Molecular mechanisms of neurotoxicity induced by polymyxins and chemo-prevention

Polymyxins (colistin and polymyxin B) are used increasingly for the treatment of life-threatening infections caused by multidrug resistant (MDR) Gram-negative pathogens, in particular Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. Neurotoxicity is one major unwanted side-effects associated with polymyxin therapy. This review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuro-protective agents to limit this neurotoxicity. In recent years, an increasing body of literature supports the notion that polymyxin-induced nerve damage is largely related to oxidative stress and mitochondrial dysfunction. P53, PI3K/Akt and MAPK pathways are also involved in colistin-induced neuronal cell death. The activation of the redox homeostasis pathways such as Nrf2/HO-1 and autophagy have also been shown to play protective roles against polymyxin-induced neurotoxicity. These pathways have been demonstrated to be up-regulat...