Rat Model Of Toxicity Research Articles

Functional connectivity in a rat model of Alzheimer's disease during a working memory task.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of memory. Impairment of working memory was typically observed in AD. The concept of brain functional connectivity plays an important role in neuroscience as a useful tool to understand the organized behavior of brain. Hence, the purpose of this study is to investigate the possible mechanism of working memory deficits in AD from a new perspective of functional connectivity. Rats were randomly divided into 2 groups: Aβ injection group (Aβ₁₋₄₂-induced toxicity rat model) and control group. Multi-channel local field potentials (LFPs) were obtained from rat prefrontal cortex with implanted microelectrode arrays while the rats performed a Y-maze working memory task. The short-time Fourier transform was utilized to analyze the power changes in LFPs and sub-bands (in particular theta and low gamma bands) were extracted via band filtering. Then the Directed transfer function (DTF) method was applied to calculate the functional connections among LFPs. From the DTF calculation, the causal networks in the sub-bands were identified. DTFmean (mean of connectivity matrix elements) was used to quantify connection strength as well as global efficiency (Eglob) was calculated to quantitatively describe the efficient of information transfer in the network. Our results showed that both connection strength and efficient of information transfer increased during the working memory task in the control group; by contrast, there was no significantly change in the Aβ injection group. These findings could lead to improve the understanding of the mechanism of working memory deficits in AD.

The effects of levosimendan and dobutamine in experimental bupivacaine-induced cardiotoxicity

BackgroundAccidental intravenous exposure to bupivacaine is highly cardiotoxic and may lead to death. Positive inotropic agents are usually utilized in resuscitative efforts. We have compared the efficacy of levosimendan, a novel inotropic agent, with dobutamine and their combination in a rat model of bupivacaine intoxication.MethodsTwenty-eight male Wistar albino rats weighing between 250-300 g were divided into these four groups: control (C), levosimendan (L), dobutamine (D) and dobutamine+levosimendan (D+L). Bupivacaine was administered at a dose of 3 mg/kg/min until cardiac arrest occurred or for 120 min. ECG, heart rate, blood pressure, arterial blood gases, and end tidal CO2 levels were monitored. Levosimendan was administered as a bolus of 12 μg/kg for 10 min and continued as an infusion at 0.3 μg/kg/min. Dobutamine was infused at a dose of 3 μg/kg/min. The time required for a 50% and 75% decrease in heart rate and blood pressure with a total time to cardiac arrest and bupivacaine dose for obtaining cardiac arrest were analyzed.ResultsTime periods for heart rate reductions of 50% and 75% were significantly longer in groups L (903, 1198 s), D (984, 1542 s) and L+D (1705, 3152 s) compared with the control group (345, 538 s p < 0.001). Median times to mean blood pressure reductions of 50% and 75% were 399 - 504 s in the control group, 1005 -1204 s in group L, 685 - 1009 s in group D and 1544- 2982 s in group L+D, and the difference was significant compared with the control group. Median time duration to asystole was 703 s in the control group compared with 1385 s in group L, 1789 s in group D and 3557 s in group L+D. Time to cardiac arrest was significantly higher in all 3 study groups. It was also significantly higher in the L+D group compared with both groups L and D separately.ConclusionA combination of dobutamine with levosimendan significantly increased survival times in this bupivacaine-induced toxicity rat model compared with the control, levosimendan, and dobutamine groups.

Low-frequency (1Hz) repetitive transcranial magnetic stimulation (rTMS) reverses Aβ1–42-mediated memory deficits in rats

Accumulating evidence shows the disruption of hippocampal neurotrophins secretion leads to memory deficits in Alzheimer's disease (AD) animal models. Invasive injection of exogenous neurotrophins into hippocampus reverses spatial memory deficits, but its clinical application is limited by traumatic brain injury during the injection procedure. Notably, recent studies have demonstrated that noninvasive repetitive transcranial magnetic stimulation (rTMS) increases endogenous neurotrophins contents in the brain of normal rats. Whether low-frequency rTMS can reverse Aβ1–42-mediated decrease in hippocampal neurotrophins contents and spatial memory impairment is still unclear. Here, we reported that severe deficit in long-term potentiation (LTP) and spatial memory were observed in an Aβ1–42-induced toxicity rat model. Furthermore, neurotrophins (NGF and BDNF) and NMDA-receptor levels were decreased after Aβ injection. However, low-frequency rTMS markedly reversed the decrease in neurotrophins contents. And the rTMS-induced increment of neurotrophins up-regulated hippocampal NMDA-receptor expression. Moreover, low-frequency rTMS rescued deficits in LTP and spatial memory of rats with Aβ-injection. These results indicate that low-frequency rTMS noninvasively and effectively increases hippocampal neurotrophins and NMDA-receptor contents in Aβ1–42-induced toxicity model rats, which helps to enhance hippocampal LTP and reverses Aβ1–42-mediated memory deficits.

