Dai Chongshan, Ciccotosto Giuseppe D, Cappai Roberto, Wang Yang, Tang Shusheng, Xiao Xilong, Velkov Tony
College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China.
Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
J Antimicrob Chemother. 2017 Jun 1;72(6):1635-1645. doi: 10.1093/jac/dkx037.
Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity.
The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells.
Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells.
To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy.
神经毒性是患者在多粘菌素治疗期间经历的一种不良反应。开发在多粘菌素治疗期间可联合使用的有效神经保护剂仍然是抗微生物化疗的一个优先领域。本研究调查了协同四环素抗生素米诺环素对多粘菌素诱导的神经毒性的神经保护作用。
使用培养的小鼠神经母细胞瘤-2a（N2a）和原代皮质神经元细胞，研究米诺环素预处理对多粘菌素诱导的细胞凋亡、半胱天冬酶激活、氧化应激和线粒体功能障碍的影响。
多粘菌素在小鼠N2a和原代皮质细胞中诱导的神经毒性会产生活性氧（ROS），随后通过细胞凋亡导致细胞死亡。在多粘菌素（200μM）暴露（24小时）前2小时，用5、10和20μM的米诺环素预处理神经元细胞，通过显著降低细胞内ROS生成并上调抗ROS酶超氧化物歧化酶和过氧化氢酶的活性，具有神经保护作用。米诺环素预处理还保护细胞免受多粘菌素诱导的线粒体功能障碍、半胱天冬酶激活和随后的细胞凋亡。免疫组织化学成像研究显示多粘菌素在原代皮质神经元细胞的树突突起和细胞体内积累。
据我们所知，这是第一项证明米诺环素通过清除ROS和抑制细胞凋亡对多粘菌素诱导的神经毒性具有保护作用的研究。我们的研究强调，联合使用米诺环素一石二鸟：除了其协同抗菌活性外，米诺环素还可能改善接受多粘菌素治疗患者不必要的神经毒性。
