Xiong Liguang, Xiang Debiao, Yuan Fang, Tong Huan, Yang Rui, Zhou Lili, Xu Bing, Deng Changhui, Li Xin
Hunan University of Chinese Medicine, Changsha, China; Department of Pharmacy, The Third Hospital of Changsha, Changsha, China.
Department of Pharmacy, The Third Hospital of Changsha, Changsha, China; The Clinical Application Research Institute of Antibiotics in Changsha, Changsha, China.
Biomed Pharmacother. 2023 May;161:114419. doi: 10.1016/j.biopha.2023.114419. Epub 2023 Feb 21.
Multidrug-resistant Gram-negative bacteria are the most pressing problem in treating infectious diseases. As one of the primary drugs for multidrug-resistant Gram-negative bacteria, the neurotoxicity of colistin has become a significant challenge in clinical practice.
This study aimed to investigate the potential effect of piceatannol-3'-O-β-D glucopyranoside (PG) on colistin-induced neurotoxicity and the underlying mechanism.
In vitro, nerve cell damage models were established by exposing N2a cells to 400 μM colistin for 24 h. The effects of PG on cell viability, apoptosis level, and oxidative stress level were analyzed. A western blot experiment was performed to determine the NRF2 pathway, apoptosis, and autophagy-related proteins. Mitochondrial morphology and mitochondrial membrane potential were detected after staining using laser confocal microscopy. In vivo, nerve injury mouse model was established by intracerebroventricular colistin administration. Morphological changes in brain tissues were observed using HE and Nissl staining.
PG significantly reduced colistin-induced neuronal apoptosis levels. The apoptosis-related protein expressions were suppressed after PG intervention. Mechanistically, PG increased the levels of antioxidant factors and decreased the levels of oxidative factors, which might be related to the activation of the NRF2 pathway. In addition, PG treatment reversed the deviations in mitochondrial morphology and membrane potential. PG suppressed autophagy levels in N2a cells, possibly because PG inhibited colistin-induced apoptosis, thus reducing the level of spontaneous protective autophagy in cells. Nrf2 knockdown N2a cell models were applied to confirm that the activation of the NRF2 pathway played a vital role in PG alleviating the nerve damage caused by colistin.
PG is a potential treatment option for colistin-induced neurotoxicity. It mitigated colistin-induced oxidative stress-associated injury and mitochondrial damage by activating the NRF2/HO-1 pathway, thus reducing nerve cell apoptosis.
耐多药革兰氏阴性菌是治疗感染性疾病中最紧迫的问题。作为治疗耐多药革兰氏阴性菌的主要药物之一，黏菌素的神经毒性已成为临床实践中的一项重大挑战。
本研究旨在探讨3'-O-β-D-吡喃葡萄糖苷白藜芦醇（PG）对黏菌素诱导的神经毒性的潜在影响及其潜在机制。
在体外，通过将N2a细胞暴露于400μM黏菌素24小时建立神经细胞损伤模型。分析PG对细胞活力、凋亡水平和氧化应激水平的影响。进行蛋白质免疫印迹实验以确定NRF2通路、凋亡和自噬相关蛋白。使用激光共聚焦显微镜染色后检测线粒体形态和线粒体膜电位。在体内，通过脑室内注射黏菌素建立神经损伤小鼠模型。使用苏木精-伊红染色和尼氏染色观察脑组织的形态学变化。
PG显著降低了黏菌素诱导的神经元凋亡水平。PG干预后凋亡相关蛋白表达受到抑制。机制上，PG增加了抗氧化因子水平并降低了氧化因子水平，这可能与NRF2通路的激活有关。此外，PG处理逆转了线粒体形态和膜电位的偏差。PG抑制了N2a细胞中的自噬水平，可能是因为PG抑制了黏菌素诱导的凋亡，从而降低了细胞中自发保护性自噬的水平。应用Nrf2基因敲低的N2a细胞模型来证实NRF2通路的激活在PG减轻黏菌素引起的神经损伤中起重要作用。
PG是治疗黏菌素诱导的神经毒性的一种潜在选择。它通过激活NRF2/HO-1通路减轻了黏菌素诱导的氧化应激相关损伤和线粒体损伤，从而减少神经细胞凋亡。
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