Despite the short ethanol treatment duration, for two behavior categories assessed, moving and rearing, an interaction was observed between the effects of chronic ethanol and dietary restriction. There were no significant differences in AChE activities among the groups. Cerebellar neural nitric oxide synthase (nNOs) activity was measured as a first step to assess oxidative stress. Dietary restriction significantly reduced NO formation. The present results indicate that dietary restriction might exert a protective effect against chronic-ethanol-induced changes in exploratory behavior. It is hypothesized that the mechanisms underlying this protection can involve prevention of oxidative stress.

  13. Recombinant interleukin-1 receptor antagonist attenuates the severity of chronic pancreatitis induced by TNBS in rats.

    PubMed

    Xu, Chunfang; Shen, Jiaqing; Zhang, Jing; Jia, Zhenyu; He, Zhilong; Zhuang, Xiaohui; Xu, Ting; Shi, Yuqi; Zhu, Shunying; Wu, Mingyuan; Han, Wei

    2015-02-15

    Chronic pancreatitis (CP) is a common disease in the department of gastroenterology, with the main symptoms of exocrine and/or endocrine insufficiency and abdominal pain. The pathogenic mechanism of CP is still not fully clarified and the aims of treatment now are to relieve symptoms. In this study, we attempted to find a connection between interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1Ra) in trinitrobenzene sulfonic acid (TNBS)-induced chronic pancreatitis, and then the therapeutic effect of recombinant IL-1Ra was also detected in the CP model. Chronic pancreatitis was induced by intraductal infusion of TNBS in SD rats followed by a consecutive administration of rIL-1Ra, and the histological changes and collagen content in the pancreas were measured, as well as the abdominal hypersensitivity. We found that rhIL-1Ra could attenuate the severity of chronic pancreatic injury, modulate the extracellular matrix secretion, focal proliferation and apoptosis, and cellular immunity in TNBS-induced CP. Interestingly, rIL-1Ra could also block the pancreatitis-induced referred abdominal hypersensitivity. In conclusion, IL-1Ra may play a protective role in CP and rIL-1Ra would be a potential therapeutic target for the treatment of CP, while its possible mechanisms and clinical usage still need further investigation.

  14. Dissociation and trafficking of rat GABAB receptor heterodimer upon chronic capsaicin stimulation.

    PubMed

    Laffray, Sophie; Tan, Kelly; Dulluc, Josette; Bouali-Benazzouz, Rabia; Calver, Andrew R; Nagy, Frédéric; Landry, Marc

    2007-03-01

    Gamma-aminobutyric acid type B receptors (GABAB) are G-protein-coupled receptors that mediate GABAergic inhibition in the brain. Their functional expression is dependent upon the formation of heterodimers between GABAB1 and GABAB2 subunits, a process that occurs within the endoplasmic reticulum. However, the mechanisms that regulate GABAB receptor oligomerization at the plasma membrane remain largely unknown. We first characterized the functional cytoarchitecture of an organotypic co-culture model of rat dorsal root ganglia and spinal cord. Subsequently, we studied the interactions between GABAB subunits after chronic stimulation of sensory fibres with capsaicin. Surface labelling of recombinant proteins showed a decrease in subunit co-localization and GABAB2 labelling, after capsaicin treatment. In these conditions, fluorescence lifetime imaging measurements further demonstrated a loss of interactions between green fluorescent protein-GABAB1b and t-dimer discosoma sp red fluorescent protein-GABAB2 subunits. Finally, we established that the GABAB receptor undergoes clathrin-dependent internalization and rapid recycling to the plasma membrane following activation with baclofen, a GABAB agonist. However, in cultures chronically stimulated with capsaicin, the agonist-induced endocytosis was decreased, reflecting changes in the dimeric state of the receptor. Taken together, our results indicate that the chronic stimulation of sensory fibres can dissociate the GABAB heterodimer and alters its responsiveness to the endogenous ligand. Chronic stimulation thus modulates receptor oligomerization, providing additional levels of control of signalling.

  15. Chronic coffee and caffeine ingestion effects on the cognitive function and antioxidant system of rat brains.

    PubMed

    Abreu, Renata Viana; Silva-Oliveira, Eliane Moretto; Moraes, Márcio Flávio Dutra; Pereira, Grace Schenatto; Moraes-Santos, Tasso

    2011-10-01

    Coffee is a popular beverage consumed worldwide and its effect on health protection has been well studied throughout literature. This study investigates the effect of chronic coffee and caffeine ingestion on cognitive behavior and the antioxidant system of rat brains. The paradigms of open field and object recognition were used to assess locomotor and exploratory activities, as well as learning and memory. The antioxidant system was evaluated by determining the activities of glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD), as well as the lipid peroxidation and reduced glutathione content. Five groups of male rats were fed for approximately 80 days with different diets: control diet (CD), fed a control diet; 3% coffee diet (3%Co) and 6% coffee diet (6%Co), both fed a diet containing brewed coffee; 0.04% caffeine diet (0.04%Ca) and 0.08% caffeine diet (0.08%Ca), both fed a control diet supplemented with caffeine. The estimated caffeine intake was approximately 20 and 40 mg/kg per day, for the 3%Co-0.04%Ca and 6%Co-0.08%Ca treatments, respectively. At 90 days of life, the animals were subjected to the behavioral tasks and then sacrificed. The results indicated that the intake of coffee, similar to caffeine, improved long-term memory when tested with object recognition; however, this was not accompanied by an increase in locomotor and exploratory activities. In addition, chronic coffee and caffeine ingestion reduced the lipid peroxidation of brain membranes and increased the concentration of reduced-glutathione. The activities of the GR and SOD were similarly increased, but no change in GPx activity could be observed. Thus, besides improving cognitive function, our data show that chronic coffee consumption modulates the endogenous antioxidant system in the brain. Therefore, chronic coffee ingestion, through the protection of the antioxidant system, may play an important role in preventing age-associated decline in the cognitive

  16. Chronic stress effects in contralateral medial pterygoid muscle of rats with occlusion alteration.

    PubMed

    Loyola, Bruno Melo; Nascimento, Glauce Crivelaro; Fernández, Rodrigo Alberto Restrepo; Iyomasa, Daniela Mizusaki; Pereira, Yamba Carla Lara; Leite-Panissi, Christie Ramos Andrade; Issa, João Paulo Mardegan; Iyomasa, Mamie Mizusaki

