QUINACRINE ATTENUATES CYCLOSPORINE-INDUCED NEPHROTOXICITY IN RATS

The biochemical mechanism underlying cyclosporine (CsA) induced nephr otoxicity is far from clear. Increased generation of oxygen derived fr ee radicals (ODFR) and enhanced activity of phospholipase A2 (PLA(2)) have been observed in experimental animals following treatment with Cs A. Several recent reports have shown that quinacrine, besides being a potent inhibitor of PLA(2), suppresses the generation of ODFR. The pre sent 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 (con trol) received appropriate vehicles only, whereas the rats in groups 2 , 3, 4, and 5 received subcutaneous injection of CsA (17.5 mg/kg disso lved in olive oil) daily for 8 weeks. The animals in groups 3, 4, and 5 were also given intraperitoneal injections of quinacrine in three di fferent doses of 2.5 mg/kg, 5 mg/kg, and 10 mg/kg body weight, respect ively, 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, anim als were sacrificed under light ether anesthesia and blood and kidney samples were collected for various biochemical and histological studie s. The biochemical parameters included blood urea nitrogen (BUN), seru m creatinine (Scr), potassium, and sodium. The blood was also analyzed for the level of CsA. The kidney samples were analyzed for malondiald ehyde (MDA), glutathione, and vitamin E (VE). Kidney sections were pre pared for histopathological studies using hematoxylin-eosin staining. There was an increase in BUN, Scr, and potassium levels and decrease i n sodium levels in cyclosporine alone treated group, suggesting a sign ificant nephrotoxicity. Quinacrine treatment significantly protected a nimals against CsA induced biochemical changes. Our studies on free ra dical indices showed that quinacrine treatment protected animals again st cyclosporine induced increase in MDA and depletion of glutathione a nd VE. The beneficial effect of quinacrine against CsA induced nephrot oxicity was also confirmed by histological studies.