Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine , China Agricultural University , No. 2 Yuanmingyuan West Road , Beijing 100193 , P. R. China.
Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine , Northeast Agricultural University , Harbin 150000 , P. R. China.
ACS Chem Neurosci. 2019 Jan 16;10(1):120-131. doi: 10.1021/acschemneuro.8b00300. Epub 2018 Nov 7.
Neurotoxicity is one major unwanted side-effects associated with polymyxin (i.e., colistin and polymyxin B) therapy. Clinically, colistin neurotoxicity is characterized by neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and facial and peripheral paresthesias. Pathologically, colistin-induced neurotoxicity is characterized by cell injury and death in neuronal cell. This Review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuroprotective 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 upregulated by neuroprotective agents including curcumin, rapamycin and minocycline. Further research is needed toward the development of novel polymyxin formulations in combination with neuroprotective agents to ameliorate this unwanted adverse effect during polymyxins therapy in patients.
神经毒性是多黏菌素（即黏菌素和多黏菌素 B）治疗相关的一种主要不良反应。临床上，黏菌素的神经毒性表现为头晕、视力障碍、眩晕、意识混乱、幻觉、癫痫、共济失调以及面部和周围感觉异常等神经症状。从病理学上看，黏菌素诱导的神经毒性的特征是神经元细胞的损伤和死亡。本综述涵盖了我们目前对多黏菌素诱导的神经毒性、其潜在机制以及发现新型神经保护剂以限制这种神经毒性的理解。近年来，越来越多的文献支持这样一种观点，即多黏菌素诱导的神经损伤在很大程度上与氧化应激和线粒体功能障碍有关。p53、PI3K/Akt 和 MAPK 通路也参与了黏菌素诱导的神经元细胞死亡。还表明，氧化还原平衡途径（如 Nrf2/HO-1 和自噬）的激活对多黏菌素诱导的神经毒性具有保护作用。已经证明这些途径可以被神经保护剂（包括姜黄素、雷帕霉素和米诺环素）上调。需要进一步研究开发新型多黏菌素制剂与神经保护剂联合应用，以改善多黏菌素治疗患者的这种不良不良反应。
