Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction

The present study was designed to explore the mechanism of hesperidin action via the nitric oxide pathway in the protection against ischemic reperfusion cerebral injury-induced memory dysfunction. Male Wistar rats (200-220 g) were subjected to bilateral carotid artery occlusion for 30 min followed by 24 h reperfusion. Hesperidin (50 and 100 mg/kg, po) pretreatment was given for 7 days before animals were subjected to cerebral I/R injury. Various behavioral tests (rotarod performance and memory retention), biochemical parameters (lipid peroxidation, nitrite concentration, glutathione levels, superoxide dismutase activity and catalase activity), mitochondrial complex enzyme dysfunctions (complex I, II, III and IV) and histopathological alterations were subsequently assessed in hippocampus. Seven days of hesperidin (50 and 100 mg/kg) treatment significantly improved neurobehavioral alterations (delayed fall off time and increased memory retention), oxidative defense and mitochondrial complex enzyme activities in hippocampus compared to control (I/R) animals. In addition, hesperidin treatment significantly attenuated histopathological alterations compared to control (I/R) animals. L-arginine (100 mg/kg) pretreatment attenuated the protective effect of the lower dose of hesperidin on memory behavior, biochemical and mitochondrial dysfunction compared with hesperidin alone. However, L-NAME pretreatment significantly potentiated the protective effect of hesperidin. The present study suggests that the L-arginine-NO signaling pathway is involved in the protective effect of hesperidin against cerebral I/R-induced memory dysfunction and biochemical alterations in rats.     

Comparison of cardioprotective efficacy resulting from a combination of atorvastatin and ischaemic post‐conditioning in diabetic and non‐diabetic rats

相似文献   

Protective effect of HMG CoA reductase inhibitors against running wheel activity induced fatigue,anxiety like behavior,oxidative stress and mitochondrial dysfunction in mice

BackgroundChronic fatigue stress (CFS) is an important health problem with unknown causes and unsatisfactory prevention strategies, often characterized by long-lasting and debilitating fatigue, myalgia, impairment of neuro-cognitive functions along with other common symptoms. The present study has been designed to explore the protective effect of statins against running wheel activity induced fatigue anxiety.MethodsMale albino Laca mice (20–30 g) were subjected to swim stress induced fatigue in a running wheel activity apparatus. Atorvastatin (10, 20 mg/kg, po) and fluvastatin (5, 10 mg/kg, po) were administered daily for 21 days, one hour prior to the animals being subjected to running wheel activity test session of 6 min. Various behavioral tests (running wheel activity, locomotor activity and elevated plus maze test), biochemical parameters (lipid peroxidation, nitrite concentration, glutathione levels and catalase activity) and mitochondrial complex enzyme dysfunctions (complex I, II, III and IV) were subsequently assessed.ResultsAnimals exposed to 6 min test session on running wheel for 21 days showed a significant decrease in number of wheel rotations per 6 min indicating fatigue stress like behavior. Treatment with atorvastatin (10 and 20 mg/kg) and fluvastatin (10 mg/kg) for 21 days significantly improved the behavioral alterations [increased number of wheel rotations and locomotor activity, and anxiety like behavior (decreased number of entries and time spent in open arm)], oxidative defence and mitochondrial complex enzyme activities in brain.ConclusionPresent study suggests the protective role of statins against chronic fatigue induced behavioral, biochemical and mito-chondrial dysfunctions.     

Atorvastatin reduces tissue damage in rat ovaries subjected to torsion and detorsion: biochemical and histopathologic evaluation

The aim of this study was to evaluate the effects of atorvastatin as an antioxidant and tissue protective agent and study the biochemical and histopathological changes in experimental ischemia and ischemia/reperfusion (I/R) injury in rat ovaries. The experiment used 48 adult female rats, and the experimental groups can be summarized as: group I, a sham operation; group II, a sham operation +10 mg/kg atorvastatin; group III, bilateral ovarian ischemia; and groups IV and V, bilateral ovarian ischemia +5 and 10 mg/kg atorvastatin before 30 min of ischemia, respectively (after a 3-h period of ischemia, the bilateral ovaries were surgically removed); group VI, 3-h period of ischemia followed by 3-h reperfusion; groups VII and VIII received 5 and 10 mg/kg atorvastatin, respectively, 2.5 h after the induction of ischemia, and at the end of a 3-h period of ischemia, bilateral vascular clips were removed and 3-h reperfusion continued. After the experiments, superoxide dismutase (SOD) and myeloperoxidase (MPO) activity and levels of glutathione (GSH) and lipid peroxidation (LPO) were determined, and histopathological changes were examined in all rat ovarian tissue. Ischemia and I/R increased the LPO level and MPO activity while decreasing the SOD activity and GSH level significantly in comparison to the sham group. The 5- and 10-mg/kg doses of atorvastatin before ischemia and I/R reversed the trend in LPO level and MPO activity. The levels of SOD and GSH were decreased by ischemia and I/R. The administration of atorvastatin before ischemia and I/R treatments also reversed the trend in the SOD and GSH levels. In the I/R plus atorvastatin groups, although minimal vascular dilation in the ovary stoma and some degenerative cell clusters were seen, most of the cellular structures showed no pathological changes. Administration of atorvastatin is effective in reversing tissue damage induced by ischemia and/or I/R in ovaries.     

