Palaninathan Varalakshmi

Combined efficacies of lipoic acid and meso-2,3-dimercaptosuccinic acid on lead-induced erythrocyte membrane lipid peroxidation and antioxidant status in rats.

One of the most intriguing phenomenon observed during lead toxicity has been attributed to lead-induced oxidative stress. The combined effect of DL-a-lipoic acid (LA) and meso 2,3-dimercaptosuccinic acid (DMSA) on lead-induced alterations in selected parameters, which are indicators of oxidative stress in erythrocytes, have been studied. Lead acetate (Pb, 0.2%) was administered in drinking water for 5 weeks to induce toxicity. LA (25 mg/ kg body weight per day i.p.) and DMSA (20 mg/kg body weight per day i.p.) were administered individually and also in combination during week 6. Clinical evidence of toxic exposure was evident from the elevated blood lead levels (BPb) along with lowered levels of haemoglobin (Hb) and haematocrit (Ht). Lead-exposed animals showed enhanced membrane lipid peroxidation (LPO) in the erythrocytes. Damage to the erythrocyte membrane was evident from the decline in the activities of the trans-membrane enzymes, viz., Na1, K1 ATPase, Ca2 1 ATPase and Mg2 1 ATPase. Lead-exposed rats also suffered an onslaught on the antioxidant defence system witnessed by lowered activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH). Serum glutamic-oxoloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) were also elevated in lead-exposed rats. Treatment with either LA or DMSA reversed the lead-induced biochemical disturbances encountered by the erythrocytes, but combined treatment with LA and DMSA was very effective in mitigating all the parameters indicative of oxidative stress.

Mitigation of oxidative stress in cyclophosphamide-challenged hepatic tissue by DL-α-lipoic acid

The present study investigated the protective effect of DL-α-lipoic acid on the tissue peroxidative damage and abnormal antioxidant levels in cyclophosphamide (CP) induced hepatotoxicity. Male Wistar rats of 140± 20 g were categorized into four groups. Two groups were administered CP (15 mg/kg body weight once a week for 10 weeks by oral gavage) to induce hepatotoxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight intraperitoneally once a week for 10 weeks; 24 h prior to the CP administration). A vehicle (saline) treated control group and a lipoic acid drug control group were also included. The extent of liver damage in CP-induced rats was evident from the increased activities of serum aminotransferases, alkaline phosphatase and lactate dehydrogenase; whereas lipoic acid pretreatment prevented the rise in these marker enzymes. We evaluated the changes in activities/levels of tissue enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase) and non-enzymic (reduced glutathione, ascorbate and α-tocopherol) antioxidants along with malondialdehyde levels in the experimental groups. In CP-administered rats the antioxidant enzymes showed significantly depressed activities (p < 0.001, p < 0.01) and the antioxidant molecules also showed depleted levels (p < 0.001, p < 0.01), in comparison with the control group. However the extent of lipid peroxidation and the abnormal antioxidant status were normalized in lipoic acid pretreated rats. The present work highlights the efficacy of lipoic acid as a cytoprotectant in CP-induced hepatic oxidative injury.

Cardioprotective effect of pentacyclic triterpene, lupeol and its ester on cyclophosphamide-induced oxidative stress

Cyclophosphamide (CP), an alkylating agent widely used in cancer chemotherapy, causes fatal cardiotoxicity. In the present study, lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate were investigated for their possible cardioprotective effects against CP-induced toxicity. Male albino rats of Wistar strain were injected with a single dose of CP (200 mg/kg body weight, ip). In CP-administered rats, activities of lactate dehydrogenase and creatine phosphokinase were elevated in serum with a concomitant decline in their activities in the cardiac tissue. Significant increases (P B < 0.001) in the levels of lipid peroxides and a decrease (P B < 0.001) in the levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-s-transferase) and nonenzymic (reduced glutathione, vitamin C and vitamin E) antioxidants in the heart were also observed. The cardioprotective effects of lupeol (50 mg/kg body weight for 10 days orally) and its ester, lupeol linoleate (50 mg/kg body weight for 10 days orally) were evident from the significant reversal of the above alterations induced by CP. These observations highlight the antioxidant property of triterpenes and their cytoprotective action against CPinduced cardiotoxicity.

