Role of RhoA in Cisplatin–Induced Neurotoxicity

Abstract

Cisplatin is an effective chemotherapeutic drug that is capable of treating various forms of cancer. However, cisplatin cytotoxicity is not limited to neoplastic tissue, and many patients sustain peripheral neuropathy from treatment. Therefore, it has become important to understand alternative cisplatin targets and explore signaling pathways for potential intervention. It is well established that Rho GTPase activation is increased following trauma in several models of neuronal injury. Thus, components of the Rho signaling pathway represent important neuroprotective targets with the potential to enhance current chemotherapy treatments. We have developed a novel mouse model of cisplatin‐induced peripheral neuropathy. Cisplatin‐induced neurotoxicity can be reduced by RhoA pathway inhibition with LM11A‐31, a small‐molecule ligand of the p75 neurotrophin receptor (p75NTR), which is known to regulate RhoA activation. LM11A‐31 treatment not only prevented decline in peripheral nerve sensation seen due to cisplatin, but abnormal sural nerve fiber morphology and decreases in fiber area were alleviated. Additionally, RhoA activity was increased with cisplatin treatment, and reduced by LM11A‐31. These results suggest that suppression of RhoA signaling pathway enhances neuroprotection in cisplatin‐induced experimental peripheral neuropathy. Supported by NIHCA111891 and NIHCA165202.