Molsidomide provides neuroprotection against vincristine-induced peripheral neurotoxicity

Peripheral neuropathy is the principal dose-limiting adverse reaction of the major frontline chemotherapeutic agents. Neuropathy can be so disabling that many patients will drop out of potentially curative therapy, negatively impacting cancer prognosis. Chemotherapy-induced peripheral neuropathy (CIPN) is refractory to treatment and persists in about 50% of cancer survivors limiting their quality of life. Vincristine is highly active, but its use is limited by the severe neurotoxicity leading to autonomic, sensory and motor impairment. The hallmark of vincristine peripheral neurotoxicity is axonopathy. Yet the underpinning mechanisms of vincristine-induced axonopathy remains uncertain. We hypothesize that agents preventing vincristine-induced axonopathy will effectively mitigate CIPN symptoms, hence improving cancer treatment outcomes and survivors’ quality of life. Based on this premise, we developed a comprehensive drug discovery pipeline to identify small molecules with neuroprotective activity against vincristine-induced axon degeneration. Among the hits identified, SIN-1 – an active metabolite of molsidomine (Covaryl) – prevents VCR-induced axon loss in both motor and sensory neurons, and it does so without compromising vincristine anti-cancer potency. To determine the neuroprotective effect of molsidomine, we used an extensively validated rat model of vincristine-induced peripheral neuropathy. Vincristine (0.2mg/kg/week) was administered via the tail vein for 4 weeks and molsidomine (10mg/kg/day or 20mg/kg/day) was administered orally for 4 weeks, starting the first day of vincristine treatment. As expected, the selected schedule of vincristine administration induced severe sensory and motor nerve damage. Importantly, vincristine-treated rats showed a significant decrease in the sensory threshold determined by the dynamic test that was prevented by molsidomine administration in a dose-dependent manner. A similar protective effect of molsidomine was evident on digital nerve amplitude and velocity. This study provides preliminary evidence of the neuroprotective properties of molsidomine and opens the way to further investigations of this drug as a therapeutic agent to prevent vincristine-induced peripheral neuropathy.