Nerve Growth Factor Confers Neuroprotection against Colistin-Induced Peripheral Neurotoxicity
Chongshan Dai, Jianli Xiong, Yang Wang, Jianzhong Shen, Tony Velkov, Xilong Xiao
Abstract
Neurotoxicity is an unwanted side effect for patients when receiving parenteral colistin therapy. The development of effective neuroprotective agents that can be coadministered during colistin therapy remains a priority area in antimicrobial chemotherapy. The present study aimed to investigate the protective effect of nerve growth factor (NGF) against colistin-induced peripheral neurotoxicity using a murine model. C57BL/6 mice were randomly divided into the following 6 groups: (i) untreated control, (ii) NGF alone (36 μg/kg/day administered intraperitoneally), (iii) colistin alone (18 mg/kg/day administered intraperitoneally), and (iv-vi) colistin (18 mg/kg/day) plus NGF (9, 18, and 36 μg/kg/day). After treatment for 7 days, neurobehavioral and electrophysiology changes, histopathological assessments of sciatic nerve damage, and oxidative stress biomarkers were examined. The mRNA expression levels of Nrf2, HO-1, Akt, Bax, and caspase-3 and -9 were assessed using quantitative RT-PCR. The results showed that, across all the groups wherein NGF was coadministered with colistin, a marked attenuation of colistin-induced sciatic nerve damage and improved sensory and motor function were observed. In comparison to the colistin only treatment group, animals that received NGF displayed upregulated Nrf2 and HO-1 mRNA expression levels and downregulated Bax and caspase-3 and -9 mRNA expression levels. In summary, our study reveals that NGF coadministration protects against colistin-induced peripheral neurotoxicity via the activation of Akt and Nrf2/HO-1 pathways and inhibition of oxidative stress. This study highlights the potential clinical application of NGF as a neuroprotective agent for coadministration during colistin therapy.