Lupeol and its ester ameliorate the cyclophosphamide provoked cardiac lysosomal damage studied in rat.

Cyclophosphamide (CP), an alkylating agent widely used in cancer chemotherapy causes fatal cardiotoxicity. Lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate possess a wide range of medicinal properties. The effect of lupeol and its ester was evaluated in CP-induced myocardial toxicity in rats. Male albino rats of Wistar strain were categorized into six groups. Group I served as control. Rats in groups II, V and VI animals were injected intraperitoneally with a single dose of CP (200 mg/kg body weight) dissolved in saline. CP-treated groups V and VI received lupeol and lupeol linoleate (50 mg/kg body weight), respectively, dissolved in olive oil for 10 days by oral gavage. CP-administered rats showed a significant increase (p < 0.001) in the activities of lysosomal hydrolases in serum and heart, a decrease (p < 0.001) in the levels of cellular thiols and myofibres were swollen with loss of myofilaments in electron microscopical analysis in heart. Lupeol and its ester showed reversal of the above alterations induced by CP. These findings demonstrate that the supplementation with lupeol and its ester could preserve lysosomal integrity, improve thiol levels, highlighting their protective effect against CP-induced cardiotoxicity.

Remedial effect of DL-α-lipoic acid against adriamycin induced testicular lipid peroxidation

Adriamycin (ADR), a cytotoxic antineoplastic drug is used in the treatment of various solid tumors. However, its efficacy continues to be challenged by significant toxicities including testicular toxicity. In the present study, the effect of lipoic acid, a “universal antioxidant” was investigated on ADR induced peroxidative damages in rat testis. Adult male albino rats of Wistar strain were administered ADR (1 mg/kg body weight, i.v.) once a week for 10 weeks. ADR injected rats showed a significant decline in the activities of enzymic antioxidants (catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymic antioxidants (reduced glutathione, Vitamin A, Vitamin C and Vitamin E) with high malondialdehyde levels. The extent of testicular toxicity was evident from the decreased activities of testicular marker enzymes (sorbitol dehydrogenase and glucose-6-phosphate dehydrogenase). Treatment with lipoic acid (35 mg/kg body weight, i.p.) one day prior to ADR administration, maintained near normal activities of the enzymes and significantly reduced lipid peroxidation, thereby proving it to be an effective cytoprotectant. (Mol Cell Biochem 267: 209–214, 2004)

Lupeol and its ester exhibit protective role against cyclophosphamide-induced cardiac mitochondrial toxicity.

Cyclophosphamide (CP), an anti-cancer and immunosuppressant drug, causes fatal cardiotoxicity during high dose chemotherapy. Lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate, possess wide range of medicinal properties. The objective of this study was to establish the pharmacological efficacy of lupeol and its ester against CP-induced mitochondrial-cardiomyopathy. Male albino rats of Wistar strain were injected with a single dose of CP (200 mg/kg body weight, i.p.). A decrease in the activities of TCA cycle enzymes such as succinate dehydrogenase, malate dehydrogenase, and isocitrate dehydrogenase were noted in CP-treated rats. Simultaneously there was a decrease in the activities of mitochondrial complexes of electron transport chain. Electron microscopical observations were also in agreement with the above changes. Mitochondria were swollen with numerous electron dense granules and showed damaged cristae, revealing the cytotoxic effect of CP. Lupeol (50 mg/kg body weight for 10 days orally) and its ester, lupeol linoleate (50 mg/kg body weight for 10 days orally) showed reversal of the above alterations induced by CP. These data suggest that the protective effects of lupeol and its ester against CP-induced cardiac damage were achieved by restoration of mitochondrial structure and function.

