Mitochondrial Dysfunction In Rats Research Articles

Sulfur Dioxide Contributes to the Cardiac and Mitochondrial Dysfunction in Rats.

Epidemiological studies have demonstrated an association between sulfur dioxide (SO2) and an increase of morbidity and mortality of cardiovascular diseases, such as ischemic heart disease, heart failure, and arrhythmia. Mitochondrion is the most sensitive organelle in myocardium of animals exposed to SO2 Here we study the molecular characterization of mitochondrial dysfunction in cardiac muscles of rat after SO2 exposure. We found that the cytochrome c oxidase (COX) activity, mitochondrial membrane potential (ΔΨm), ATP contents, mitochondrial DNA (mtDNA) contents, and mRNA expression of complexes IV and V subunits encoded by mtDNA were decreased after NaHSO3 treatment in vitro or SO2 inhalation in vivo The mitochondrial dysfunctions were accompanied by depressions of co-activator of peroxisome proliferator activated receptor gamma (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (TFAM) mRNA and protein. We observed swollen mitochondria and lower amounts of cristae in hearts of rats after 3.5 mg/m(3) SO2 inhalation for 30 days. Interestingly, NaHSO3 induced mitochondrial dysfunctions marked by ΔΨm and ATP reduction could be inhibited by an antioxidant N-acetyl-L-cysteine (NALC), accompanied by the restoration of transcriptional factors expressions. The cardiac mitochondrial dysfunctions could also be alleviated by overexpression of TFAM. SO2 induced abnormal left ventricular function was restored by NALC in vivo Our findings demonstrate that SO2 induces cardiac and mitochondrial dysfunction. And inhibition of reactive oxygen species and enhancing the transcriptional network controlling mitochondrial biogenesis can mitigate the SO2-induced mitochondrial dysfunction.

Thymol, a dietary monoterpene phenol abrogates mitochondrial dysfunction in β-adrenergic agonist induced myocardial infarcted rats by inhibiting oxidative stress

Mitochondrial dysfunction has been suggested to be one of the important pathological events in isoproterenol (ISO), a synthetic catecholamine and β-adrenergic agonist induced myocardial infarction (MI). In this context, we have evaluated the impact of thymol against ISO induced oxidative stress and calcium uniporter malfunction involved in the pathology of mitochondrial dysfunction in rats. Male albino Wistar rats were pre and co-treated with thymol (7.5 mg/kg body weight) daily for 7 days. Isoproterenol (100 mg/kg body weight) was subcutaneously injected into rats on 6th and 7th day to induce MI. To explore the extent of cardiac mitochondrial damage, the activities/levels of cardiac marker enzymes, mitochondrial lipid peroxidation products, antioxidants, lipids, calcium, adenosine triphosphate and multi marker enzymes were evaluated. Isoproterenol induced myocardial infarcted rats showed a significant increase in the activities of cardiac diagnostic markers, heart mitochondrial lipid peroxidation, lipids, calcium, and a significant decrease in the activities/levels of heart mitochondrial superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, isocitrate, malate, α-ketoglutarate and NADH-dehydrogenases, cytochrome-C-oxidase, and adenosine triphosphate. Thymol pre and co-treatment showed near normalized effects on all the biochemical parameters studied. Transmission electron microscopic findings and mitochondrial swelling studies confirmed our biochemical findings. The in vitro study also revealed the potent free-radical scavenging activity of thymol. Thus, thymol attenuates the involvement of ISO against oxidative stress and calcium uniporter malfunction associated with mitochondrial dysfunction in rats.

Role of Rho Kinase Inhibition in the Protective Effect of Fasudil and Simvastatin Against 3-Nitropropionic Acid-Induced Striatal Neurodegeneration and Mitochondrial Dysfunction in Rats.

