Peripheral neuropathy caused by DCA-induced oxidative stress

Dichloroacetate (DCA) is water chlorination by product. Initial toxicology studies suggested that DCA can be carcinogenic, but the dosage found in water is much lower than hazardous. DCA activates pyruvate dehydrogenase and facilitates pyruvate metabolism to acetyl-CoA. DCA's ability to activate mitochondria and lower lactic level has attracted attention and it has been proposed as a therapeutic agent to treat lactic acidosis, mitochondrial diseases and cancer. However, peripheral neuropathy has been reported in patients received DCA treatment. Peripheral neuropathy includes distal numbness, decreased nerve conduction velocity, thermal hypoalgesia, and allodynia. The underlying mechanism of DCA-induced peripheral neuropathy is unclear. We established animal models that mimic DCA-induced peripheral neuropathy to investigate the mechanism. Oxidative stress is observed in animals treated with DCA so we have examined the efficacy of known antioxidants. We found that ellagic acid can prevent DCA-induced peripheral neuropathy and that DHA has transient protective effects. In contrast, lipoic acid appeared to worsen DCA-induced peripheral neuropathy while fisetin appeared to have no effects. We have also begun to explore two pathways that may be involved in DCA-induced oxidative stress. Results from [delta]-ALA and 2-CP pathway are inconclusive and both studies are currently on -going. Oxidative stress in peripheral neurons from these animals will be measured. Finally, we investigated a potential cause of painful neuropathy in DCA treated rats. There was no difference in expression of spinal KCC2 transporters between control and DCA treated rat