Protective effect of conjugated linolenic acid isomers present in vegetable oils against arsenite-induced renal toxicity in rat model

ObjectiveThe aim of the present study was to investigate the protective effect of conjugated linolenic acid (CLnA), present in vegetable oils against arsenite-induced renal oxidative stress. MethodsAlbino rats were divided into six groups. Group 1 was control and group 2 was treated with sodium arsenite (Sa; 10 mg/kg BW). Rats in groups 3 and 4 were treated with mixture of α-eleostearic acid and punicic acid (1:1) (0.5% and 1.0%, respectively), whereas rats in the groups 5 and 6 were treated with 0.5% of α-eleostearic acid and 0.5% of punicic acid, respectively, along with Sa by oral gavage once daily. ResultsResults revealed that activity of antioxidant enzymes and total reduced glutathione content, total protein content, and phospholipid content in kidney were decreased significantly in arsenite-treated group compared with control. Activity of nitric oxide synthase, peroxidation of lipid, protein oxidation, total cholesterol content, total lipid content of kidney, and plasma creatinine level were increased significantly (P < 0.05) in arsenite-treated rats compared with control. Fatty-acid composition of renal lipids showed significant decrease in monounsaturated fatty acid, polyunsaturated fatty acid (PUFA) content, and increase in saturated fatty acid content due to oxidative stress. PUFA such as γ-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid decreased significantly with significant (P < 0.05) increase in arachidonic acid content after Sa treatment. Administration of blended product of both the isomers caused better restoration of renal fatty acids and other altered parameters. ConclusionCLnA isomers caused amelioration of renal oxidative stress and the isomers showed synergistic activity.

Amelioration of aluminium induced toxicity by Allium sativum

Garlic (Allium sativum L., Liliaceae) is a nature’s boon to mankind, which has played an important dietary and therapeutic medicinal role throughout the history of mankind. Aluminum (Al) is a potent neurotoxin and has been associated with Alzheimer's disease causality for decades. The study aims to demonstrate the ameliorative effect of garlic extract against aluminium-induced toxicity in rat model. Animals received aluminium nitrate 32.5 mg/kg (1/2 LD50 of Al (NO3)3 i.p.) once only. Different doses of garlic extract (25, 50 and 100 mg/kg) was administered for 3 days after 24 h of Al exposure. The activity of AChE was inhibited in all the parts of the brain, significant rise was observed in the activities of serum LDH, AST and ALT whereas serum protein was declined after toxicant exposure. The activity of δ-aminolevulinic acid dehydratase in blood and δ-aminolevulinic acid synthetase in brain depicted fall after Al exposure. Al provoked significant increase in the level of cholesterol, triglyceride, creatinine and urea level in serum. TBARS level, total and esterified cholesterol in liver, kidney and brain were significantly higher with concomitant fall in reduced glutathione content during toxicity. Garlic markedly attenuated oxidative stress by scavenging various free radicals significantly restored the deranged biochemical variables. Histopathological changes in liver, kidney and brain were also recouped and biochemical findings substantiated. Results of present study concluded that garlic can counteract the deleterious effects of aluminium. Key words: Garlic extract, aluminium, oxidative stress, liver, kidney, brain.