CoQ10 augments candesartan protective effect against tourniquet-induced hind limb ischemia-reperfusion: Involvement of non-classical RAS and ROS pathways

Tourniquet is a well-established model of hind limb ischemia–reperfusion (HLI/R) in rats. Nevertheless, measures should be taken to alleviate the expected injury from ischemia/ reperfusion (I/R). In the present study, 30 adult male Sprague-Dawley rats were randomly divided into 5 groups (n = 6): control, HLI/R, HLI/R given candesartan (1 mg/kg, P.O); HLI/R given Coenzyme Q10 (CoQ10) (10 mg/kg, P.O); HLI/R given candesartan (0.5 mg/kg) and CoQ10 (5 mg/kg). The drugs were administered for 7 days starting one hour after reperfusion. Candesartan and CoQ10 as well as their combination suppressed gastrocnemius content of angiotensin II while they raised angiotensin-converting enzyme 2 (ACE2) activity, angiotensin (1–7) expression, and Mas receptor mRNA level. Consequently, candesartan and/or CoQ10 reversed the oxidative stress and inflammatory changes that occurred following HLI/R as demonstrated by the rise of SOD activity and the decline of MDA, TNF-α, and IL-6 skeletal muscle content. Additionally, candesartan and/or CoQ10 diminished gastrocnemius active caspase-3 level and phospho-p38 MAPK protein expression. Our study proved that CoQ10 enhanced the beneficial effect of candesartan in a model of tourniquet-induced HLI/R by affecting classical and non-classical renin-angiotensin system (RAS) pathway. To our knowledge, this is the first study showing the impact of CoQ10 on skeletal muscle RAS in rats.     

Pioglitazone alleviates the mitochondrial apoptotic pathway and mito‐oxidative damage in the d‐galactose‐induced mouse model

相似文献   

Fibroblast growth factor 10 ameliorates renal ischaemia–reperfusion injury by attenuating mitochondrial damage

Ischaemia–reperfusion (I/R) injury is one of the leading causes of acute kidney injury (AKI). Its pathologic mechanism is quite complex, involving oxidative stress, inflammatory response, autophagy, and apoptosis. Fibroblast growth factor 10 (FGF10) and 5-hydroxydecanoate (5-HD) play essential roles in kidney injury. Rats were divided into four groups: (i) sham group, sham-operated animals with an unconstructed renal artery; (ii) I/R group, kidneys were subjected to 50 min of ischaemia followed by reperfusion for 2 days; (iii) I/R + FGF10 group, animals treated with 0.5 mg/kg FGF10 (i.p.) 1 h before ischaemia; and (iv) 5-HD group, animals treated with 5 mg/kg 5-HD (i.m.) 30 min before FGF10 treatment. Renal injury, apoptosis damage, mitochondrial oxidative damage, mitochondrial membrane potential (MMP), and expression of the ATP-sensitive K+ (KATP) channel subunit Kir6.2 were evaluated. FGF10 treatment significantly alleviated I/R-induced elevation in the serum creatinine level and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling–positive tubular cells in the kidney. In addition, FGF10 dramatically ameliorated renal mitochondrial-related damage, including reducing mitochondrial-dependent apoptosis, alleviating oxidative stress, maintaining the mitochondrial membrane potential, and opening the mitochondrial KATP channels. The protective effect of FGF10 was significantly compromised by the ATP-dependent potassium channel blocker 5-HD. Our data suggest that FGF10 offers effective protection against I/R and improves animal survival by attenuating mitochondrial damage.     

