College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing, 100193, People's Republic of China.
Department of Pathology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
Mol Neurobiol. 2018 Jan;55(1):421-434. doi: 10.1007/s12035-016-0276-6. Epub 2016 Dec 12.
Neurotoxicity is an unwanted side-effect seen in patients receiving therapy with the "last-line" polymyxin antibiotics. This is the first study to show that colistin-induced neurotoxicity in neuroblastoma-2a (N2a) cells gives rise to an inflammatory response involving the IL-1β/p-IκB-α/NF-κB pathway. Pretreatment with curcumin at 5, 10, and 20 μM for 2 h prior to colistin (200 μM) exposure for 24 h, produced an anti-inflammatory effect by significantly down-regulating the expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2), phosphorylation of the inhibitor of nuclear factor-kappa B (NF-κB) (p-IκB)-α, and concomitantly NF-κB levels. Moreover, curcumin significantly decreased intracellular reactive oxygen species (ROS) production and increased the activities of the anti-ROS enzymes superoxide dismutase, catalase, and the intracellular levels of glutathione. Curcumin pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation, and subsequent apoptosis. Overall, our findings demonstrate for the first time, a potential role for curcumin for treating polymyxin-induced neurotoxicity through the modulation of NF-κB signaling and its potent anti-oxidative and anti-apoptotic effects.
神经毒性是接受“最后一线”多黏菌素类抗生素治疗的患者中出现的一种不良副作用。这是第一项表明多粘菌素诱导的神经母细胞瘤-2a（N2a）细胞神经毒性会引发涉及 IL-1β/p-IκB-α/NF-κB 途径的炎症反应的研究。在用 200 μM 多粘菌素处理 24 小时之前，用 5、10 和 20 μM 的姜黄素预处理 2 小时，通过显著下调促炎介质环氧化酶-2（COX-2）、核因子-κB（NF-κB）抑制剂磷酸化（p-IκB）-α的表达以及同时 NF-κB 水平，产生抗炎作用。此外，姜黄素可显著减少细胞内活性氧（ROS）的产生并增加抗氧化酶超氧化物歧化酶、过氧化氢酶的活性以及细胞内谷胱甘肽水平。姜黄素预处理还可以防止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。总的来说，我们的研究结果首次表明，姜黄素通过调节 NF-κB 信号通路及其强大的抗氧化和抗凋亡作用，可能成为治疗多粘菌素诱导的神经毒性的一种方法。