Salubrious effect of low molecular weight heparin on atherogenic diet-induced cardiac, hepatic and renal lipid peroxidation and collapse of antioxidant defences

The present work showcases the distressing picture of oxidative stress in the cardiac, hepatic and renal tissues, in an experimental model based on early phase atherogenesis. The protection rendered by LMWH intervention forms part of the same study. Male Wistar rats of 140 ± 10 g were categorized as four groups. One group served as untreated control and another as LMWH drug control group. Two groups were fed a hypercholesterolemic atherogenic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil; CCT diet) for 2 weeks; one of these groups received LMWH treatment of 300 μg/day/rat for 7 days. The biochemical index of tissue lipid peroxidation (LPO) was assessed in terms of MDA formation. Heart, liver and kidney tissues of CCT-diet fed rats showed significantly elevated levels of LPO. In the early phase atherosclerotic group, we observed abnormal changes in the activities/levels of tissue enzymic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymic (reduced glutathione, ascorbate and α-tocopherol) antioxidants. We report normalized LPO levels and antioxidant defences in the atherogenic rats treated with LMWH. Thus the present study highlights the hepatic, cardiac and renal oxidative changes induced by experimental atherogenesis, and the protection rendered by LMWH treatment in atherosclerotic cardiovascular conditions.

Protective role of DLa-lipoic acid against adriamycin-induced cardiac lipid peroxidation:

The cytoprotective activity of a-lipoic acid against free radical toxicity manifested during adriamycin (ADR)induced cardiotoxicity has been investigated. ADR is a potent antitumour drug known to cause severe cardiotoxicity. Although ADR generates free radicals, the role of these radicals in the development of cardiac toxicity is still not well understood. In the present study, we evaluated the influence of chronic ADR treatment on the cellular defence mechanism against free radicals and the effect of a-lipoic acid supplementation on ADR-induced cardiotoxicity in male Wistar rats. The increase in lipid peroxidation (LPO) and activities of serum myocardial enzymes, namely lactate dehydrogenase (LDH) and creatinephosphokinase, associated with the decrease in activities of enzymatic (SOD, CAT, GPx, G6PD and GR) and non-enzymatic (GSH, Vit C and Vit E) antioxidants levels were the salient features observed in ADR-induced cardiotoxicity. Lipoic acid pretreated groups showed significant increase in activities of both enzymatic and non-enzymatic antioxidant levels. These observations highlight the antioxidant property ofa-lipoic acid and its cytoprotective action against ADR-induced cardiotoxicity.

The influence of lipoic acid on adriamycin-induced hyperlipidemic nephrotoxicity in rats

Adriamycin widely used in the treatment of neoplastic conditions is nephrotoxic. In the present study the protective effect of lipoic acid was investigated in adriamycin-induced nephrotoxicity in adult male albino Wistar rats. Adriamycin-induced nephrotoxicity was characterized by hyperlipidemia, proteinuria, and hypoproteinemia, by decreased activities of the enzymes N-acetyl-β-D-glucosaminidase and cathepsin D, by increased lipid peroxidation and decreases in serum catalase and glutathione activities, and by increased urinary and serum urea, creatinine and urinary glycosaminoglycans. Pretreatment with lipoic acid restored the changes, indicating that lipoic acid is renoprotective in adriamycin nephrotoxicity.

Effect of Withania somnifera on Lysosomal Acid Hydrolases in Adjuvant‐induced Arthritis in Rats

The effect of Withania somnifera Linn. Dunal (Solanaceae) on adjuvant arthritic rats was studied and compared with that of indomethacin. These results indicate that Withania somnifera has promising anti-arthritic activity as a result of its stabilizing action on lysosomal enzyme activity. The anti-inflammatory activity of Withania somnifera was assessed by measuring paw swelling and lysosomal enzyme activity in control and experimental rats. Increased paw diameter and lysosomal enzyme activity in the arthritic animals were significantly suppressed to near normal levels in rats treated with 1000 mg kg−1Withania somnifera root powder and 3 mg kg−1 indomethacin.