Vascular calcification abrogates the nicorandil mediated cardio-protection in ischemia reperfusion injury of rat heart

The present study was aimed to determine the efficacy of nicorandil in treating cardiac reperfusion injury with an underlying co-morbidity of vascular calcification (VC). Adenine diet was used to induce VC in Wistar rat and the heart was isolated to induce global ischemia reperfusion (IR) by Langendorff method, with and without the nicorandil (7.5 mg/kg) pre-treatment and compared with those fed on normal diet. The adenine-treated rats displayed abnormal ECG changes and altered mitochondrial integrity compared to a normal rat heart. These hearts, when subjected to IR increased the infarct size, cardiac injury (measured by lactate dehydrogenase and creatine kinase activity in the coronary perfusate) and significantly altered the hemodynamics compared to the normal perfused heart. Nicorandil pretreatment in rat fed on normal diet enhanced the hemodynamics significantly (P < 0.05) along with a substantial reduction in the mitochondrial dysfunction (measured by high ADP to oxygen consumption ratio, respiratory control ratio, enzyme activities and less swelling behavior) when subjected to IR. However, this cardio-protective effect of nicorandil was absent in rat heart with underlying calcification. Our results suggest that, the protective effect of nicorandil, a known mitochondrial ATP linked K⁺ channel opener, against myocardial reperfusion injury was confined to normal rat heart.     

Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats

Objectives To investigate the possible modification of the cardioprotective effect of amlodipine when co‐administered with quercetin in myocardial ischaemia/reperfusion‐induced functional, metabolic and cellular alterations in rats. Methods Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 week. Rats were then subjected to myocardial ischaemia/reperfusion (35_min/10_min). Heart rates and ventricular arrhythmias were recorded during ischaemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were determined. In addition, cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NO_x) were estimated. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. Key findings Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiologic functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NO_x contents. Conclusion Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischaemia/reperfusion.     

Withdrawal of fenofibrate treatment partially abrogates preventive neuroprotection in stroke via loss of vascular protection

To explore the mechanisms of action of preventive neuroprotection induced by PPAR-α activation, we have evaluated the neuronal, vascular effects of preventive treatment with fenofibrate up until the induction of experimental brain ischaemia and fenofibrate treatment withdrawn 3 days before ischaemia induction. Fenofibrate (200 mg/kg/day) was administered in rats for 14 days or withdrawn 3 days before induction of cerebral ischaemia. Animals underwent a 1-hour middle cerebral artery occlusion (MCAo), followed by reperfusion for 24 h. The MCA's vasoreactivity was analyzed and brain sections were used to assess infarct size, inflammatory and oxidative stress markers.Fenofibrate administration significantly decreases the cerebral infarct volume. This effect was associated with partial prevention of post-ischaemic endothelial dysfunction. However, withdrawal of the fenofibrate treatment 3 days before the induction of ischaemia reduced the neuroprotection and was less beneficial in preventing endothelial dysfunction as well as superoxide anion production. In contrast, fenofibrate significantly reduced microglial activation and neutrophil infiltration into the ischaemic zone to a similar extent in both treatment modes.Our results show that the fenofibrate-induced cerebral protective effect may be related to both an acute effect and a preconditioning-like mechanism. The vascular protective effect appears rather to translate the acute effects of fenofibrate administration.     

Effect of caffeic acid and rofecoxib and their combination against intrastriatal quinolinic acid induced oxidative damage, mitochondrial and histological alterations in rats

Oxidative stress has long been implicated in the neurotoxic effects of glutamate acting through N-methyl-D-aspartate (NMDA) receptors. Therefore, present study has been designed to explore the effect of rofecoxib and caffeic acid on the involvement of oxidative stress, mitochondrial dysfunction and neuronal linked with NMDA receptor-mediated excitotoxicity. Caffeic acid, is a well-known antioxidant flavanoid, implicate anti-inflammatory and immunomodulatory like actions. The present study is an attempt to investigate the antioxidant-like effect of caffeic acid and rofecoxib and their combination against QA-induced oxidative damage, mitochondrial dysfunction and histological alterations. Intrastriatal injection of quinolinic acid (300 nmol) significantly increased oxidative stress (raised lipid peroxidation, nitrite concentration, depleted SOD and catalase), altered mitochondrial complex enzyme activities and histological alteration in the ex vivo striatum. Caffeic acid (5 and 10 mg/kg, p.o.) and rofecoxib (10 and 20 mg/kg, p.o.) treatment for 21 days significantly attenuated oxidative damage and impairment in mitochondrial activities of complex enzymes in the ex vivo striatum. Further, combination of sub effective doses of rofecoxib (10 mg/kg, p.o.) and caffeic acid (5 mg/kg, p.o.) potentiated their protective effect which was significant as compared to their effect per se. The present study suggests the therapeutic effect of caffeic acid and rofecoxib combination against QA-induced ex vivo oxidative damage, mitochondrial and histological alterations in rats.     

