Protective effect of arjunolic acid against atorvastatin induced hepatic and renal pathophysiology via MAPK, mitochondria and ER dependent pathways.
3-Hydroxy-3-methylglutaryl-CoA reductase inhibitor, atorvastatin (ATO), is a highly effective drug used for the treatment of hypercholesterolemia and hypertriglyceridemia. Its application is restricted now-a-days due to several acute and chronic side effects. ATO induced anti hypercholesterolemia and hepatic tissue toxicity has been reported to follow different mechanisms. The present study has been carried out to investigate the protective role of arjunolic acid (AA) against ATO induced oxidative impairment and cell death in hepatic and renal tissue in mice. Administration of ATO (at a dose 30 mg/kg/day for 8 weeks) enhanced serum markers, increased reactive oxygen species (ROS) production and altered the pro oxidant-antioxidant status of liver and kidney tissues. Our experimental evidence suggests that ATO exposure induces apoptotic cell deathby the activation of caspase-3 and reciprocal regulation of Bcl-2/Bax with the concomitant reduction of mitochondrial membrane potential and increased level of cytosolic cytochrome c, Apaf1, caspase-9. Besides, ATO markedly increased the phosphorylation of MAPKs, enhanced caspase-12 and calpain level. Histological studies and DNA fragmentation analysis also support the toxic effect of ATO in these organs pathophysiology. Post treatment with AA (at a dose of 20 mg/kg body weight for 4 days), however, reduced ATO-induced oxidative stress and suppressed all these apoptotic events. Results suggest that AA could effectively and extensively counteract these adverse effects and might protect liver and kidney from ATO-induced severe tissue toxicity.
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India.
Sankhadeep
S
Pal
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India.
Abhijit
A
Sarkar
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India.
Pabitra Bikash
PB
Pal
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India. Electronic address: parames@jcbose.ac.in.
Parames C
PC
Sil
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin / Q000009:adverse effects* / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008099:Liver / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014315:Triterpenes; C061640:arjunolic acid; D000069059:Atorvastatin
Antioxidant; Apoptosis; Arjunolic acid; Atorvastatin; Oxidative stress; ROS