Anticonvulsant effects of novel and repurposed drugs on docetaxel-induced neuropathy in C. elegans

Chemotherapeutic agents used for most common cancers are frequently associated with neurotoxicity, which often include debilitating side effects such as seizures. Docetaxel, one of the most widely and effectively used chemotherapeutic drugs, is associated with an array of symptoms referred to as Docetaxel-Induced Peripheral Neuropathies (DIPNs), including acute or chronic seizures. In this study, we use the electroconvulsive assay to model DIPN-related seizures in C. elegans. We show that exposing the nematodes to docetaxel increases time-to-recovery from seizure. Screening for compounds that protect the nematodes from the seizure-like behaviors induced by acute or chronic exposure to docetaxel, we find that sildenafil citrate, a PDE-5 inhibitor, and a novel bicyclic bridge compound, Resveramorph-3 (RVM-3), are both effective at rescuing the animals from DIPN-related seizures. The results demonstrate that sildenafil citrate and RVM-3 are potential candidates for mitigating the neurological deficits resulting from DIPNs.