Systemic administration of Zn2+ during the reperfusion phase of transient cerebral ischaemia protects rat hippocampus against iron-catalysed postischaemic injury

1. The aim of the present study was to test the protective role of intravenous Zn(2+) against iron-catalysed reperfusion injury in the hippocampus of ischaemic rats. 2. One hundred adult male Wistar albino rats were randomly divided into five groups. Rats in the first group were subjected to surgery (sham operation) without induction of cerebral ischaemia and injected with normal saline (i.v.). The second group of sham-operated rats were injected with 6 mg/kg, i.v., ZnCl(2). In the third group, rats were subjected to cerebral ischaemia for 60 min. Animals in the fourth group were subjected to cerebral ischaemia for 60 min followed by 8 h reperfusion. In the fifth group, rats were subjected to cerebral ischaemia for 60 min, followed by 8 h reperfusion with injection of a single dose of ZnCl(2) (6 mg/kg, i.v.) during the first 5 min of the reperfusion period. After reperfusion, animals were killed, their brains were dissected out on ice and the two hippocampi from each animal were isolated and analysed. 3. Cerebral ischaemia induced an increase in the iron content, lipidic peroxidation, apoptosis and metallothionein (MT) in the hippocampus. These effects were significantly increased in the hippocampus of ischaemic rats subjected to 8 h reperfusion compared with ischaemic non-reperfused rats. Intravenous administration of ZnCl(2)decreased the accumulation of iron, lipidic peroxidation and apoptosis produced by reperfusion, but increased the level of MT. 4. Data from the present study suggest that, after 1 h ischaemia, there is an increase in the permeability of the blood-brain barrier and this allows penetration of i.v. injected ZnCl(2), which can induce expression of brain MT, increase the anti-oxidant capacity and diminish iron-catalysed lipid peroxidation and apoptosis. This may give new insights as to how to improve the outcome for stroke patients.     

Effects of ischemia-reperfusion and pretreatment with mildronate on rat liver mitochondrial function

Mildronate (3-(2,2,2-trimethylhydrazinium) propionate), which is mostly used in cardiological practice and is considered an anti-ischemic drug, was designed to inhibit carnitine biosynthesis in order to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation. Recently it was shown that the mitochondrial respiratory chain may also be a target for mildronate action. In this study, we aimed to investigate whether mildronate can protect the liver against a 90-min normothermic ischemia/30-min reperfusion-induced mitochondrial dysfunction. Rats were pre-treated for one or two weeks with mildronate (100 mg/kg/day or 200 mg/kg/day) or Ringer solution and subjected to ischemia/reperfusion. We found that ischemia/reperfusion caused a decrease in mitochondrial State 3 respiration rate and in the respiratory control index (RCI), and an increase in State 2 respiration rate with succinate, glutamate + malate and palmitoyl-L-carnitine + malate. One or two weeks of pre-treatment of rats with different doses of mildronate did not reduce the ischemia/reperffusion-induced decrease in the State 3 respiration rate or RCI; however, a one week pre-treatment slightly diminished the increase in the State 2 respiration rate with glutamate + malate substrates. The leakage of the liver enzymes, aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase, was similar in both the untreated and pre-treated with mildronate groups. No steatotic livers were observed in any experimental groups after mildronate pre-treatment. In conclusion, 90 min of liver ischemia followed by a 30 min reperfusion has a deleterious effect on rat liver mitochondrial function. Mildronate pre-treatment of rats at doses of 100 or 200 mg/kg/day for one or two weeks did not prevent ischemia/reperfusion-induced mitochondrial dysfunction and liver injury.     

Protective effects of epigallocatechin gallate following 3-nitropropionic acid-induced brain damage: possible nitric oxide mechanisms

Introduction

The role of oxidative stress has been well known in neurodegenerative disorders. 3-Nitropropionic acid (3-NP) is a plant-based mycotoxin that produces HD like symptoms in animals. Oxidative stress and nitric oxide mechanisms have been recently proposed in the 3-NP-induced neurotoxicity. Epigallocatechin gallate (EGCG) is one of the major components of green tea, known for its potent antioxidant activity. Besides, neuroprotective effect of EGCG has also been suggested in different experimental models.

