QUINACRINE ATTENUATES CYCLOSPORINE-INDUCED NEPHROTOXICITY IN RATS1

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Abstract
The biochemical mechanism underlying cyclosporine (CsA)* induced nephrotoxicity is far from clear. Increased generation of oxygen derived free radicals (ODFR) and enhanced activity of phospholipase A2(PLA2) have been observed in experimental animals following treatment with CsA. Several recent reports have shown that quinacrine, besides being a potent inhibitor of PLA2, suppresses the generation of ODFR. The present study was designed to investigate the effect of quinacrine on CsA induced nephrotoxicity in rats. Male Wistar rats (weighing 280-300 g) were randomized into eight groups of eight animals each. Group 1 (control) received appropriate vehicles only, whereas the rats in groups 2, 3, 4, and 5 received subcutaneous injection of CsA (17.5 mg/kg dissolved in olive oil) daily for 8 weeks. The animals in groups 3, 4, and 5 were also given intraperitoneal injections of quinacrine in three different doses of 2.5 mg/kg, 5 mg/kg, and 10 mg/kg body weight, respectively, in addition to CsA. The animals in groups 6, 7, and 8 received intraperitoneal injection of quinacrine alone at doses of 2.5 mg/kg, 5 mg/kg, and 10 mg/kg respectively for eight weeks. After 8 weeks, animals were sacrificed under light ether anesthesia and blood and kidney samples were collected for various biochemical and histological studies. The biochemical parameters included blood urea nitrogen (BUN), serum creatinine(Scr), potassium, and sodium. The blood was also analyzed for the level of CsA. The kidney samples were analyzed for malondialdehyde (MDA), glutathione, and vitamin E (VE). Kidney sections were prepared for histopathological studies using hematoxylin-eosin staining. There was an increase in BUN, Scr, and potassium levels and decrease in sodium levels in cyclosporine alone treated group, suggesting a significant nephrotoxicity. Quinacrine treatment significantly protected animals against CsA induced biochemical changes. Our studies on free radical indices showed that quinacrine treatment protected animals against cyclosporine induced increase in MDA and depletion of glutathione and VE. The beneficial effect of quinacrine against CsA induced nephrotoxicity was also confirmed by histological studies.