3-Nitropropionic acid (3-NP)-induced neurotoxicity is an experimental model which mimics the pathology and motor abnormalities seen in Huntington's disease (HD) in human. The present investigation was directed to estimate the role of rho kinase (ROCK) inhibition in the possible protective effect of fasudil and simvastatin in 3-NP-induced striatal neurodegeneration in rats. Animals were injected s.c. with 3-NP (20mg/kg/day) for 1week with or without administration of fasudil (10mg/kg/day, p.o.) or simvastatin (20mg/kg/day, p.o.). At the end of experiment, motor and behavioral abnormalities were evaluated. Animals were then sacrificed for measurement of mitochondrial membrane potential as well as succinate dehydrogenase (SDH) and caspase-3 activities in striatum. Moreover, tumor necrosis factor-alpha (TNF-α) level and protein expressions of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ROCK, phosphorylated-Akt (p-Akt), endothelial and inducible nitric oxide synthase (eNOS and iNOS), Bax, and Bcl-2 were estimated. Finally, histological changes as demonstrated by striatum injury score, glial activation, and percentage of altered mitochondria were assessed. Both fasudil and simvastatin effectively inhibited 3-NP-induced behavioral, biochemical, and histological changes through inhibition of ROCK activity. However, fasudil provided more amelioration in histological changes, mitochondrial membrane potential and SDH activity in addition to p-Akt and PGC-1α protein expressions. The present study highlights a significant role of ROCK/p-Akt/eNOS pathway in the protective effects of fasudil and simvastatin on neurotoxicity and mitochondrial dysfunction induced by 3-NP in rats. Thus, specific inhibition of ROCK may be considered a promising new approach in the management of HD.

Protective effects of N-acetylcysteine against hyperoxaluria induced mitochondrial dysfunction in male wistar rats.

The purpose of the present study was to evaluate the nephro-protective potential of N-acetylcysteine against hyperoxaluria-induced renal mitochondrial dysfunction in rats. Nine days dosing of 0.4 % ethylene glycol +1 % ammonium chloride, developed hyperoxaluria in male wistar rats which resulted in renal injury and dysfunction as supported by increased level of urinary lactate dehydrogenase, calcium, and decreased creatinine clearance. Mitochondrial oxidative strain in hyperoxaluric animals was evident by decreased levels of superoxide dismutase, glutathione peroxidase, glutathione reductase, reduced glutathione, and an increased lipid peroxidation. Declined activities of respiratory chain enzymes and tricarboxylic acid cycle enzymes showed mitochondrial dysfunction in hyperoxaluric animals. N-acetylcysteine (50 mg/kg, i.p.), by virtue of its -SH reviving power, was able to increase the glutathione levels and thus decrease the oxidative stress in renal mitochondria. Hence, mitochondrial damage is, evidently, an essential event in ethylene glycol-induced hyperoxaluria and N-acetylcysteine presented itself as a safe and effective remedy in combating nephrolithiasis.

Bufei Jianpi granules improve skeletal muscle and mitochondrial dysfunction in rats with chronic obstructive pulmonary disease.