Objectives

The present study has been designed to examine possible effect of EGCG against 3-NP induced behavioral, oxidative stress, mitochondrial dysfunction, and striatal damage in rats and its possible interaction with nitric oxide modulators.

Material and methods

Systemic 3-NP (10 mg/kg) administration for 14 days significantly reduced locomotor activity, body weight, grip strength, oxidative defense (raised levels of lipid peroxidation, nitrite concentration, depletion of antioxidant enzyme), and mitochondrial enzymes activity in striatum, cortex, and hippocampal regions of the brain.

Results

Fourteen days of EGCG pretreatment (10, 20, and 40 mg/kg) significantly attenuated behavioral alterations, oxidative damage, mitochondrial complex enzymes dysfunction, and striatal damage in 3-NP-treated animals. l-arginine (50 mg/kg) pretreatment with sub-effective dose of EGCG (20 mg/kg) significantly reversed the protective behavioral, biochemical, cellular, and histological effects of EGCG. However, l-NAME (10 mg/kg) pretreatment with EGCG (20 mg/kg) significantly potentiated the protective effect of EGCG which was significant as compared to their effect per se.

Conclusion

The present study shows that EGCG attenuate 3-NP-induced neurotoxicity, and nitric oxide modulation might be involved in its protective action.     

Attenuation of contractile dysfunction by atorvastatin after intestinal ischemia reperfusion injury in rats

Growing number of studies implicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have beneficial effects on ischemia/reperfusion injury that are unrelated to their cholesterol-lowering action. In the present study, we aimed to evaluate possible effects of atorvastatin on oxidative stress, neutrophil accumulation, and contractile response of terminal ileum segments in rats subjected to intestinal ischemia/reperfusion. Intestinal ischemia/reperfusion model was generated by clamping the superior mesenteric artery for 30 min followed by reperfusion for 3 h. Oral administration of atorvastatin at a dose of 10 mg/kg/day lasted 3 days just before induction of intestinal ischemia. At the end of reperfusion period, terminal ileum samples were removed to determine the concentrations of malondialdehyde, reduced glutathione, and myeloperoxidase. Samples were collected also to assess histopathological alterations and contractile response to agonists. Ischemia/reperfusion significantly decreased contractile responses, and this decrease was attenuated by atorvastatin. Pretreatment with atorvastatin caused remarkable decrease in both oxidative stress and neutrophil accumulation. Atorvastatin appeared to be restoring amount of reduced glutathione back to about control level. Furthermore, the pretreatment lowered mucosal damage at histopathological level. Our results suggested that pretreatment with atorvastatin attenuated intestinal muscle dysfunction associated with ischemia/reperfusion. This remarkable effect of atorvastatin is accomplished at least by decreasing oxidative stress and neutrophil accumulation as well as preventing the depletion of reduced glutathione.     

Effect of carvedilol on behavioral, mitochondrial dysfunction, and oxidative damage against d-galactose induced senescence in mice

Growing evidence indicates that oxidative stress and mitochondrial dysfunction plays a critical role in brain aging. Chronic injection of d-galactose can cause gradual deterioration in learning and memory capacity and serve as an animal model of aging. Recently, potential therapeutic effect of carvedilol (CAR) has been reported by virtue of which its antioxidant and mitochondrial permeability transitional property. The present study has been designed to explore the CAR effect against d-galactose-induced behavioral, biochemical, and mitochondrial dysfunction in mice. Systemic administration of d-galactose for 6 weeks significantly impaired behavioral (learning and memory and locomotor activity), biochemical parameters (raised lipid peroxidation, nitrite concentration, depletion of reduced glutathione, and catalase activity), and mitochondrial enzymes (decreased complex I, II and III enzymes levels) as compared to sham group. CAR (2.5 and 5 mg/kg) treatment significantly improved behavioral abnormalities and biochemical and cellular alterations as compared to control. Chronic administration of d-galactose for a period of 6 week results into a significant increase of acetylcholine esterase enzyme level. CAR (2.5 and 5 mg/kg) treatment significantly attenuated the elevated level of acetylcholine esterase of mice. In conclusion, present studies highlight the protective effects of CAR against d-galactose-induced behavioral, biochemical, and mitochondrial dysfunction in mice. The study further provides a hope that CAR could be used in the management of cognitive dysfunction and related symptoms during aging.     

