Nerve growth factor confers neuroprotection against colistin-induced peripheral neurotoxicity.

Neurotoxicity is an unwanted side effect patient's experience when receiving parenteral colistin therapy. The development of effective neuroprotective agents that can be co-administered 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, caspase-3 and -9 were assessed using quantitative RT-PCR. The results showed that across all the groups wherein NGF was co-administered 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 up-regulated Nrf2 and HO-1 mRNA expression levels and down-regulated Bax, caspase-3 and -9 mRNA expression levels. In summary, our study reveals that NGF co-administration 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 co-administration during colistin therapy.