    2016-10-01

    Temporomandibular disorder (TMD) has a high prevalence in our society, characterized by a severe pain condition of the masticatory muscles and temporomandibular joint. Despite the indication of multiple factor initiators of TMD, there is still controversy about its etiology and its pathophysiology is poorly understood. Using rats as experimental animals we investigated the effect of unpredictable chronic stress with or without unilateral molar extraction on the contralateral medial pterygoid muscle. Our hypothesis is that these two factors induce changes in morphology, oxidative metabolism and oxidative stress of muscle fibers. Young adult male Wistar rats (±200g) were divided into four groups: a group with extraction and unpredictable chronic stress (E+US); with extraction and without stress (E+C); without extraction and with unpredictable chronic stress (NO+US); and a control group without either extraction or stress (NO+C). The animals were subjected to unilateral extraction of the upper left molars, under intraperitoneal anesthesia with 4% Xylazine (10mg/kg) and 10% Ketamine (80mg/kg) on day zero. The rats of groups E+US and NO+US were submitted to different protocols of stress, from the 14th day after the extraction. The protocols were different every day for five consecutive days, which were repeated from the 6th day for five days more. Contralateral medial pterygoid muscles were obtained on the 24th day after the start of the experiment for morphological, metabolic, capillary density, and oxidative stress analysis. The data from capillary density showed a decrease of capillaries in animals subjected to dental extraction, compared with those without extraction and an increase of laminin expression in the group submitted to the unpredictable chronic stress when compared to the unexposed to stress. SDH test revealed a decrease of light fibers in the group submitted to unilateral extraction of molars, compared with this area in the control group. In E+US and NO

  17. Gabapentin: a promising drug for the treatment of uremic pruritus.

    PubMed

    Naini, Afsoon Emami; Harandi, Ali Amini; Khanbabapour, Saeid; Shahidi, Shahrzad; Seirafiyan, Shiva; Mohseni, Masood

    2007-09-01

    Despite advances made in treatment, uremic pruritus remains a common and distressing symptom in patients on hemodialysis (HD). Gabapentin is an effective drug in the management of neuropathic pain. Considering that neuropathic pain and pruritus share similar pathogenic mechanisms, we conducted this study to evaluate the efficacy of gabapentin in controlling uremic itch. In a double blind, placebo-controlled trial, 34 adult patients on maintenance HD were enrolled. The patients were assigned to receive four weeks of treatment with either gabapentin (400 mg) or placebo administered twice weekly after HD sessions. Pruritus scores were measured using a visual analogue scale and compared between the two groups.After four weeks of treatment, the mean decrease in pruritus score in gabapentin and placebo groups was 6.7 +/- 2.6 and 1.5 +/- 1.8, respectively (p< 0.001). None of the patients was forced to drop out of the study due to side effects of the treatment. Our study suggests that gabapentin is a safe and effective treatment for uremic itch.

  18. Gases as uremic toxins: is there something in the air?

    PubMed

    Jankowski, Joachim; Westhof, Timm; Vaziri, Nosratola D; Ingrosso, Diego; Perna, Alessandra F

    2014-03-01

    The field of uremic toxicity comprises the study of a large number of different substances, classified in relation to various characteristics, for example, protein-binding, dimensions, and so forth. The endogenous compounds of a gaseous nature have received much attention lately from the scientific community because of their increasingly recognized importance in health and disease. Among these substances, some are uremic toxins per se, others are related to uremic toxins, or can become toxic under some circumstances. We divided them into two broad categories: organic and inorganic compounds. Among the organic compounds are phenols, indols, 2-methoxyresorcinol, p-hydroxy hippuric acid and phenyl acetic acid, trimethylamine, and dimethylamine; among the inorganic solutes are ammonia, nitric oxide, carbon monoxide, and hydrogen sulfide. In this article, these substances are described in relation to the elements that they affect or by which they are affected in uremia, which are the blood, breath, stools, and the gastrointestinal tract. In addition, the effect of the dialysis procedure on exhaled gases are described.

  19. The anti-arrhythmic effect of chronic intermittent hypobaric hypoxia in rats with metabolic syndrome induced with fructose.

    PubMed

    Zhou, Jing-Jing; Ma, Hui-Jie; Liu, Yan; Guan, Yue; Maslov, Leonid N; Li, De-Pei; Zhang, Yi

    2015-04-01

    This study investigated the anti-arrhythmic effects from chronic intermittent hypobaric hypoxia (CIHH) and the cellular mechanisms in rats with metabolic syndrome. Male Sprague-Dawley rats were randomly distributed among the control, fructose-fed (fed with 10% fructose in the drinking water to induce metabolic syndrome), CIHH (42 days of hypobaric hypoxia treatment simulating an altitude of 5000 m a.s.l.: PB = 404 mm Hg, PO2 = 84 mm Hg, 6 h per day), and the CIHH plus fructose (CIHH-F) groups. In anesthetized rats, the arrhythmia score was determined after 30 min of cardiac ischemia followed by 120 min of reperfusion. Action potentials (AP) were recorded from isolated ventricular papillary muscles. The arrhythmia score was much lower in CIHH-F rats than in the fructose-fed rats. Under basic conditions, AP duration (APD) was significantly shortened in fructose-fed rats, but obviously prolonged in CIHH rats compared with that of the control rats. During ischemia, the AP amplitude, the maximal rate of rise of phase 0, APD, and resting potential, were lower in the control, fructose-fed, and CIHH-F groups, but were not changed in the CIHH rats. The lower AP during ischemia did not recover after washout for the fructose-fed rats. In conclusion, CIHH protects the heart against ischemia-reperfusion induced arrhythmia in rats with metabolic syndrome. This effect of CIHH is possibly related to baseline prolongation of the AP and attenuation of AP reduction during ischemia-reperfusion.

  20. The effect of chronic cholesterol feeding on intestinal lipoproteins in the rat.

    PubMed

    Riley, J W; Glickman, R M; Green, P H; Tall, A R

    1980-09-01

    Chronic cholesterol feeding has been shown to produce abnormal plasma lipoproteins in a variety of experimental animals and man. In order to explore the role of the intestine in the production of these abnormal lipoproteins, rats were chronically fed a diet containing 1% cholesterol and 10% olive oil and were compared to control animals, fed either normal chow or normal chow containing 10% olive oil. Mesenteric lymph lipoproteins from fasting lymph and from lymph obtained after acutely infusing cholesterol and olive oil were examined and compared to plasma lipoproteins from these animals. There were no differences in apoA-I output, cholesterol output, or distribution in lymph lipoproteins between the two groups of controls. The cholesterol-olive oil diet produced a mild hyperlipidemia (plasma cholesterol 81 --> 95 mg/dl, plasma triglyceride 95 --> 162 mg/dl). Plasma lipoprotein electrophoresis revealed an abnormal band with broad beta mobility and a reduction in HDL. Lipid analysis of ultracentrifugally separated fractions demonstrated the appearance of an intermediate density (1.006-1.030 g/ml) lipoprotein in plasma markedly enriched in cholesteryl esters. Analysis of fasting mesenteric lymph from chronically cholesterol-fed animals revealed similar apoA-I, cholesterol, and triglyceride outputs when compared to controls. Although in both groups most of the cholesterol was transported in d < 1.006 g/ml lipoproteins, there was a redistribution of cholesterol transport in d > 1.006 g/ml lipoproteins. In the chronically cholesterol-fed animals, 19% of fasting lymph cholesterol was transported in a lipoprotein of density 1.006-1.030 g/ml, compared to 4% in this density in controls. During the acute infusion of cholesterol and olive oil, the output of lymph apoA-I (226 +/- 20 versus 374 +/- 5 micro g/hr, P < 0.025) and lymph cholesterol (970 +/- 82 +/- 1774 micro g/hr, P < 0.01) was significantly lower in the chronically cholesterol-fed group, despite no significant

