The Expression of Copper Transporters in Rat Dorsal Root Ganglion Neurons and its role in Oxaliplatin Neurotoxicity

Abstract

Oxaliplatin is a platinum-based anticancer agent used for the treatment of colorectal cancer. Oxaliplatin chemotherapy is associated with peripheral neuropathy and dorsal root ganglia neurons are the putative target, however the mechanism of toxicity is currently unknown. Recent evidence suggests that copper transporters may be implemented in the transport and neurotoxicity of platinum drugs. We hypothesis that platinum drugs induce neurotoxicity by mechanisms involving copper transporters. To examine the mechanisms by which dorsal root ganglia neurons are damaged by oxaliplatin, the mRNA and protein expressions of copper transporters were investigated in healthy and oxaliplatin treated adult rats. Adult rat dorsal root ganglion tissue exhibited a specific pattern of expression of copper transporters with distinct subsets of neurons intensely expressing either ATP7A or CTR1, but not both or ATP7B. Neurons expressing the copper influx transporter, CTR1, were more susceptible to oxaliplatin-induced neurotoxicity compared to neurons expressing the copper efflux transporter ATP7A. Based on the abovementioned findings, a series of compounds used for the treatment of Menkes and Wilson's disease were tested in a rat model of oxaliplatin-induced neurotoxicity. Copper histidine (0.02-20 mg/kg) and ammonium tetrathiomolybdate (1 - 30 mg/kg) showed initial protection in a pilot study but did not significantly reduce the neurotoxicity of oxaliplatin, based on DRG morphometric changes, in a subsequent definitive study. Copper treatment did not increase the systemic copper level or reduce the neurotoxicity of oxaliplatin in the current in vivo rat model. Primary cultures of dorsal root ganglion neurons were employed to investigate the expressions of copper transporters in untreated and in oxaliplatin treated neurons. It was found that CTR1 and ATP7A were expressed in distinct sub-population of cultured rat DRG neurons. Oxaliplatin caused atrophy in the neurons expressing CTR1 and a loss of membrane staining frequency without altering the number of neurons. Neurons expressing ATP7A was not affected by oxaliplatin treatment.