VINCRISTINE-INDUCED NEUROTOXICITY IN RATS MEDIATED BY UPREGULATION OF INOS, IBA1, NESTIN, PARP AND CASPASE 3: AMELIORATIVE EFFECT OF ERYTHROPOIETIN AND THYMOQUINONE

Abstract

Vincristine (VCR) is an effective anticancer medication, although it has neurotoxic side effects. Erythropoietin (EPO) is the main regulator of erythropoiesis. Thymoquinone (TQ) protects brain cells from oxidative stress that causes neurodegenerative disorders such as Alzheimer's and Parkinson's. This study aims to investigate the VCR toxicity on the cerebrum as well as the possible neuroprotective effects of TQ and EPO against VCR toxicity in a rat model. An intraperitoneal injection of VCR (150 μg/kg) 3 times a week for 5 weeks caused marked histopathological changes in the brain such as neuronal degeneration with aggregations of glial cells around the degenerated neurons (satellitosis), congestion of blood vessels and severe demyelination in the white matter of the cerebrum. VCR considerably increased nestin, iBA1 and iNOS expression, while synaptophysin expression decreased. It also caused upregulation of caspase 3 and PARP expression, resulting in hemorrhage, demyelination, and neuronal degeneration. Treatment of rats with TQ or EPO either alone or in combination improved histopathological changes through down-regulation of nestin, iBA1, iNOS, caspase 3 and PARP. It was concluded that EPO and TQ ameliorate the neurotoxic effect of VCR on the cerebrum, however, a synergetic effect was evident when TQ and EPO were combined.