College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.
College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471023, P. R. China.
ACS Infect Dis. 2020 Jun 12;6(6):1451-1459. doi: 10.1021/acsinfecdis.0c00107. Epub 2020 May 21.
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.
神经毒性是患者接受肠外黏菌素治疗时的一种非预期的副作用。开发可在黏菌素治疗期间联合使用的有效神经保护剂仍然是抗菌化学治疗的重点领域。本研究旨在使用小鼠模型研究神经生长因子 (NGF) 对黏菌素诱导的周围神经毒性的保护作用。C57BL/6 小鼠被随机分为以下 6 组：（i）未处理对照组，（ii）NGF 单独组（36μg/kg/天腹腔内给药），（iii）黏菌素单独组（18mg/kg/天腹腔内给药），和（iv-vi）黏菌素（18mg/kg/天）加 NGF（9、18 和 36μg/kg/天）。治疗 7 天后，检查神经行为和电生理学变化、坐骨神经损伤的组织病理学评估以及氧化应激生物标志物。使用定量 RT-PCR 评估 Nrf2、HO-1、Akt、Bax 和 caspase-3 和 -9 的 mRNA 表达水平。结果表明，在所有与黏菌素联合使用 NGF 的组中，均观察到黏菌素诱导的坐骨神经损伤明显减轻，感觉和运动功能得到改善。与仅接受黏菌素治疗的组相比，接受 NGF 的动物表现出 Nrf2 和 HO-1 mRNA 表达水平上调，Bax 和 caspase-3 和 -9 mRNA 表达水平下调。总之，我们的研究表明，NGF 联合给药通过激活 Akt 和 Nrf2/HO-1 途径以及抑制氧化应激来保护黏菌素诱导的周围神经毒性。这项研究强调了 NGF 作为黏菌素治疗期间联合使用的神经保护剂的潜在临床应用。