  1. Suppression of hypothalamic-pituitary-adrenal axis by acute heroin challenge in rats during acute and chronic withdrawal from chronic heroin administration

    PubMed Central

    Zhou, Yan; Leri, Francesco; Ho, Ann; Kreek, Mary Jeanne

    2013-01-01

    It is known that heroin dependence and withdrawal are associated with changes in the hypothalamic-pituitary-adrenal (HPA) axis. The objective of these studies in rats was to systematically investigate the level of HPA activity and response to a heroin challenge at two time points during heroin withdrawal, and to characterize the expression of associated stress-related genes 30 minutes after each heroin challenge. Rats received chronic (10-day) intermittent escalating-dose heroin administration (3×2.5 mg/kg/day on day 1; 3×20 mg/kg/day by day 10). Hormonal and neurochemical assessments were performed in acute (12 hours after last heroin injection) and chronic (10 days after the last injection) withdrawal. Both plasma ACTH and corticosterone levels were elevated during acute withdrawal, and heroin challenge at 20 mg/kg (the last dose of chronic escalation) at this time point attenuated this HPA hyperactivity. During chronic withdrawal, HPA hormonal levels returned to baseline, but heroin challenge at 5 mg/kg decreased ACTH levels. In contrast, this dose of heroin challenge stimulated the HPA axis in heroin naïve rats. In the anterior pituitary, pro-opiomelanocortin (POMC) mRNA levels were increased during acute withdrawal and retuned to control levels after chronic withdrawal. In the medial hypothalamus, however, the POMC mRNA levels were decreased during acute withdrawal, and increased after chronic withdrawal. Our results suggest a long-lasting change in HPA abnormal responsivity during chronic heroin withdrawal. PMID:23771528

  2. Insulin binding and glycolytic activity in erythrocytes from dialyzed and nondialyzed uremic patients.

    PubMed

    Weisinger, J R; Contreras, N E; Cajias, J; Bellorin-Font, E; Amair, P; Guitierrez, L; Sylva, V; Paz-Martínez, V

    1988-01-01

    Insulin resistance in uremia has been attributed to impaired hormone-receptor binding or to postbinding defects. Oral glucose tolerance tests, insulin binding, and in vitro glycolytic activity were studied in purified red blood cells from normal control subjects (C) and from uremic patients belonging to three groups: nondialyzed (U), on chronic hemodialysis (HD), and on continuous ambulatory peritoneal dialysis (CAPD). Glucose intolerance and hyperinsulinemia were demonstrated in all groups of patients. Maximal specific binding of 125I-insulin to erythrocytes, kinetically derived receptor numbers per cell, and affinity constants for insulin binding did not differ between control and patient groups. No correlation was found between the degree of glucose intolerance and insulin binding parameters. Basal lactate production by erythrocytes incubated in vitro was significantly higher in U and HD patients than in C, whereas CAPD patients did not differ from C in this respect. Addition of 1 mM dibutyryl-cAMP and 0.5 mM isobutyl-methyl-xanthine during incubation of erythrocytes caused an increase in the rate of lactate production that was similar in magnitude in the U, HD and C groups, whereas cells from CAPD subjects showed a significantly larger absolute response to these compounds after 1 h of incubation. There was no evidence of impairment of glycolytic capacity in red blood cells from uremic patients. In addition, no correlation was found between the degree of glucose intolerance and basal or stimulated lactate production by erythrocytes. Our results obtained in human erythrocytes suggest that the insulin resistance observed in uremia does not involve a defect in hormone binding or in the intracellular capacity to utilize glucose through glycolysis.

  3. Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

    PubMed Central

    Bisgaard, Line S.; Bosteen, Markus H.; Fink, Lisbeth N.; Sørensen, Charlotte M.; Rosendahl, Alexander; Mogensen, Christina K.; Rasmussen, Salka E.; Rolin, Bidda; Nielsen, Lars B.

    2016-01-01

    Chronic kidney disease (CKD) leads to uremia. CKD is characterized by a gradual increase in kidney fibrosis and loss of kidney function, which is associated with a progressive increase in risk of atherosclerosis and cardiovascular death. To prevent progression of both kidney fibrosis and atherosclerosis in uremic settings, insight into new treatment options with effects on both parameters is warranted. The GLP-1 analogue liraglutide improves glucose homeostasis, and is approved for treatment of type 2 diabetes. Animal studies suggest that GLP-1 also dampens inflammation and atherosclerosis. Our aim was to examine effects of liraglutide on kidney fibrosis and atherosclerosis in a mouse model of moderate uremia (5/6 nephrectomy (NX)). Uremic (n = 29) and sham-operated (n = 14) atherosclerosis-prone low density lipoprotein receptor knockout mice were treated with liraglutide (1000 μg/kg, s.c. once daily) or vehicle for 13 weeks. As expected, uremia increased aortic atherosclerosis. In the remnant kidneys from NX mice, flow cytometry revealed an increase in the number of monocyte-like cells (CD68+F4/80-), CD4+, and CD8+ T-cells, suggesting that moderate uremia induced kidney inflammation. Furthermore, markers of fibrosis (i.e. Col1a1 and Col3a1) were upregulated, and histological examinations showed increased glomerular diameter in NX mice. Importantly, liraglutide treatment attenuated atherosclerosis (~40%, p < 0.05) and reduced kidney inflammation in NX mice. There was no effect of liraglutide on expression of fibrosis markers and/or kidney histology. This study suggests that liraglutide has beneficial effects in a mouse model of moderate uremia by reducing atherosclerosis and attenuating kidney inflammation. PMID:27992511

  4. Chronic toxicity and oncogenicity study with vinyl acetate in the rat: in utero exposure in drinking water.

    PubMed

    Bogdanffy, M S; Tyler, T R; Vinegar, M B; Rickard, R W; Carpanini, F M; Cascieri, T C

    1994-08-01

    The purpose of this study was to evaluate vinyl acetate for potential chronic toxicity and oncogenicity when given to rats in drinking water from the time of gestation. Target concentrations were 0, 200, 1000, and 5000 ppm (v/v). Drinking water solutions were prepared daily and analyzed at approximately 4-week intervals. F0 rats were given solutions of vinyl acetate for 10 weeks and then mated. Offspring (F1 rats) were culled to equal group sizes of 60 main study rats and 30 rats for satellite groups. F1 rats were treated for up to 104 weeks with interim kills of satellite groups at 52 and 78 weeks. Body weights and clinical signs of toxicity were monitored in F0 and F1 rats. Food and water consumption were measured in F1 rats. At Weeks 52 and 78 of the test, clinical pathology and urine analysis examinations were conducted on 10 rats per group from satellite animals. A complete gross and histopathological examination of F1 rats was conducted at the interim kills and on main study rats at Week 104. Average vinyl acetate consumption over the course of the study in male rats of the 200, 1000, and 5000 ppm groups was 10, 47, and 202 mg/kg/day, respectively. Female rats consumed an average of 16, 76, and 302 mg/kg/day, respectively. Compound-related effects observed during the study included a concentration-related decrease in water consumption among rats of the 1000 and 5000 ppm groups and a decrease in food consumption among rats of the 5000 ppm groups. Concurrent body weight decrement was observed only in the 5000 ppm groups.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Acute and chronic administration of gold nanoparticles cause DNA damage in the cerebral cortex of adult rats.

