Colistin induced peripheral neurotoxicity involves mitochondrial dysfunction and oxidative stress in mice

Polymyxin is a critical antibiotic against the infection caused by multidrug-resistant gram-negative bacteria. Neurotoxicity is one of main dose-limiting factors. The present study aimed to investigate the underlying molecular mechanism on colistin induced peripheral neurotoxicity using a mouse model. Forty mice were divided into control, colistin 1-, 3- and 7-day groups, the mice were intravenously injected with saline or colistin (sulfate) at the dose of 15mg/kg/day for 1, 3 and 7days, respectively. The results showed that, colistin treatment for 7days markedly resulted in the demyelination, axonal degeneration and mitochondria swelling in the mice's sciatic tissues. Colistin treatment induces oxidative stress as well as the increases of mitochondrial permeability transition, decreases of membrane potential ((m)) and activities of mitochondrial respiratory chain in the mice's sciatic nerve tissues. Furthermore, in the colistin-7day group, adenosine-triphosphate (ATP) level Na+/K+-ATPase activity decreased to 75.2% (p<0.01) and 80.1% (p<0.01), respectively. Meanwhile, colistin treatment down-regulates the expression of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) mRNAs and up-regulates the expression of Bax and caspase-3 mRNAs. Our results reveal that colistin induced sciatic nerves damage involves oxidative stress, mitochondrial dysfunction and the inhibition of Akt/mTOR pathway.