TRPV4 Inhibition Prevents Paclitaxel-induced Neurotoxicity in Preclinical Models

Paclitaxel is a cytotoxic drug which frequently causes sensory peripheral neuropathy in patients. Increasing evidence suggests that altered intracellular calcium (Ca) signals play an important role in the pathogenesis of this condition. In the present study, we examined the interplay between Ca release channels in the endoplasmic reticulum (ER) and Ca permeable channels in the plasma membrane in the context of paclitaxel mediated neurotoxicity. We observed that in small to medium size dorsal root ganglia neurons (DRGN) the inositol-trisphosphate receptor (InsPR) type 1 was often concentrated in the periphery of cells, which is in contrast to homogenous ER distribution. G protein-coupled designer receptors were used to further elucidate phosphoinositide mediated Ca signaling: This approach showed strong InsP mediated Ca signals close to the plasma membrane, which can be amplified by Ca entry through TRPV4 channels. In addition, our results support a physical interaction and partial colocalization of InsPR1 and TRPV4 channels. In the context of paclitaxel-induced neurotoxicity, blocking Ca influx through TRPV4 channels reduced cell death in cultured DRGN. Pretreatment of mice with the pharmacological TRPV4 inhibitor HC067047 prior to paclitaxel injections prevented electrophysiological and behavioral changes associated with paclitaxel-induced neuropathy. In summary, these results underline the relevance of TRPV4 signaling for the pathogenesis of paclitaxel-induced neuropathy and suggest novel preventive strategies.