Vincristine-Induced Neuropathy in Rats is Mediated Via NMDA Excitotoxicity and Impairment of CGRP: Possible Neuroprotective Effect of Erythropoietin
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- Category: Vol. 77, September 2009
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Vincristine-Induced Neuropathy in Rats is Mediated Via NMDA Excitotoxicity and Impairment of CGRP: Possible Neuroprotective Effect of Erythropoietin, LOBNA A. KASSEM, MAHA M. GAMAL EL DIN and NADIA A. YASSIN
Abstract
Background/Aims: Vincristine (VCR) is a potent anticancer drug and neurotoxicity is one of its most important dose-limiting toxicities. In this study, we investigated the effect of VCR by neurophysiological recordings and the tail flick test. To elucidate the underlying mechanism of action of VCR, expression of both N-methyl-D-aspartate (NMDA) receptor, an index of glutamate excitotoxity and calcitonin gene-related peptide (CGRP), an important regulator of vascular tone, were measured in both spinal cord and sciatic nerves. The role of erythropoietin (EPO) in the protection against VCR-induced neurotoxicity was also examined.
Methods: Rats were divided into control group, VCR-treated group and two groups given EPO in two different doses concomitant with VCR administration.
Results: VCR significantly decreased the amplitude of maximum compound action potential (MCAP) and prolonged the duration of action potential (AP) and relative refractory period (RRP), decreased chronaxie and the latency of tail flick test, but it had no effect on conduction velocity. VCR increased NMDA receptor expression and it decreased CGRP expression. The smaller dose of EPO improved all VCR-induced changes, except chronaxie, while its higher dose reversed all parameters and its effect was more prominent on tail flick test latency and NMDA receptor expression.
Conclusion: VCR resulted in axonal degeneration. It caused increased neuronal excitability and induced a state of glutamate excitotoxicity. Finally, VCR caused a decrease in blood flow in the nervous tissue resulting in vascular neuro-toxicity. EPO had an obvious neuroprotective effect probably through decreasing NMDA receptor expression and increasing CGRP expression both centrally and peripherally.