Dimethyl fumarate ameliorates chemotherapy agent-induced neurotoxicity in vitro

Abstract

Chemotherapy agents such as oxaliplatin, cisplatin, paclitaxel, and bortezomib frequently cause severe peripheral neuropathy and there is currently no effective strategy to prevent this. Dimethyl fumarate (DMF) is a new oral drug for the treatment of multiple sclerosis, and has neuroprotective effects via up-regulation of the nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response. In this study, we investigated the effect of DMF on chemotherapy agent-induced neurodegenerations in cultured cells. We found that DMF and its metabolite monomethyl fumarate (MMF) attenuated oxaliplatin-, cisplatin-, and bortezomib- (but not paclitaxel-) induced inhibition of neurite outgrowth, but had no effect on cell death as a result of these agents in cultured PC12 cells and primary cultured rat dorsal root ganglion (DRG) neurons. Furthermore, Nrf2 DNA binding activity was increased by DMF and MMF in PC12 cells. These findings suggest that DMF, which activates Nrf2 pathway, has a potential protective action against chemotherapy-induced neurotoxicity, particularly neurite impairments. Keywords: Dimethyl fumarate, Neurotoxicity, Oxaliplatin, Chemotherapy agents, Nuclear factor-erythroid-2-related factor 2 (Nrf2)