S-Allyl-Cysteines Reduce Amelioration of Aluminum Induced Toxicity in Rats

Problem statement: Aluminum (Al) is a trivalent cation found in its ionic form in most kinds of animal tissues and in natural waters everywhere. Approach: It is a potent neurotoxin and has been associated in the pathogenesis of several clinical disorders including Alzheimer’s disease. Results: The aim of the study was to demonstrate the protective effect of S-Allyl-Cysteines (SAC) against Al-induced toxicity in rat model on certain biochemical parameters, lipid peroxidation and oxidative stress enzymes of white albino rats. Six rats per group were divided into various treatment groups. Group one rats were given normal saline and served as control group. Group two animals received Al as aluminum nitrate 32.5 mg (i.p.) for the induction of toxicity. Group three to five received different doses of SAC (25, 50 and 100 mg kg-1) for 3 days after 24 h of Al toxicity. Rats were orally administered their respective doses every day for 3 days. Evaluations were made in blood and tissues. The activity of Acetylcholinesterase (AchE) was inhibited in all the parts of brain after Al intoxication. Significant rise were observed the Activities of Serum Transaminases (AST and ALT) after toxicant exposure. The activity of δ-Aminolevulinic acid Dehydratase (ALAD) in blood and δ-Aminolevulinic Acid Synthetase (ALAS) in brain was decreased after Al exposure. Al significant increased cholesterol, triglyceride, creatinine and urea level in serum. TBARS level was significantly higher and GSH content were significantly lower during toxicity. Total and esterified cholesterol in liver, kidney and brain were increased after Al exposure. Histopathological changes in liver, kidney and brain were also recouped with the therapy. Conclusion/Recommendations: Our data proved that SAC which is a bioactive and bioavailable component of garlic has organosulfur compounds which regulates the thiol status of the cell and scavenges free radicals and work as an antioxidant. Thus SAC effectively reduces cognitive dysfunction and oxidative damage induced by Al.

Characterization of Renal Papillary Antigen 1 (RPA-1), a Biomarker of Renal Papillary Necrosis

Renal papillary necrosis (RPN) is a relatively common toxicity observed in preclinical drug safety testing. It is also observed in a variety of human diseases. RPN is difficult to diagnose without expensive scanning methods or histopathology. A noninvasive biomarker that could be detected at early stages of kidney damage would be of great value both to preclinical drug safety testing and in the clinic. An antibody raised to an unknown epitope of an antigen in rat kidney papilla was found to be specific for collecting duct cells in the kidney; this was termed renal papillary antigen 1 (RPA-1). In this study, the authors show that RPA-1 is an early biomarker of RPN in two different rat models of toxicity: 2-bromoethanamine (BEA) and N-phenylanthranilic acid (NPAA). RPA-1 can be detected in urine at early stages of toxicity and correlates well with the histopathology observed. We also characterized the biochemical properties of RPA-1 and found that the antigen is a high molecular weight membrane bound glycoprotein, with the epitope likely to be carried on an N-linked carbohydrate structure. This study demonstrates that RPA-1 is an excellent marker of RPN that can be used to detect this toxicity in preclinical safety testing.

Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper–indomethacin in rats

To evaluate, for the first time, the efficacy of copper-indomethacin in the inhibition of aberrant crypt foci formation using the azoxymethane-induced adenocarcinoma model, to examine cell viability in the HCT-116 colorectal cancer cell line, gastrointestinal permeability, mitochondrial oxidative damage, and renal toxicity in rat models. Azoxymethane-induced adenocarcinoma rats were dosed with indomethacin and copper-indomethacin for 28 days and aberrant crypt foci were evaluated. HCT-116 colorectal cancer cells were exposed to indomethacin and copper-indomethacin at 0-250 microg/mL (0-698 microM for indomethacin, and 0-147 microM for copper-indomethacin), and cell viability was measured. Acute gastrointestinal toxicity was measured using gastrointestinal permeability markers, gastrointestinal ulceration and bleeding, and measurement of an acute-phase protein haptoglobin. Effects of acute and chronic administration of indomethacin and copper-indomethacin on urinary electrolyte concentrations were examined. Both indomethacin and copper-indomethacin resulted in a significant reduction in aberrant crypt foci in azoxymethane-treated rats. In parallel, high concentrations of indomethacin and copper-indomethacin also reduced cell viability in HCT-116 colorectal cancer cells. However, copper-indomethacin was considerably safer in all measures of gastrointestinal toxicity compared to indomethacin. In addition, indomethacin reduced urinary electrolytes at an ulcerogenic dose of 10 mg/kg acutely and chronically at 3.0 mg/kg for 28 days, whereas copper-indomethacin at equimolar doses of indomethacin affected urine electrolytes after acute dosing but not after chronic dosing for 28 days. Copper-indomethacin has both gastrointestinal and renal sparing properties while maintaining efficacy in experimental adenocarcinoma.