    PubMed

    Cardoso, Eria; Rezin, Gislaine Tezza; Zanoni, Elton Torres; de Souza Notoya, Frederico; Leffa, Daniela Dimer; Damiani, Adriani Paganini; Daumann, Francine; Rodriguez, Juan Carlos Ortiz; Benavides, Roberto; da Silva, Luciano; Andrade, Vanessa M; da Silva Paula, Marcos Marques

    2014-01-01

    The use of gold nanoparticles is increasing in medicine; however, their toxic effects remain to be elucidated. Studies show that gold nanoparticles can cross the blood-brain barrier, as well as accumulate in the brain. Therefore, this study was undertaken to better understand the effects of gold nanoparticles on rat brains. DNA damage parameters were evaluated in the cerebral cortex of adult rats submitted to acute and chronic administration of gold nanoparticles of two different diameters: 10 and 30nm. During acute administration, adult rats received a single intraperitoneal injection of either gold nanoparticles or saline solution. During chronic administration, adult rats received a daily single injection for 28 days of the same gold nanoparticles or saline solution. Twenty-four hours after either single (acute) or last injection (chronic), the rats were euthanized by decapitation, their brains removed, and the cerebral cortices isolated for evaluation of DNA damage parameters. Our study showed that acute administration of gold nanoparticles in adult rats presented higher levels of damage frequency and damage index in their DNA compared to the control group. It was also observed that gold nanoparticles of 30nm presented higher levels of damage frequency and damage index in the DNA compared to the 10nm ones. When comparing the effects of chronic administration of gold nanoparticles of 10 and 30nm, we observed that occurred significant different index and frequency damage, comparing with control group. However, there is no difference between the 10 and 30nm groups in the levels of DNA damage for both parameters of the Comet assay. Results suggest that gold nanoparticles for both sizes cause DNA damage for chronic as well as acute treatments, although a higher damage was observed for the chronic one.

  6. Prenatal stress in rats predicts immobility behavior in the forced swim test. Effects of a chronic treatment with tianeptine.

    PubMed

    Morley-Fletcher, S; Darnaudery, M; Koehl, M; Casolini, P; Van Reeth, O; Maccari, S

    2003-11-07

    Prenatally-stressed (PS) rats are characterized by a general impairment of the hypothalamo-pituitary-adrenal (HPA) axis and sleep disturbances indicating that this model has face validity with some clinical features observed in a subpopulation of depressed patients. The prolonged corticosterone secretion shown by PS rats in response to stress was positively correlated with an increased immobility behavior in the forced swim test. To investigate the predictive validity of this model, a separate group of animals was chronically treated with the antidepressant tianeptine (10 mg/kg i.p. for 21 days). Such chronic treatment reduced in PS rats immobility time in the forced swim test. These findings suggest that the PS rat is an interesting animal model for the evaluation of antidepressant treatment.

  7. The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats.

    PubMed

    Marona-Lewicka; Nichols

    1997-12-01

    Chronic exposure to mild unpredictable stress has been found to depress the consumption of, and preference for, highly palatable sucrose solution in rats. Stress-induced behavioral deficits may be maintained for a long time, however chronic administration of clinically effective antidepressants can restore normal behavior. This is the first report showing that Sprague-Dawley rats can be used in this model. A preference deficit in this strain of rats took at least 7 weeks to develop; about twice the time required when hooded Lister or Wistar rats are used in this model. Water consumption was not effected by chronic exposure to the mild stress regime and/or by chronic administration of the selective serotonin (5-HT) releasing agent MMAI (5-methoxy-6-methyl-2-aminoindan). The stress-induced deficit in sucrose intake was completely reversed by chronic treatment with MMAI (5 mg/kg, 2 x day) over 3 weeks in the two-bottle tests. In single-bottle tests, chronic treatment with the selective 5-HT releasers, MMAI (5 mg/kg, 2 x day) or MTA (p-methylthioamphetamine; 5 mg/kg, 2 x day), reversed the deficit in rewarded behavior (anhedonia) measured as a decrease in the consumption of 1% sucrose solution in the chronic mild stress model of depression in rats. With the experimental procedure employed, and at a dose of 10 mg/kg/day of 5-HT releasers, the magnitude and onset of this effect were greater than observed following similar administration of the selective 5-HT reuptake inhibitor (SSRI) sertraline (10 mg/kg/day), used as a standard anti-depressant drug.

  8. [Sarcopenia or uremic myopathy in CKD patients].

    PubMed

    Chauveau, Philippe; Moreau, Karine; Lasseur, Catherine; Fouque, Denis; Combe, Christian; Aparicio, Michel

    2016-04-01

    Often underestimated or misunderstood in chronic renal failure (CRF), muscle wasting is nevertheless common and concerns about 50% of dialysis patients. The consequences of this myopathy on quality of life and outcomes of patients are unfavorable, identical to those observed in sarcopenia in elderly subjects with sarcopenia. The similarities between the two situations also concern the symptoms, the underlying muscle damages and the pathogenic mechanisms and may be partly explained by the frequently high age of ESRD patients. Skeletal muscle involvement should be systematically investigated in the IRC patient as in the elderly with sarcopenia to propose as early as possible a treatment of which physical activity and nutritional interventions are the mainstay.

