Wang Jun, Qian Wenyi, Liu Jingli, Zhao Jingjing, Yu Pan, Jiang Lei, Zhou Jing, Gao Rong, Xiao Hang
Key Lab of Modern Toxicology, Ministry of Education. Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
Key Lab of Modern Toxicology, Ministry of Education. Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China ; Departments of Experimental Medicine, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, China.
PLoS One. 2014 Feb 12;9(2):e88642. doi: 10.1371/journal.pone.0088642. eCollection 2014.
Methamphetamine (Meth) abusing represents a major public health problem worldwide. Meth has long been known to induce neurotoxicity. However, the mechanism is still remained poorly understood. Growing evidences indicated that the voltage-gated potassium channels (Kv) were participated in neuronal damage and microglia function. With the whole cell patch clamp, we found that Meth significantly increased the outward K⁺ currents, therefore, we explored whether Kv1.3, one of the major K⁺ channels expressed in microglia, was involved in Meth-induced microglia damage. Our study showed that Meth significantly increased the cell viability in a dose dependent manner, while the Kv blocker, tetraethylamine (TEA), 4-Aminopyridine (4-AP) and Kv1.3 specific antagonist margatoxin (MgTx), prevented against the damage mediated by Meth. Interestingly, treatment of cells with Meth resulted in increasing expression of Kv1.3 rather than Kv1.5, at both mRNA and protein level, which is partially blocked by MgTx. Furthermore, Meth also stimulated a significant increased expression of IL-6 and TNF-α at protein level, which was significantly inhibited by MgTx. Taken together, these results demonstrated that Kv1.3 was involved in Meth-mediated microglial damage, providing the potential target for the development of therapeutic strategies for Meth abuse.
甲基苯丙胺（冰毒）滥用是一个全球性的重大公共卫生问题。长期以来，人们都知道冰毒会诱发神经毒性。然而，其机制仍知之甚少。越来越多的证据表明，电压门控钾通道（Kv）参与了神经元损伤和小胶质细胞功能。通过全细胞膜片钳技术，我们发现冰毒显著增加了外向钾离子电流，因此，我们探讨了小胶质细胞中主要表达的钾离子通道之一Kv1.3是否参与了冰毒诱导的小胶质细胞损伤。我们的研究表明，冰毒以剂量依赖的方式显著增加细胞活力，而钾通道阻滞剂四乙铵（TEA）、4-氨基吡啶（4-AP）和Kv1.3特异性拮抗剂玛格毒素（MgTx）可预防冰毒介导的损伤。有趣的是，用冰毒处理细胞导致Kv1.3而非Kv1.5在mRNA和蛋白质水平上的表达增加，这被MgTx部分阻断。此外，冰毒还在蛋白质水平上刺激了白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的显著表达增加，这被MgTx显著抑制。综上所述，这些结果表明Kv1.3参与了冰毒介导的小胶质细胞损伤，为开发冰毒滥用治疗策略提供了潜在靶点。