Identification of Urinary Biomarkers Useful for Distinguishing a Difference in Mechanism of Toxicity in Rat Model of Cholestasis

This (1)H nuclear magnetic resonance metabonomics study was aimed to determine urinary biomarkers of cholestasis resulting from inhibition of biliary secretion of bile or obstruction of bile flow. To inhibit biliary secretion of bile, cyclosporine A was administered to male Sprague-Dawley rats. Obstruction of bile flow was induced by administration of 4,4'-methylene dianiline, alpha-naphthylisothiocyanate or bile duct ligation. Clinical pathological and histopathological examinations were performed to confirm cholestatic injury and (1)H nuclear magnetic resonance spectral data for urine samples were analysed to determine similarities and differences in profiles of metabolites using the Spotfire. In cyclosporine A-treated groups, serum total bilirubin and bile acid were significantly increased but no remarkable hepatic histopathological-changes were observed. In 4,4'-methylene dianiline-, alpha-naphthylisothiocyanate- and bile duct ligation-treated groups, serum alkaline phosphatase, gamma-glutamyltranspeptidase and total bilirubin levels increased significantly, and hepatic histopathological-changes were observed. On urinary (1)H nuclear magnetic resonance spectral analysis, area intensities derived from 0.66 to 1.90 ppm were decreased by cyclosporine A, whereas they were increased by other treatments. These metabolites were identified using the NMR suite as bile acids, branched-chain amino acids, n-butyrate, propionate, methyl malonate and valerate. These metabolites were further investigated by K-means clustering analysis. The cluster of these metabolites is considered to be altered by cholestasis. We conclude that bile acids, valine and methyl malonate have a possibility to be urinary cholestatic biomarkers, which distinguish a difference in mechanism of toxicity. (1)H nuclear magnetic resonance metabonomics thus appears to be useful for determining the mechanisms of toxicity and can be front-loaded in drug safety evaluation and biomarker discovery.

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. A number of non-hydroxamic acid-containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1alpha- and oncostatin M-induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean +/- SEM damage score 1.3 +/- 0.3, versus 2.2 +/- 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs.

Effects of Caffeic Acid Phenethyl Ester, Ellagic Acid, Sulforaphane and Curcumin on Diazinon Induced Damage to the Lungs, Liver and Kidneys in An Acute Toxicity Rat Model

The aim of this study was to investigate the possible protective effects of caffeic acid phenethyl ester (CAPE), ellagic acid (EA), sulforaphane (SFN) and curcumin (CUR) against the toxic effects of diazinon (DI). Sixty Sprague Dawley rats were randomly divided into 10 groups. Five groups were allocated as control groups comprising unmedicated control, CAPE, EA, SFN and CUR control groups. The remaining five groups were the study groups comprising DI, DI + CAPE, DI + EA, DI + SFN, and DI + CUR groups. The animals were sacrified 24 h after drug administrations. DI caused a decrease in acetyl cholinesterase (AChE) activity (P<0.05) and increases in γ-glutamyltransferase (GGT) and amylase activities. It also damaged the kidney, liver, and lung tissues. The negative effects of DI on these enzymes were confirmed histopathologically. Also, CAPE, EA, SFN and CUR reduced amylase and GGT activities and caused an increase in the AChE activities that were increased due to the toxic effects of DI. Thus, it was determined biochemically and histopathologically that these medication reduced the degenerative toxic effects created by DI in the lung, liver and kidney tissues. These findings led us to believe that CAPE, EA, SFN and CUR may be used as protective medicines in acute DI intoxication.

Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models

Dosing and route of administration of N-acetylcysteine (NAC) for protection against cisplatin (CDDP) nephrotoxicity was investigated in rats. Two models of toxicity were tested: a single high dose of CDDP (10 mg/kg intraperitoneally (IP)), and multiple low dose treatments (1 mg/kg IP twice a day for 4 days, 10 days rest, then repeated). NAC (50-1,200 mg/kg) was given to the rats by IP, oral (PO), intravenous (IV) and intra-arterial (IA) routes. Renal toxicity was determined by blood urea nitrogen (BUN) and creatinine (CR) levels 3 days after treatment. Blood collected 15 min after NAC was analyzed for total NAC. Both models of CDDP administration produced renal toxicity. In the single dose CDDP model, NAC 400 mg/kg given IP and PO produced no renal protection as measured by BUN (131.8 +/- 8.2 and 123.3 +/- 8.2, respectively) or CR (2.3 +/- 0.38 and 1.77 +/- 0.21, respectively). IV NAC reduced nephrotoxicity, (BUN 26.3 +/- 6.8, CR 0.47 +/- 0.15). NAC 50 mg/kg IA gave better protection than IV. In the repeated-dose CDDP model, nephrotoxicity was blocked by 800 mg/kg NAC given IV but not IP. Blood concentrations of total NAC showed a dose response after IV NAC, but high dose NAC (1,200 mg/kg) by the PO route gave very low levels of NAC. Thus the protective properties of NAC are affected by the dose and route of administration.