  9. Chronic trimethyltin chloride exposure and the development of kidney stones in rats

    PubMed Central

    Ren, Xuefeng; Wu, Xin; Sui, Gang; Gong, Zhihong; Yawson, Emmanuel; Wu, Banghua; Lai, Guanchao; Ruan, Xiaolin; Gao, Hongbin; Zhou, Feng; Su, Bing; Olson, James R.; Tang, Xiaojiang

    2015-01-01

    We recently reported that occupational exposure to trimethyltin (TMT) is a risk factor for developing kidney stones. To further examine the association between TMT exposure and the formation of kidney stones, we conducted a 180-day animal study and exposed the randomly grouped Sprague–Dawley (SD) rats to TMT in the drinking water at doses of 0, 8.2, 32.8 and 131.3 μg kg−1 day−1. Transient behavioral changes were observed in the high-dose group during the first 2weeks of exposure. TMT exposure led to a significant dose-dependent inhibition of renal H+/K+-ATPase and an increase in urinary pH. In comparison to no kidney stones being identified in the control and the lowest dose group, 1 rat in the 32.8 μg kg−1 day−1 dose group and 3 out of 9 rats in the 131.3 μg kg−1 day−1 dose group were found to have stones in the kidney/urinary tract. Pathological analysis showed that more wide spread calcium disposition was observed in kidneys of rats with TMT exposure compared with the rats in the control group. However, X-ray diffraction (XRD) analysis found that the kidney stones were mainly composed of struvite with the formula: NH4MgPO4 6H2O, while calcium-containing components were also detected. Together, this study further demonstrates through animal studies that chronic exposure to a relatively low level of TMT induces nephrotoxicity and increases the risk for developing kidney stones. PMID:25224689

  10. The treatment of Uygur medicine Dracocephalum moldavica L on chronic mountain sickness rat model

    PubMed Central

    Maimaitiyiming, Dilinuer; Hu, Guangmei; Aikemu, Ainiwaer; Hui, Shi Wen; Zhang, Xiangyang

    2014-01-01

    Aim: Dracocephalum moldavica L, a traditional Uygur medicine, possesses some key cardiac activities. However, till date, no reports are available on the use of D. moldavica against chronic mountain sickness (CMS), which is a medical condition that affects the residents of high altitude. The present study was designed to explore the treatment efficacy of D. moldavica on CMS. Materials and Methods: 80 of the 100 Sprague Dawley rats enrolled were bred in simulated high altitude environment and the remaining 20 rats were kept in the plains. Water and alcohol extracts of D. moldavica were prepared. CMS rat model was prepared, and the rat hearts were removed for histopathological analysis. Blood samples were taken for hematological and biochemical analyses. Rat pulmonary artery pressure was determined to study the treatment efficacy. Results: In the CMS model group, the levels of interleukin-6 (IL-6), C-reactive protein (CRP), and malondialdehyde (MDA) were found to be significantly higher than the control group; while the concentrations of SOD and GSH-Px decreased. D. moldavica could improve these levels, decrease pulmonary artery pressure, and improve the cardiac pathological state. Conclusions: The study results show that IL-6, CRP, MDA, SOD and GSH-Px participate and mediate the formation of CMS and D. moldavica is found to possess noticeable effects on CMS. The present study explored the basics of high altitude sickness and laid the foundation for further progress of Uygur medicines on the treatment of altitude sickness. Further preclinical and clinical studies with more sample size are recommended. PMID:25422549

  11. Chronic Alternate Day Fasting Results in Reduced Diastolic Compliance and Diminished Systolic Reserve in Rats

    PubMed Central

    Ahmet, Ismayil; Wan, Ruiqian; Mattson, Mark P; Lakatta, Edward G.; Talan, Mark I.

    2010-01-01

    Background Based on animal experiments and limited data from few human trials, alternate day fasting (ADF) resulted in weight loss; prolonged life; reduced metabolic risk factors for diabetes and cardiovascular diseases; and reduced prevalence of age-related diseases. The present study is the first comprehensive examination of the long-term effects of ADF on general cardiovascular fitness in rats. Methods and Results Four months old male Sprague-Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months with serial echocardiography. A comprehensive hemodynamic evaluation including a combined dobutamine - volume stress test was performed at the end of the study, and hearts were harvested for histological assessment. The six-month long ADF diet resulted in a 9% reduction (p<0.01) of cardiomyocyte diameter and 3 fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the E/A in Doppler-measured mitral flow was reduced (p<0.01). Pressure-volume loop analyses revealed a “stiff” heart during diastole in ADF rats, while combined dobutamine and volume loading showed a significant reduction in LV diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve. Conclusion Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted. PMID:20932467

  12. Renal denervation causes chronic hypotension in rats: role of beta1-adrenoceptor activity.

    PubMed

    Jacob, Frédéric; LaBine, Brian G; Ariza, Pilar; Katz, Stephen A; Osborn, John W

    2005-04-01

    1. Renal denervation (RDNX) chronically lowers mean arterial pressure (MAP) in normal rats but mechanisms leading to this hypotensive response remain unknown. 2. We hypothesized that this sustained decrease in arterial pressure was because of a loss of beta1-adrenoceptor mediated renin secretion. Male Sprague-Dawley rats were assigned to sham (SHAM; n = 9), unilateral (UniRDNX; n = 9), or bilateral (RDNX; n = 10) renal denervation groups and instrumented for telemetric MAP measurements, plasma renin concentration (PRC) measurements and intravenous infusion. Twenty-four h MAP, heart rate, sodium and water balances were recorded 5 days before, 3 days during and 3 days after 1-adrenoceptor blockade with atenolol. 3. The 5-day control MAP was significantly lower in RDNX (97 +/- 1 mmHg) compared to SHAM (105 +/- 2 mmHg) and UniRDNX (102 +/- 2 mmHg) rats. No significant differences in basal PRC were observed between RDNX (2.2 +/- 0.3 ngAng1/mL per h), UniRDNX (2.6 +/- 0.4 ng/Ang1/mL per h) and SHAM (2.6 +/- 0.4 ngAng1/mL per h) rats. By day 1 of atenolol, PRC was significantly lower in UniRDNX rats (1.8 +/- 0.2 ngAg1/mL per h) compared to control values, but was unchanged during atenolol infusion in the other groups. By day 3 of atenolol, MAP was significantly decreased in all groups, but the absolute levels of MAP remained statistically different between RDNX (87 +/- 1 mmHg) and SHAM (91 +/- 1 mmHg) groups. 4. We conclude that the arterial pressure lowering effect of RDNX is not solely dependent on the loss of neural control of renin release.

  13. Chronic trimethyltin chloride exposure and the development of kidney stones in rats.

    PubMed

    Ren, Xuefeng; Wu, Xin; Sui, Gang; Gong, Zhihong; Yawson, Emmanuel; Wu, Banghua; Lai, Guanchao; Ruan, Xiaolin; Gao, Hongbin; Zhou, Feng; Su, Bing; Olson, James R; Tang, Xiaojiang

    2015-05-01

    We recently reported that occupational exposure to trimethyltin (TMT) is a risk factor for developing kidney stones. To further examine the association between TMT exposure and the formation of kidney stones, we conducted a 180-day animal study and exposed the randomly grouped Sprague-Dawley (SD) rats to TMT in the drinking water at doses of 0, 8.2, 32.8 and 131.3 µg kg(-1) day(-1). Transient behavioral changes were observed in the high-dose group during the first 2 weeks of exposure. TMT exposure led to a significant dose-dependent inhibition of renal H(+)/K(+)-ATPase and an increase in urinary pH. In comparison to no kidney stones being identified in the control and the lowest dose group, 1 rat in the 32.8 µg kg(-1) day(-1) dose group and 3 out of 9 rats in the 131.3 µg kg(-1) day(-1) dose group were found to have stones in the kidney/urinary tract. Pathological analysis showed that more wide spread calcium disposition was observed in kidneys of rats with TMT exposure compared with the rats in the control group. However, X-ray diffraction (XRD) analysis found that the kidney stones were mainly composed of struvite with the formula: NH4MgPO4 6H2O, while calcium-containing components were also detected. Together, this study further demonstrates through animal studies that chronic exposure to a relatively low level of TMT induces nephrotoxicity and increases the risk for developing kidney stones.

