A fungicide miconazole ameliorates tri-o-cresyl phosphate-induced demyelination through inhibition of ErbB/Akt pathway

Abstract

Organophosphorus compound (OP)-induced delayed neuropathy (OPIDN) is characterized by distal axonal degeneration and demyelination of the central and peripheral axons, which leads to progressive muscle weakness, ataxia and paralysis in several days after OP intoxication. This study aimed to investigate the possible use of an imidazole fungicide miconazole as a novel therapy for OPIDN. Adult hens, the most commonly used animal models in OPIDN studies, were orally given tri-o-cresyl phosphate (TOCP). We showed that miconazole, which was administered daily to hens beginning on the 7th day after TOCP exposure, drastically ameliorated the neurotoxic symptoms and histopathological damages in spinal cord and sciatic nerves. Mechanistically, miconazole inhibited the TOCP-induced activation of ErbB/Akt signaling, and enhanced the myelin basic protein (MBP) expression. In a glial cell model sNF96.2 cells, miconazole restored the TOCP-inhibited MBP expression, and promoted cell differentiation as well as cell migration by inhibiting the activation of ErbB/Akt signaling pathway. In sum, miconazole, a synthetic imidazole fungicide, could ameliorate the symptoms and histopathological changes of OPIDN, probably by promoting glial cell differentiation and migration to enhance myelination via inhibiting the activation of ErbB/Akt. Thus, miconazole is a promising candidate therapy for the clinical treatment of OPIDN.