Evaluation of multi-neuroprotective effects of erythropoietin using cisplatin induced peripheral neurotoxicity model.

Cisplatin (CDDP) is severely neurotoxic anti-neoplastic drug that causes peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. The ameliorating effects of erythropoeitin on cisplatin-induced neuropathy, which seem to be mediated by enhancing the cell resistance to side effects of cisplatin rather than by influencing the formation or repair rates of cisplatin-induced cross-links in the nuclear DNA, had been previously reported. The main objective of our study is to investigate the roles of nitro-oxidative stress, nuclear factor kappa B (NFκB) gene expressions and TNF levels on the previous reported erythropoietin anti-apoptotic neuroprotective effects during cisplatin induced neurotoxicity. The present study compared the effects of erythropoietin (50 μg/kg/d thrice weekly) on cisplatin (2mg/kg/d i.p. twice weekly for 4 weeks) induced neurophysiologic changes and the associated changes in the inflammatory mediators (TNF alpha and NFKB), oxidative stress (malondialdehyde (MDA), superoxide dismutases (SOD) and glutathione) and gene expression of both neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). In addition, sciatic nerve pro-apoptotic and anti-apoptotic indicators (Bcl, Bax, Caspase 3) were measured. We found that concomitant administration of erythropoietin significantly reversed the cisplatin induced nitro-oxidative stress - with significant increases in sciatic nerve glutathione and superoxide dismutase antioxidant enzyme levels and a significant decrease in iNOS gene expression. We conclude that erythropoietin anti-apoptotic neuro-protective effects could partially contribute to observed antioxidant effects of erthropoietin.