  14. Study of hemorheological parameters following partial hepatectomy in rats with chronic aluminium intoxication.

    PubMed

    Contini, María del Carmen; Mahieu, Stella; Bazzoni, Graciela; Bernal, Claudio A; Carnovale, Cristina E

    2006-01-01

    The aim of our work was to analyze the hemorheological parameters following partial hepatectomy in rats with chronic Al-intoxication (Al). Male Wistar rats were randomly assigned into four experimental groups (n=6 each one): Sham (rats subjected to simulated surgery); Al+Sham; Partial Hepatectomy (animals subjected to 65% liver resection) and Al+Partial Hepatectomy. Our results show that both Partial Hepatectomy and Al treatment produce a decrease of plasma cholesterol level, which showed a negative association with Rigidity Index increase (r(s)=-0.6475, p<0.05). The increase of Rigidity Index observed in Partial Hepatectomy, Al+Sham and Al+Partial Hepatectomy could be related to the increase of the proportion of non-discocytic erythrocytes, particularly stomatocytes, which determines a diminution of the Morphological Index. In the Altreated groups, greater changes in Rigidity Index and Morphological Index were observed. The relative viscosity of blood at a standard haematocrit of 40% was increased in Partial Hepatectomy, Al+Sham and Al+Partial Hepatectomy as compared to Sham, due to erythrocyte rigidity. On the other hand, we observed that the increase of plasma fibrinogen concentration correlates with augmentation of plasma viscosity (r(s)=0.689, p=0.004) for all the experimental groups studied. The results indicate that both administration of Al and Partial Hepatectomy induce microcytic hypocromic anaemia in the rats reflected by a significant decrease of haematocrit, mean corpuscular volume and mean corpuscular haemoglobin concentration. From these results, we conclude that in partially hepatectomized, Al-overloaded rats the decrease in erythrocyte deformability may be an important factor leading to the installation of anaemia.

  15. Plasma cortisol activity in rats under conditions of chronic stress supplemented with resveratrol

    PubMed Central

    Hurtado Salazar, Alejandro; Uribe-Velásquez, Luis F

    2012-01-01

    Objective: To determine the activity of cortisol in rats treated with exogenous adrenocorticotropic hormone (ACTH) and a resveratrol supplement. Methods: Forty-eight adult female rats and 16 male rats of the strain (Rattus norvegicus) that were three months old and with body weights ranging from 200 to 250 g for females and 300 to 350 g for males were used and kept in controlled environmental conditions: temperature of 20±2° C and light-dark cycles of 14 and 10 hours. They were fed a balanced diet and had free access to water. The rats were randomly divided into four groups: group 1 - was treated with 5 µg/kg of ACTH i.p. every twelve hours; group 2 - received the same treatment with ACTH plus a grape extract supplement (resveratrol) of 40 mg/kg; group 3 - only received grape extract (resveratrol); and group 4 - received a saline solution (0.9%) i.p. and oral, and served as controls. The experimental design was a 2×2 factorial with two levels ACTH and two polyphenol levels (grape extract). Results: No significant differences were found in blood cortisol concentrations, by day and gender, or by treatment effects (0.75 µg/dL ± 0.11; p <0.001). Conclusion: Results suggest that chronic stress and consumption of resveratrol did not directly alter levels of plasmatic cortisol in either stressed or unstressed rats. It was concluded that the given dosage levels of ACTH possibly did not produce sufficient stimulation of the adrenal gland for these animals. PMID:24893196

  16. Chronic administration of oxprenolol and metoprolol attenuate sympathetic cardiovascular responses only in non-adrenalectomized pithed rats.

    PubMed

    Vila, E; Badia, A

    1995-10-01

    1. Oxprenolol and metoprolol (30 mg kg-1) were injected intraperitoneally (i.p.) for 1 day (acute treatment) and 6 weeks (chronic treatment) to Sprague-Dawley rats. 2. Increases of mean blood pressure and heart rate to noradrenaline (0.1-10 micrograms kg-1) and to electrical stimulation (0.5 msec, supramax V, 0.25-5 Hz) of the entire sympathetic outflow were measured in non-adrenalectomized (acute and chronic) and adrenalectomized (chronic) pithed rats. 3. Acute beta-adrenoceptor antagonist administration was without effect on mean blood pressure and heart rate increases to noradrenaline and electrical stimulation. 4. Chronic administration with oxprenolol significantly diminished the stimulation-induced increases of mean blood pressure and heart rate in non-adrenalectomized pithed rats. 5. Increases in heart rate, elicited by stimulation of the entire sympathetic outflow in non-adrenalectomized but not in adrenalectomized pithed rats, were decreased by metoprolol treatment. Both treatments were without effect on noradrenaline responses. 6. These results indicate that chronic beta-adrenoceptor antagonist treatment is associated with a reduction in the cardiovascular responses to sympathetic nerve-stimulation. However, this mechanism only operates when adrenomedullary adrenaline is present to facilitate the noradrenaline release through activation of presynaptic beta 2-adrenoceptors.

  17. Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment.

    PubMed

    Kim, Helena K; Isaacs-Trepanier, Cameron; Elmi, Nika; Rapoport, Stanley I; Andreazza, Ana C

    2016-05-01

    Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder.

  18. Sea buckthorn (Hippophae rhamnoides L.) oil protects against chronic stress-induced inhibitory function of natural killer cells in rats.

    PubMed

    Diandong, Hou; Feng, Gu; Zaifu, Liang; Helland, Timothy; Weixin, Fu; Liping, Cai

    2016-03-01

    Chronic stress can suppress natural killer (NK) cell activity; this may also be related to the effect of stress on the neuroendocrine-immune network. Sea buckthorn (SBT) (Hippophae rhamnoides L.) is a thorny nitrogen fixing deciduous shrub, native to both Europe and Asia. It has been used as a medicinal plant in Tibetan and Mongolian traditional medicines. SBT has multifarious medical properties, including anti-fatigue as well as immunoregulatory effects. This study reports the effects of SBT oil with regard to the cytotoxicity and quantity of NK cells in the blood of a chronic-stress rat model, in addition to its mechanisms on the neuroendocrine-immune network. These results show that SBT oil, given by gavage to rats with chronic stress, could increase the following: body weight, NK cell quantities, and cytotoxicity, as well as the expression of perforin and granzyme B. The results also show that SBT oil in rats with chronic stress could suppress cortisol, ACTH, IL-1β and TNF-α levels, in addition to increasing 5-HT and IFN-γ serum levels. This leads to suggest that SBT oil, in rats with chronic stress, can increase NK cell cytotoxicity by upregulating the expression of perforin and granzyme B, thus causing associated effects of SBT oil on the neuroendocrine-immune network.