BackgroundBufei Jianpi granules has been confirmed effective in improving pulmonary function, alleviating acute exacerbations, improving six-minute walk distance and quality of life, and benefited in 12-month follow-up in chronic obstructive pulmonary disease (COPD) patients with syndrome of lung-spleen qi deficiency. Skeletal muscle dysfunction (SMD), an important extrapulmonary complication, occurs in the very initiation of COPD and is closely related to morbidity and mortality. To evaluate the efficacy of Bufei Jianpi granules on SMD, we observed skeletal muscular function and histomorphology, mitochondrial morphormetry and proteins in COPD rats induced by cigarette-smoke and Klebsiella pneumoniae.MethodsSeventy-two Sprague–Dawley rats were randomized into Control + Saline, Control + Bufei Jianpi, Control + Aminophylline, COPD + Saline, COPD + Bufei Jianpi and COPD + Aminophylline groups. From week 9 to 20, rats were administrated intragastricly by normal saline, Bufei Jianpi granules and aminophylline, respectively. Muscular tension and fatigue index of intercostal muscle, quadriceps, biceps and soleus were detected by using electrophysiological technology. Pathological and ultrastructural changes and expressions of mitochondrial Bcl-2 nineteen-kilodalton interacting protein 3 (Bnip3) and cytoplasm cytochrome C (Cyto C) in the four skeletal muscles were observed by using optical and electron microscope and western blotting.ResultsThere was no statistical difference among the control rats treated with saline, Bufei Jianpi granules or aminophylline in above-mentioned parameters. Muscular tension, mitochondria volume density (Vv) and compared membrane surface (δm) of the four muscles were significantly lower in COPD + Saline group compared to Control + Saline group, while fatigue index, mitochondria surface area (δ), Bnip3 and Cyto C were higher (P < 0.05). COPD rats showed more morphological changes in muscle tissues than controls, such as atrophy, degeneration, necrosis and matrix hyperplasia. Utrastructurally, mitochondria populations decreased significantly in the four muscles, and were shrunken and even cavitation changed. The up-mentioned parameters were improved in Bufei Jianpi group (P < 0.05) in the four muscles.ConclusionsBufei Jianpi granules can improve skeletal muscle function via improving mitochondria population and function, reducing apoptotic factors such as Bnip3 and Cyto C, and is more effective than aminophylline.

Protective effect of administration of Withania somifera against bromobenzene induced nephrotoxicity and mitochondrial oxidative stress in rats

Background: The present study was conducted to elucidate the protective role of Withania somnifera against bromobenzene induced nephrotoxicity and mitochondrial dysfunction in rats. Methods: In this study, Wistar albino rats of either sex were divided into six groups consisting of six animals each. The first one was control, those in group II received bromobenzene (10 mmol/kg, intragastric intubation) once, but group III and IV animals received W. somnifera (250 and 500 mg/kg, orally), respectively for 8 days followed by bromobenzene once on the 8th day and silymarin (100 mg/kg, orally) was given for 8 days to group V animals and then bromobenzene on the last day. Group VI animals received only W. somnifera (500 mg/kg) for 8 days. Results: The levels of renal lipid peroxidation, lysosomal enzymes and glycoprotein were increased significantly (p < 0.05) in the bromobenzene alone treated rats and antioxidant status and mitochondrial enzymes were found to be decreased, when compared to the control group. The levels of kidney functional markers (urea, uric acid and creatinine) were also found to be abnormal in serum of bromobenzene alone treated rats. On the other hand, administration of W. somnifera (250 and 500 mg/kg) along with bromobenzene offered a significant dose-dependent protection to the biochemical alterations as observed in the bromobenzene alone treated rats, which was also evidenced by histopathology. Conclusion: Thus, the oral administration of W. somnifera significantly protected against the bromobenzene induced nephrotoxicity and renal mitochondrial dysfunction in rats.

Osthole attenuates spinal cord ischemia–reperfusion injury through mitochondrial biogenesis–independent inhibition of mitochondrial dysfunction in rats

BackgroundOsthole, the main bioactive compounds isolated from the traditional Chinese medical herb broad Cnidium monnieri (L.) cusson, has been shown to exert spectrum of pharmacologic activities. The aim of this study was to investigate the potential neuroprotective effects of osthole against spinal cord ischemia–reperfusion injury in rats. Materials and methodsOsthole was administrated at the concentration of 0.1, 1, 10, 50, or 200 mg/kg (intraperitoneally) 1 h before spinal cord ischemia. The effects on spinal cord injury were measured by spinal cord water content, infarct volume, hematoxylin and eosin staining, and neurologic assessment. Mitochondria were purified from injured spinal cord tissue to determine mitochondrial function. ResultsWe found that treatment with osthole (10 and 50 mg/kg) significantly decreased spinal cord water content and infarct volume, preserved normal motor neurons, and improved neurologic functions. These protective effects can be also observed even if the treatment was delayed to 4 h after reperfusion. Osthole treatment preserved mitochondrial membrane potential level, reduced reactive oxygen species production, increased adenosine triphosphate generation, and inhibited cytochrome c release in mitochondrial samples. Moreover, osthole increased mitochondria respiratory chain complex activities in spinal cord tissue, with no effect on mitochondrial DNA content and the expression of mitochondrial-specific transcription factors. ConclusionsAll these findings demonstrate the neuroprotective effect of osthole in spinal cord ischemia–reperfusion injury model and suggest that oshtole-induced neuroprotection was mediated by mitochondrial biogenesis–independent inhibition of mitochondrial dysfunction.