Acute atorvastatin treatment exerts antidepressant-like effect in mice via the l-arginine–nitric oxide–cyclic guanosine monophosphate pathway and increases BDNF levels

Atorvastatin is a synthetic and lipophilic statin that presents a good effect in decreasing cholesterol levels and is safe and well tolerated. Population-based studies have suggested a positive role of statins in reducing depression risk. This study aimed at investigating the atorvastatin effect in the tail suspension test (TST) and in the forced swimming test (FST). The participation of NMDA receptors and l–arginine–NO–cGMP in an atorvastatin antidepressant-like effect in the TST was evaluated. Acute atorvastatin administration (0.1–30 mg/kg) reduced the immobility time both in TST and FST. A similar effect was observed by using imipramine as a positive control in the TST and FST (1 and 0.1–1 mg/kg, p.o., respectively). An atorvastatin (0.1 mg/kg) antidepressant-like effect was prevented by the pretreatment of mice with NMDA (0.1 pmol/site, i.c.v.), l-arginine (750 mg/kg, i.p.) or sildenafil (5 mg/kg, i.p.). The administration of MK-801 (0.001 mg/kg, i.p.), ketamine (0.1 mg/kg, i.p.), 7-nitroindazole (50 mg/kg, i.p.), methylene blue (20 mg/kg, i.p.), or ODQ (30 pmol/site i.c.v.) in combination with a subeffective dose of atorvastatin (0.01 mg/kg, p.o.) reduced the immobility time in the TST compared to drugs alone, showing the participation of the pathway l-arginine–NO–cGMP. The administration of drugs did not produce any significant alteration in locomotor activity in the open-field test. Acute atorvastatin treatment (0.1–10.0 mg/kg, v.o.) increased the hippocampal BDNF levels, which is an effect that has not been observed in imipramine-treated mice. These results demonstrate that atorvastatin exerts an antidepressant-like effect and point to dependence on the inhibition of NMDA receptors and NO–cGMP synthesis, and on the increase of hippocampal BDNF levels.     

Atorvastatin ameliorates inflammatory hyperalgesia in rat model of monoarticular arthritis

Statins, the cholesterol lowering drugs, have been shown to exhibit anti-inflammatory properties. The aim of the present study was to evaluate the efficacy of atorvastatin in ameliorating joint dysfunction associated with arthritis. Monoarticular arthritis was induced by the intra-articular injection of FCA (0.1 mL of 0.1%). The effect of atorvastatin (10 and 50 mg/kg, A10 and A50) following oral administration was evaluated on joint inflammation, locomotor function and hyperalgesia daily for first 4 days and every 4th day till 28 days. The effect of atorvastatin was compared with that of diclofenac (5 mg/kg, D5). Daily oral administration of atorvastatin produced a significant reduction in joint inflammation (21% in A10 and 33% in A50) and associated hyperalgesia. Atorvastatin also produced a marked improvement in the stair climbing ability and motility of the arthritic rats. The beneficial effect of atorvastatin was also evident from the histological analysis of joint carried out on day 28. Our results show that atorvastatin is more effective in decreasing the joint inflammation and hyperalgesia as compared to diclofenac while the efficacy of both the drugs in ameliorating functional disability was comparable.     

Alpha-lipoic acid protects oxidative stress,changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50 ppm sodium arsenite in drinking water or in combination with DDVP (4 mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50 mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid.     

Preserved cardiac mitochondrial function and reduced ischaemia/reperfusion injury afforded by chronic continuous hypoxia: Role of opioid receptors

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to acute ischaemia/reperfusion injury. The objective of this study was to find out whether the cardioprotective effect of CNH mediated by opioid receptors is associated with preservation of mitochondrial function. Rats were adapted to CNH (12% oxygen) for 3 weeks. Isolated perfused hearts were subjected to 45 min of global ischaemia and 30 min of reperfusion; subgroups were pretreated with non‐selective opioid receptor antagonist naloxone (300 nmol/L) for 10 min. Cardiac contractile function, creatine kinase activity in coronary effluent, mitochondrial respiration rate, and calcium retention capacity were assessed. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the post‐ischaemic recovery of contractile function, mitochondrial state 3 and uncoupled respiration rates, and calcium retention capacity compared to the normoxic group. These protective effects were completely abolished by naloxone. The contractile recovery positively correlated with state 3 respiration and calcium retention capacity. The results suggest that the preserved mitochondrial function contributes to the protected cardiac phenotype afforded by adaptation to CNH and point to an important role of opioid receptor activation.