Ginkgo biloba extract protects against mercury(II)-induced oxidative tissue damage in rats

Mercury(II) is a highly toxic metal which induces oxidative stress in the body. In this study we aimed to investigate the possible protective effect of Ginkgo biloba (EGb), an antioxidant agent, against experimental mercury toxicity in rat model. Following a single dose of 5 mg/kg mercuric chloride (HgCl 2; Hg group) either saline or EGb (150 mg/kg) was administered for 5 days. After decapitation of the rats trunk blood was obtained and the tissue samples from the brain, lung, liver, and kidney were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Formation of reactive oxygen species in the tissue samples was monitored by chemiluminescence (CL) technique. BUN, creatinin, ALT, and AST levels and tumor necrosis factor-α (TNF-α) and lactate dehydrogenase (LDH) activity were assayed in serum samples. The results revealed that HgCl 2 induced oxidative damage caused significant decrease in GSH level, significant increase in MDA level, MPO activity and collagen content of the tissues. Treatment of rats with EGb significantly increased the GSH level and decreased the MDA level, MPO activity, and collagen contents. Similarly, serum ALT, AST and BUN levels, as well as LDH and TNF-α, were elevated in the Hg group as compared to control group. On the other hand, EGb treatment reversed all these biochemical indices. Our results implicate that mercury-induced oxidative damage in brain, lung, liver, and kidney tissues protected by G. biloba extract, with its antioxidant effects.

Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen

Cisplatin ototoxicity has been associated with the generation of toxic levels of reactive oxygen species (ROS) which can lead to injury or loss of outer hair cells in the organ of Corti, damage to the stria vascularis, and loss of spiral ganglion cells, resulting in permanent hearing loss. In an attempt to reduce the formation of ROS and to bolster the innate oxidative stress defenses of the cochlea, we tested individual and combined formulations of allopurinol, a xanthine oxidase inhibitor, and ebselen, a glutathione peroxidase mimic. We used an acute cisplatin toxicity rat model (16 mg/kg i.p.) to analyze allopurinol and ebselen alone and in combination for their ability to reduce cisplatin associated hearing loss and nephrotoxicity. The results from our studies indicate that a combined formulation of ebselen and allopurinol affords significant protection to the cochlea and kidney from cisplatin toxicity. In the cochlea, protection is dependent on the preservation of outer hair cell number, while in the kidney, protection is associated with the preservation of proximal tubular epithelia. Further evaluation of the chemoprotective effects of ebselen and allopurinol on cisplatin side effects in the presence of tumor appears warranted.

Pentoxifylline in amphotericin B toxicity rat model

The mechanism of acute nephrotoxicity following the administration of amphotericin B (AmpB) remains unclear despite a number of studies describing hypermagnesuria, hyperkaluria, and hemodynamic changes. The present experiments attempted to elucidate the mechanism by using a novel hemorheologic probe, pentoxifylline (PTX). Acute studies were performed with rats given single intravenous doses of AmpB (1 mg/kg of body weight) with or without intraperitoneal PTX (45 mg/kg). Renal function, assessed by inulin clearance (CLIN) and electrolyte handling, and morphology were compared with those of controls given sterile water and PTX. A significant decrease in CLIN not observed in rats given AmpB and PTX or in the controls was found in rats given AmpB. Electrolyte handling was not different among groups. Whereas pronounced (3 and 4+ on a scale of mild to significant [1+ to 4+]) vascular congestion was found in rats given AmpB, rats coadministered PTX had mild (1 and 2+) medullary and glomerular vascular congestion. In chronic studies, intravenous AmpB (1 mg/kg per day) or sterile water was coadministered with intraperitoneal PTX (45 mg/kg every 12 h) or saline for 10 days. Mean CLIN of rats coadministered AmpB and PTX was not significantly different from that of PTX control rats (1.61 +/- 0.19 versus 1.31 +/- 0.29 ml/min per g of kidney weight). A 46% decline in CLIN was found in rats treated with AmpB and saline (P less than 0.05). Renal sodium and potassium excretions were increased in both AmpB-treated groups compared with controls. Coupled with histologic evidence of the acute studies, these data suggest that the benefit of PTX in the prevention of AmpB-induced nephrotoxicity is, in part, due to vascular decongestion.