DPP4‐inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high‐fat diet consumption

High-fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase-4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12weeks, after which rats in each group were fed with either vildagliptin (3mg/kg/day) or vehicle for 21days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin-induced long-term depression and neuronal IR phosphorylation, IRS-1 phosphorylation and Akt/PKB-ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon-like-peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.

Interaction of TNF with Angiotensin II Contributes to Mitochondrial Oxidative Stress and Cardiac Damage in Rats

Recent evidence suggests that tumor necrosis factor alpha (TNF) and angiotensin II (ANGII) induce oxidative stress contribute to cardiovascular disease progression. Here, we examined whether an interaction between TNF and ANGII contributes to altered cardiac mitochondrial biogenesis and ATP production to cause cardiac damage in rats. Rats received intraperitoneal injections of TNF (30 µg/kg), TNF + losartan (LOS, 1 mg/kg), or vehicle for 5 days. Left ventricular (LV) function was measured using echocardiography. Rats were sacrificed and LV tissues removed for gene expression, electron paramagnetic resonance and mitochondrial assays. TNF administration significantly increased expression of the NADPH oxidase subunit, gp91phox, and the angiotensin type 1 receptor (AT-1R) and decreased eNOS in the LV of rats. Rats that received TNF only had increased production rates of superoxide, peroxynitrite and total reactive oxygen species (ROS) in the cytosol and increased production rates of superoxide and hydrogen peroxide in mitochondria. Decreased activities of mitochondrial complexes I, II, and III and mitochondrial genes were observed in rats given TNF. In addition, TNF administration also resulted in a decrease in fractional shortening and an increase in Tei index, suggesting diastolic dysfunction. TNF administration with concomitant LOS treatment attenuated mitochondrial damage, restored cardiac function, and decreased expression of AT1-R and NADPH oxidase subunits. Mitochondrial biogenesis and function is severely impaired by TNF as evidenced by downregulation of mitochondrial genes and increased free radical production, and may contribute to cardiac damage. These defects are independent of the downregulation of mitochondrial gene expression, suggesting novel mechanisms for mitochondrial dysfunction in rats given TNF.

Okadaic acid induced neurotoxicity leads to central cholinergic dysfunction in rats

Central cholinergic system is involved in regulation of memory and disturbances in these results in memory loss. Previously, we examined the effect of okadaic acid, OKA (200ng, i.c.v.) on memory impairment and mitochondrial dysfunction in rats. In the present study, we investigated effect of OKA (i.c.v) on cholinergic function by observing acetylcholine level (ACh), acetylcholinestrase (AChE) activity, and mRNA expression of acetylcholinestrase and α7nicotinic receptor (α7-nAChR) as a cholinergic markers in brain areas (cerebellum, striatum cortex and hippocampus). In present work OKA, caused a significant decrease in acetylcholine level, acetylcholinestrase activity and mRNA expression of acetylcholinestrase and α7-nicotinic receptor in rat but these changes were mainly observed in cortex and hippocampus. Further, histopathological study by cresyl violet staining showed neuronal loss in cortex and hippocampus after OKA administration indicating neurotoxicity. Pretreatment with anti-dementic drugs donepezil (AChE inhibitor; 5mg/kg, p.o) and memantine (NMDA receptor antagonist; 10mg/kg, p.o) daily for 13 day prevented cholinergic dysfunction and neuronal loss in cortex and hippocampus of OKA treated rat. Daily per se treatment for 13 day with donepezil decreased acetylcholinestrase activity and increased mRNA expression of acetylcholinestrase and α7-nicotinic receptor. Whereas, per se treatment with memantine daily for 13 day did not affect acetylcholinestrase activity, mRNA expression of acetylcholinestrase and α7-nicotinic receptor. Findings of this work shows that OKA (i.c.v.), apart from memory impairment and mitochondrial dysfunction, as our previous study showed, also induced cholinergic dysfunction and neuronal loss, which can be addressed by antidementic drugs like donepezil and memantine.

