Protective potential of deprenyl in paraquat-induced nephrotoxicity in rats

ABSTRACT

Deprenyl, a selective and irreversible monoamine oxidase B [MAO-B] inhibitor, has various pharmacological effects unrelated to MAO-B inhibition including antioxidant ones. Paraquat [PQ], a well known herbicide, causes severe nephrotoxicity mediated by redox-cycling and extensive production of superoxide anions in the kidney. The kidney is a primary site for PQ toxicity as it is the main organ of its excretion. Consequently, the possible protective effects of deprenyl [10 mg/kg, i.p.] against nephrotoxicity induced by long-term administration of PQ in rats were examined. PQ was intraperitoneally injected once weekly [20 mg/kg] with or without daily injections of deprenyl for 6 successive weeks. Nephrotoxicity was assessed by measuring serum levels of creatinine, urea nitrogen and uric acid as well as histological examination of kidney sections. Changes in renal oxidant status were monitored by measurements of reduced glutathione [GSH] content and that of thiobarbituric acid reactive substances [TBARS], an index of renal lipid peroxidation. In addition, determination of total nitrate/nitrite [NOx] content, which reflects nitric oxide [NO] content of renal tissues, was performed. Finally, changes in renal enzymatic activities of lactate dehydrogenase [LDH], superoxide dismutase [SOD] and myeloperoxidase [MPO] were also measured. PQ administration resulted in marked nephrotoxicity manifested by severe increase in serum creatinine and urea nitrogen levels accompanied by changes in renal oxidant status of rats demonstrated by elevated TBARS content and increased activities of MPO and SOD. It also resulted in depletion of renal GSH and NOx contents as well as reduced activity of cytosolic LDH. However, no significant effect was noted on serum uric acid level. Six weeks of regular daily treatment with deprenyl significantly protected against most of PQ-induced biochemical changes evidenced by lowering of elevated creatinine level and reduction of elevated TBARS content and MPO activity. Deprenyl also attenuated PQ-induced depletion of GSH and NOx contents. On the other hand, deprenyl failed to ameliorate PQ-induced effects on serum urea nitrogen level or on kidney cytosolic LDH and SOD activities. Histological examinations of kidney sections revealed marked lesions with PQ especially in renal proximal tubules and fair protection by deprenyl. It could be concluded that deprenyl offered remarkable protection against PQ-induced nephrotoxicity in rats which could expand its use in other areas outside the central nervous system