  19. Chronic mild stress induces variations in locomotive behavior and metabolic rates in high fat fed rats.

    PubMed

    García-Díaz, D F; Campion, J; Milagro, F I; Lomba, A; Marzo, F; Martínez, J A

    2007-12-01

    Chronic mild stress (CMS) has been often associated to the pathogenesis of many diseases including obesity. Indeed, visceral obesity has been linked to the development of metabolic syndrome features and constitutes a serious risk factor for cardiovascular diseases and diabetes. In order to study possible mechanistic relationships between stress and the onset of obesity, we developed during 11 weeks a model of high-fat dietary intake (cafeteria diet) together with a CMS regimen in male Wistar rats. During the experimental period, basal metabolism by indirect calorimetry, rectal temperature, food intake, and locomotive markers were specifically analyzed. After 77 days, animals were sacrificed and body, adiposity and plasma biochemical profiles were also examined. As expected, cafeteria diet in unstressed animals induced a significative increase in body weight, adiposity, and insulin resistance markers. Locomotive variables, specifically distance, rearing and meander, were significantly increased by CMS on the first weeks of stress. Moreover, this model of CMS in Wistar rats increased significantly energy expenditure, and apparently interplayed with the dietary treatment on the muscle weight/fat weight ratio. In summary, this chronic stress model did not affected weight gain in control and high fat fed animals, but induced an interaction concerning the metabolic muscle/fat repartitioning.

  20. The effects of chronic administration of nandrolone decanoate on redox status in exercised rats.

    PubMed

    Nikolic, Tamara; Zivkovic, Vladimir; Jevdjevic, Maja; Djuric, Marko; Srejovic, Ivan; Djuric, Dragan; Jeremic, Nevena; Djuric, Dusan; Bolevich, Sergey; Jakovljevic, Vladimir

    2016-01-01

    For the past 40 years, anabolic-androgenic steroids have been used by a wide variety of athletes with the hope of improving their training, endurance, and performance. The aim of this study was to examine the chronic effects of nandrolone decanoate (20 mg/kg, s.c, Deca-Durabolin DECA(®)) on oxidative stress biomarkers in the hearts of sedentary and exercised rats. The male Wistar albino rats (n = 180, four groups with three subgroups, 15 per subgroup, age 10 weeks, body mass 200-220 g) were sacrificed, and in the collected samples of blood, the following markers of oxidative stress were measured spectrophotometrically: (1) index of lipid peroxidation (measured as TBARS-thiobarbituric acid reactive substances); (2) nitrites (NO2 (-)); (3) hydrogen peroxide (H2O2); (4) superoxide anion radical (O2 (-)), and superoxide dismutase, catalase, and glutathione reductase. The results clearly show that the impact of ND alone, or in combination with physical training in general, is mildly pro-oxidative. The chronic physical training probably induces the protective antioxidant enzyme system , which may be of clinical interest when faced with overdosage of this drug.

  1. Temporal evaluation of cardiac myocyte hypertrophy and hyperplasia in male rats secondary to chronic volume overload.

    PubMed

    Du, Yan; Plante, Eric; Janicki, Joseph S; Brower, Gregory L

    2010-09-01

    The temporal myocardial remodeling induced by chronic ventricular volume overload in male rats was examined. Specifically, left ventricular (LV) cardiomyocyte length and width, sarcomere length, and number of nuclei were measured in male rats (n = 8 to 17) at 1, 3, 5, 7, 21, 35, and 56 days after creation of an infrarenal aortocaval fistula. In contrast to previously published reports of progressive increases in cardiomyocyte length and cross-sectional area at 5 days post-fistula and beyond in female hearts, cardiomyocyte length and width did not increase significantly in males during the first 35 days of volume overload. Furthermore, a significant decrease in cardiomyocyte length relative to age-matched controls, together with a reduced number of sarcomeres per cell, was noted in male hearts at 5 days post-fistula. There was a concurrent increase in the percentage of mononucleated cardiomyocytes from 11.6% to 18% at 5 days post-fistula. These initial differences could not be attributed to cardiomyocyte proliferation, and treatment with a microtubule stabilizing agent prevented them from occurring. The subsequent significant increase in LV weight without corresponding increases in cardiomyocyte dimensions is indicative of hyperplasia. Thus, these findings indicate hyperplasia resulting from cytokinesis of cardiomyocytes is a key mechanism, independent of hypertrophy, that contributes to the significant increase in LV mass in male hearts subjected to chronic volume overload.

  2. Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats

    PubMed Central

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Rojas, Patricia; Chávez-Saldaña, Margarita; Pérez, Oscar Gutiérrez; Montes, Sergio; Ríos, Camilo

    2011-01-01

    Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals. PMID:21324006

  3. Characterization of flexible ECoG electrode arrays for chronic recording in awake rats

    PubMed Central

    Yeager, John D.; Phillips, Derrick J.; Rector, David M.; Bahr, David F.

    2008-01-01

    We developed a 64 channel flexible polyimide ECoG electrode array and characterized its performance for long term implantation, chronic cortical recording and high resolution mapping of surface evoked potentials in awake rats. To achieve the longest possible recording periods, the flexibility of the electrode array, adhesion between the metals and carrier substrate, and biocompatibility was critical for maintaining the signal integrity. Experimental testing of thin film adhesion was applied to a gold – polyimide system in order to characterize relative interfacial fracture energies for several different adhesion layers, yielding an increase in overall device reliability. We tested several different adhesion techniques including: gold alone without an adhesion layer, titanium-tungsten, tantalum and chromium. We found the titanium-tungsten to be a suitable adhesion layer considering the biocompatibility requirements as well as stability and delamination resistance. While chromium and tantalum produced stronger gold adhesion, concerns over biocompatibility of these materials require further testing. We implanted the polyimide ECoG electrode arrays through a slit made in the skull of rats and recorded cortical surface evoked responses. The arrays performed reliably over a period of at least 100 days and signals compared well with traditional screw electrodes, with better high frequency response characteristics. Since the ultimate goal of chronically implanted electrode arrays is for neural prosthetic devices that need to last many decades, other adhesion layers that would prove safe for implantation may be tested in the same way in order to improve the device reliability. PMID:18640155

  4. Effects of concurrent chronic administration of alcohol and nicotine on rat sperm parameters.

    PubMed

    Ezzatabadipour, M; Azizollahi, S; Sarvazad, A; Mirkahnooj, Z; Mahdinia, Z; Nematollahi-Mahani, S N

    2012-10-01

    The prevalence of cigarette and alcohol consumption is high among young adult males during the reproductive period. The current study aimed to evaluate the impact of concurrent chronic administration of nicotine and ethanol on the quality of sperm in the rat. Fifty healthy Wistar male rats were randomly divided into five groups (n = 10) and were given the following for a period of 50 days: ethanol (E), nicotine (N), ethanol and nicotine (E/N); the control group (C) and an intact (I) group. Body weight as well as the weight, volume and dimensions of the testes and the weight of the cauda epididymidis and vas deference were measured. The concentration, motility, viability and membrane integrity of sperm were also assessed. There were no significant differences between body weight and all testis parameters including weight, volume and dimensions. The concentration and motility of sperm in the E/N group was significantly reduced compared with the control group (P < 0.01). Nevertheless, only a marginally significant decrease in sperm viability was found in the E/N group compared with the control group. The study indicates that concurrent chronic administration of ethanol and nicotine may disturb male reproductive function.