Valproate-induced liver mitochondrial dysfunction in rats: A metabonomic approach

Valproate-induced liver mitochondrial dysfunction in rats: A metabonomic approach

Behavioral changes and mitochondrial dysfunction in a rat model of schizophrenia induced by ketamine

Evidence from the literature indicates that mitochondrial dysfunction occurs in schizophrenia and other psychiatric disorders. To produce an animal model that simulates psychotic symptoms analogous to those seen in schizophrenic patients, sub-anesthetic doses of N-methyl-D-aspartate (NMDA) receptor antagonists (such as ketamine) have been used. The aim of this study was to evaluate behavioral changes and mitochondrial dysfunction in rats administered ketamine for 7 consecutive days. Behavioral evaluation was performed using an activity monitor 1, 3 and 6 h after the last injection. The activities of mitochondrial respiratory chain complexes I, II, I-III and IV in multiple brain regions (prefrontal cortex, striatum and hippocampus) were also evaluated. Our results showed that hyperlocomotion occurred in the ketamine group 1 and 3 h after the last injection. Stereotypic movements were elevated only when animals were evaluated 1 h after receiving ketamine. In addition, we found that ketamine administration affects the respiratory chain, altering the activity of respiratory chain complexes in the striatum and hippocampus after 1 h, those in the prefrontal cortex and hippocampus after 3 h and those in the prefrontal cortex and striatum 6 h after the last administration of ketamine. These findings suggest that ketamine alters the behavior of rats and changes the activity of respiratory chain complexes in multiple brain regions at different time points.

Protective effect of ursodeoxycholic acid on liver mitochondrial function in rats with alloxan-induced diabetes: Link with oxidative stress

We investigated the effects of ursodeoxycholic acid (UDCA) on mitochondrial functions and oxidative stress and evaluated their relationships in the livers of rats with alloxan-induced diabetes. Diabetes was induced in male Wistar rats by a single alloxan injection (150 mg kg − 1 b.w., i.p.). UDCA (40 mg kg − 1 b.w., i.g., 30 days) was administered from the 5th day after the alloxan treatment. Mitochondrial functions were evaluated by oxygen consumption with Clark oxygen electrode using succinate, pyruvate + malate or palmitoyl carnitine as substrates and by determination of succinate dehydrogenase and NADH dehydrogenase activities. Liver mitochondria were used to measure chemiluminiscence enhanced by luminol and lucigenin, reduced liver glutathione and the end-products of lipid peroxidation. The activities of both NADH dehydrogenase and succinate dehydrogenase as well as the respiratory control (RC) value with all the substrates and the ADP/O ratio with pyruvate + malate and succinate as substrates were significantly decreased in diabetic rats. UDCA developed the beneficial effect on the mitochondrial respiration and oxidative phosphorylation parameters in alloxan-treated rats, whereas the activities of mitochondrial enzymes were increased insignificantly after the administration of UDCA. The contents of polar carbonyls and MDA as well as the chemiluminescence with luminol were elevated in liver mitochondria of diabetic rats. The treatment with UDCA normalized all the above parameters measured except the MDA content. UDCA administration prevents mitochondrial dysfunction in rats treated with alloxan and this process is closely connected with inhibition of oxidative stress by this compound.

