The Protective Effect of Modafinil on Vincristine-induced Peripheral Neuropathy in Rats: A Possible Role for TRPA1 receptors

Aim: Vincristine (VCR) as an anticancer agent for leukemia and lymphoma, can lead to painful peripheral neuropathy. This study was carried out to assess the efficacy of modafinil, a central nervous system stimulant, on VCR-induced neuropathy in rats.Methods: Neuropathy was induced by intraperitoneal injections of VCR (0.1 mg/kg, i.p.), and the treatments were continued for 14 consecutive days. Four groups were received modafinil (5, 25 and 50 mg/kg, i.p.), and gabapentin (20 mg/kg, i.p.). On the other hand, six neuropathic groups were received modafinil (5, 25 and 50 mg/kg); gabapentin (20 mg/kg); combination of modafinil (5 and 50 mg/kg) and gabapentin (20 mg/kg, i.p.). To evaluate the sensory and motor neuropathy, tail-flick and von Frey filament tests were performed, and motor nerve conduction velocity (MNCV) and excitation of nerve conduction were measured. The transient receptor potential cation channel ankyrin 1 (TRPA1), the transient receptor potential vanilloid-1 (TRPV1) and N-Methyl-D-aspartic acid (NMDA) proteins were detected in the dorsal root ganglion (DRG). Further, the DRG levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) were assessed. Results: In VCR-treated rats, tail flick and von Frey latencies were significantly decreased, MNCV and excitation of the sciatic nerve significantly decreased. Pretreatment with modafinil at dose of 50 mg/kg, strongly diminished TNF-α and IL-1β levels, and prevented mixed sensory-motor neuropathy. Conclusion: Modafinil significantly improved behavioral, electrophysiological, and pathological changes. Further, combination of modafinil and gabapentin markedly improved the effect of gabapentin. As a result, modafinil might be a neuroprotective agent in prevention of VCR-induced neuropathy, which may be mediated at least in part via TRPA1 receptors.

Keywords:

Peripheral neuropathy , vincristine , modafinil , gabapentin , DRG neurons , TRPA1 , TRPV1 , NMDA , TNF-α , IL-1β