  5. Effects of chronic treatment with methylphenidate on oxidative stress and inflammation in hippocampus of adult rats.

    PubMed

    Motaghinejad, Majid; Motevalian, Manijeh; Shabab, Behnaz

    2016-04-21

    Methylphenidate (MPH) is a central stimulant, prescribed for the treatment of attention deficit/hyperactivity disorder. The long-term behavioral consequences of MPH treatment are unknown. In this study, the oxidative stress and neuroinflammation induced by various doses of MPH were investigated. Forty adult male rats were divided into 5 groups; and treated with different doses of MPH for 21 days. Twenty four hours after drug treatment, Open Field Test (OFT) was performed in all animals. At the end of the study, blood cortisol level (BCL) was measured and hippocampus was isolated and oxidative stress and inflammation parameters and histological changes were analyzed. Chronic MPH at all doses decreased central square entries, number of rearing, ambulation distance and time spent in central square in OFT. BCL increased in doses 10 and 20mg/kg of MPH. Furthermore, MPH in all doses markedly increased lipid peroxidation, mitochondrial oxidized glutathione (GSSG) level, Interleukin 1β (IL-1β) and Tumor Necrosis Factor α (TNF-α) in isolated hippocampus. MPH (10 and 20mg/kg) treated groups had decreased mitochondrial reduced glutathione (GSH) content, and reduced superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRx) activities. 10 and 20mg/kg of MPH change cell density and morphology of cells in Dentate Gyrus (DG) and CA1 areas of hippocampus. Chronic treatment with high doses of MPH can cause oxidative stress, neuroinflammation and neurodegeneration in hippocampus of adult rats.

  6. Relationships between NOS2 and HO-1 in liver of rats with chronic bile duct ligation.

    PubMed

    Flores, Olga; Criado, Manuela; Sánchez-Rodríguez, Angel; Hidalgo, Froilán; Collía, Francisco; López-Novoa, José Miguel; Esteller, Alejandro

    2005-05-01

    An increased expression and activity of the heme oxygenase-1 (HO-1) in the liver has been observed in models of hepatic damage. Nitric oxide (NO) seems to be involved in HO-1 regulation. The aim of this work is to assess HO-1 induction and heme oxygenase (HO) activity in rats with bile duct ligation (BDL). We have assessed the effect of chronic inhibition of the NO synthesis by N(G)-nitro-l-arginine methyl ester (l-NAME) on HO-1 induction and HO activity. In the BDL animals, compared with sham-operated ones, we found an increased plasma nitrite and bilirubin concentration, and a marked liver expression of inducible nitric oxide synthase and HO-1, assessed by both Western blot and immunohistochemistry. Chronic l-NAME treatment prevented plasma nitrite increase in animals subjected to BDL. BDL animals treated with l-NAME, compared with untreated BDL rats, showed an important decrease in HO-1 expression and in HO activity (assessed as a decreased plasma bilirubin and bilirubin excretion). In conclusion, our experiments show parallel changes in expression and activity of HO-1 and NOS2 activity in the BDL model of liver damage and suggest that increased NO production is involved in HO-1 overexpression.

  7. Acute and chronic head-down tail suspension diminishes cerebral perfusion in rats

    NASA Technical Reports Server (NTRS)

    Wilkerson, M. Keith; Colleran, Patrick N.; Delp, Michael D.

    2002-01-01

    The purpose of this study was to test the hypothesis that regional brain blood flow and vascular resistance are altered by acute and chronic head-down tail suspension (HDT). Regional cerebral blood flow, arterial pressure, heart rate, and vascular resistance were measured in a group of control rats during normal standing and following 10 min of HDT and in two other groups of rats after 7 and 28 days of HDT. Heart rate was not different among conditions, whereas mean arterial pressure was elevated at 10 min of HDT relative to the other conditions. Total brain blood flow was reduced from that during standing by 48, 24, and 27% following 10 min and 7 and 28 days of HDT, respectively. Regional blood flows to all cerebral tissues and the eyes were reduced with 10 min of HDT and remained lower in the eye, olfactory bulbs, left and right cerebrum, thalamic region, and the midbrain with 7 and 28 days of HDT. Total brain vascular resistance was 116, 44, and 38% greater following 10 min and 7 and 28 days of HDT, respectively, relative to that during control standing. Vascular resistance was elevated in all cerebral regions with 10 min of HDT and remained higher than control levels in most brain regions. These results demonstrate that HDT results in chronic elevations in total and regional cerebral vascular resistance, and this may be the underlying stimulus for the HDT-induced smooth muscle hypertrophy of cerebral resistance arteries.

  8. Characterization of flexible ECoG electrode arrays for chronic recording in awake rats.

    PubMed

    Yeager, John D; Phillips, Derrick J; Rector, David M; Bahr, David F

    2008-08-30

    We developed a 64-channel flexible polyimide ECoG electrode array and characterized its performance for long-term implantation, chronic cortical recording and high resolution mapping of surface-evoked potentials in awake rats. To achieve the longest possible recording periods, the flexibility of the electrode array, adhesion between the metals and carrier substrate, and biocompatibility were critical for maintaining the signal integrity. Experimental testing of thin film adhesion was applied to a gold-polyimide system in order to characterize relative interfacial fracture energies for several different adhesion layers, yielding an increase in overall device reliability. We tested several different adhesion techniques including the following: gold alone without an adhesion layer, titanium-tungsten, tantalum and chromium. We found titanium-tungsten to be a suitable adhesion layer considering the biocompatibility requirements as well as stability and delamination resistance. While chromium and tantalum produced stronger gold adhesion, concerns over biocompatibility of these materials require further testing. We implanted the polyimide ECoG electrode arrays through a slit made in the skull of rats and recorded cortical surface evoked responses. The arrays performed reliably over a period of at least 100 days and signals compared well with traditional screw electrodes, with better high frequency response characteristics. Since the ultimate goal of chronically implanted electrode arrays is for neural prosthetic devices that need to last many decades, other adhesion layers that would prove safe for implantation may be tested in the same way in order to improve the device reliability.

  9. Nit