Protective Effect of Bacoside A on Cigarette Smoking-Induced Brain Mitochondrial Dysfunction in Rats

Chronic exposure to cigarette smoke affects the structure and function of mitochondria, which may account for the pathogenesis of smoking-related diseases. Bacopa monniera Linn., used in traditional Indian medicine for various neurological disorders, was shown to possess mitrochondrial membrane-stabilizing properties in the rat brain during exposure to morphine. We investigated the protective effect of bacoside A, the active principle of Bacopa monniera, against mitochondrial dysfunction in rat brain induced by cigarette smoke. Male Wistar albino rats were exposed to cigarette smoke and administered bacoside A for a period of 12 weeks. The mitochondrial damage in the brain was assessed by examining the levels of lipid peroxides, cholesterol, phospholipid, cholesterol/phospholipid (C/P) ratio, and the activities of isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase, and cytochrome C oxidase. The oxidative phosphorylation (rate of succinate oxidation, respiratory control ratio and ADP/O ratio, and the levels of ATP) was evaluated for the assessment of mitochondrial functional capacity. We found significantly elevated levels of lipid peroxides, cholesterol, and C/P ratio, and decreased levels of phospholipids and mitochondrial enzymes in the rats exposed to cigarette smoke. Measurement of oxidative phosphorylation revealed a marked depletion in all the variables studied. Administration of bacoside A prevented the structural and functional impairment of mitochondria upon exposure to cigarette smoke. From the results, we suggest that chronic cigarette smoke exposure induces damage to the mitochondria and that bacoside A protects the brain from this damage by maintaining the structural and functional integrity of the mitochondrial membrane.

Characterization of mitochondrial dysfunction in rats with carbon tetrachloride-induced cirrhosis: the effect of insulin-like growth factor-I (IGF-I)

Characterization of mitochondrial dysfunction in rats with carbon tetrachloride-induced cirrhosis: the effect of insulin-like growth factor-I (IGF-I)

Characterization of mitochondrial dysfunction in rats with carbon tetrachloride-induced cirrhosis: the effect of insulin-like growth factor-I (IGF-I)

Characterization of mitochondrial dysfunction in rats with carbon tetrachloride-induced cirrhosis: the effect of insulin-like growth factor-I (IGF-I)

Role of the autonomic nervous system in cyclophosphamide-induced heart mitochondrial dysfunction in rats

Role of the autonomic nervous system in cyclophosphamide-induced heart mitochondrial dysfunction in rats

Effects of Prostaglandin E1on the Recovery of Ischemia-Induced Liver Mitochondrial Dysfunction in Rats with Cirrhosis

Interruption of hepatic blood supply for 60 min deteriorated liver mitochondrial respiratory functional indices--that is, respiratory control index (RCI) and the rate of oxygen consumption in state-III respiration (ST III O2). Recovery of ischemia-induced decreases in these functional indices in a saline-administered cirrhotic liver group was retarded compared with that in a normal liver group, and significantly low RCI and ST III O2 persisted 15 min after reperfusion. Prostaglandin E1 (PGE1) did not improve ischemia-induced decreases in RCI and ST III O2 but accelerated the recovery of mitochondrial respiratory function after reperfusion. Adenosine triphosphate (ATP) levels were markedly decreased during ischemia, and retardation of ATP recovery was also observed in rats with cirrhosis. PGE1 improved the recovery of ATP level in rats with cirrhosis. Liver blood flow in the cirrhotic liver was significantly lower than that of the normal liver. PGE1 enhanced liver blood flow. These results indicate that retardation of the recovery of RCI and ST III O2 in the cirrhotic liver might be based on the decrease in tissue blood flow and that agents increasing tissue blood flow might contribute to the acceleration of the recovery of mitochondrial respiratory function.