Mechanisms of vincristine-induced neurotoxicity: Possible reversal by erythropoietin

Abstract

Vincristine (VCR) is a potent anticancer drug, but neurotoxicity is one of its most important dose-limiting toxicities. In this study, we investigated the neurotoxic effect of VCR, the possible mechanisms and the role of erythropoietin (EPO) in the protection against VCR-induced neurotoxicity in a rat model. The neurotoxicity of VCR and protective effect of EPO were examined using the tail flick test and by recording electrophysiological characteristics in isolated sciatic nerve. To elucidate the underlying mechanisms, mRNA expression of N-methyl-Daspartate (NMDA) receptor, an index of glutamate excitotoxicity, and calcitonin gene-related peptide (CGRP), an important regulator of vascular tone, were measured in both spinal cord and sciatic nerves using an RT-PCR method. After intraperitoneal injection at a dose of 150 μg/kg three times weekly for five consecutive weeks, VCR significantly decreased the latency of tail withdrawal reflex, the amplitude of maximum compound action potential (MCAP) and chronaxie, and prolonged the duration of action potential (AP) and relative refractory period (RRP), but it had no effect on conduction velocity. VCR increased NMDA receptor expression and decreased CGRP expression. Forty μg/kg of EPO improved all VCR-induced changes, except chronaxie, while a higher dose of 80 μg/kg reversed all parameters and its effect was more prominent on tail flick test latency and NMDA receptor expression. These results suggested that VCR might cause increased nerve excitability and induce a state of glutamate excitotoxicity through enhancing NMDA receptor expression and diminishing CGRP expression, thus resulting in axonal degeneration. EPO had an obvious neuroprotective effect probably through decreasing NMDA receptor expression and increasing CGRP expression both centrally and peripherally.

Erythropoietin protects neuroblastoma cells against etoposide and vincristine by activating ERK and AKT pathways but has no effect in kidney cells

“…This is in agreement with former reports showing that Epo protects haematopoietic cells from etoposide-induced hemotoxicity in vivo [5] and in vitro [1]. Similarly, Kassem and colleagues reported that administration of vincristine to healthy rats caused a state of glutamate excitotoxicity both centrally and peripherally, and that concomitant application of Epo reversed vincristine-induced neurotoxicity [14]. Unlike MSN, cytotoxicity of etoposide and vincristine on HEK 293 cells was not modified by Epo.…”

The Influence of Low Doses of Zearalenone and T-2 Toxin on Calcitonin Gene Related Peptide-Like Immunoreactive (CGRP-LI) Neurons in the ENS of the Porcine Descending Colon

“…The cooperation of CGRP and nitric oxide has been also confirmed during the present study, where the relatively high degree of the co-localization of CGRP with nNOS (a marker of nitrergic neurons) has been observed in all types of enteric plexuses, especially after the mycotoxins administration. Moreover, it is relatively well established that CGRP expression may change during the neurotoxicity in various parts of the nervous system and/or neuropathies of different origins [48,49,50,51,52], which can confirm neuroprotective and adaptive functions of this neuronal factor.…”

Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy

“…Vincristine enhances NMDA receptor expression and diminishes CGRP expression, leading to a state of glutamate excitotoxicity that results in axonal degeneration. This may cause increased sciatic nerve excitability [49]. In the thalamus and periaqueductal areas of the brain, oxaliplatin increases protein kinase C activity and upregulates the gamma isoform associated with neuropathic pain development and the epsilon isoform associated with apoptosis [50,51].…”