The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity

Vincristine (VCR) peripheral neuropathy is a dose-limiting side effect. Several studies have shown that tropisetron, a 5-HT3 receptor antagonist, exerts anti-inflammatory and immunomodulatory properties. Current study was designed to investigate a suppressive effect of tropisetron on VCR-induced neuropathy and whether this effect exerts through the 5-HT3 receptor or not. Neuropathy was induced in rats by administration of vincristine (0.5mg/kg, 3 intraperitoneal injections on alternate days) and in treatment group, tropisetron (3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3 receptor agonist (15mg/kg); tropisetron (3mg/kg) plus mCPBG (15mg/kg); granisetron, another selective 5-HT3 receptor antagonist (3mg/kg) were administered intraperitoneally 1h prior to vincristine injection. Hot plate, open field tests (total distance moved, mean velocity and percentage of total duration of the movement) and motor nerve conduction velocity (MNCV) were performed to evaluate the sensory and motor neuropathy. Further, plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) and the level of TNF-α in sciatic nerve were assessed as well as histological examination. In only VCR-treated rats hot plate latencies were significantly increased, total distance moved, mean velocity, total duration of the movement and sciatic MNCV significantly decreased compared with control. In tropisetron and tropisetron plus mCPBG groups, one injection of tropisetron prior to each VCR injection robustly diminished TNF-α and IL-2 levels, and also prevented mixed sensory-motor neuropathy, as indicated by less mortality rate, better general conditions, behavioral and electrophysiological studies. Moreover, pathological evidence confirmed the results obtained from other findings. But granisetron and mCPBG had no significant effect on the mentioned parameters. In conclusion, these studies demonstrate that tropisetron significantly suppressed VCR-induced neuropathy and could be a neuroprotective agent for prevention of VCR-induced neuropathy via a receptor-independent pathway.