Methamphetamine (Meth) abuse not only increases the risk of human immunodeficiency virus-1 (HIV-1) infection, but exacerbates HIV-1-associated neurocognitive disorders (HAND) as well. The mechanisms underlying the co-morbid effect are not fully understood. Meth and HIV-1 each alone interacts with microglia and microglia express voltage-gated potassium (KV) channel KV1.3. To understand whether KV1.3 functions an intersecting point for Meth and HIV-1, we studied the augment effect of Meth on HIV-1 glycoprotein 120 (gp120)-induced neurotoxic activity in cultured rat microglial cells. While Meth and gp120 each alone at low (subtoxic) concentrations failed to trigger microglial neurotoxic activity, Meth potentiated gp120-induced microglial neurotoxicity when applied in combination. Meth enhances gp120 effect on microglia by enhancing microglial KV1.3 protein expression and KV1.3 current, leading to an increase of neurotoxin production and resultant neuronal injury. Pretreatment of microglia with a specific KV1.3 antagonist 5-(4-Phenoxybutoxy)psoralen (PAP) or a broad spectrum KV channel blocker 4-aminopyridine (4-AP) significantly attenuated Meth/gp120-treated microglial production of neurotoxins and resultant neuronal injury, indicating an involvement of KV1.3 in Meth/gp120-induced microglial neurotoxic activity. Meth/gp120 activated caspase-3 and increased caspase-3/7 activity in microglia and inhibition of caspase-3 by its specific inhibitor significantly decreased microglial production of TNF-α and iNOS and attenuated microglia-associated neurotoxic activity. Moreover, blockage of KV1.3 by specific blockers attenuated Meth/gp120 enhancement of caspase-3/7 activity. Taking together, these results suggest an involvement of microglial KV1.3 in the mediation of Meth/gp120 co-morbid effect on microglial neurotoxic activity via caspase-3 signaling.

中文翻译：

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甲基苯丙胺通过增强小胶质细胞向外K +电流来增强HIV-1gp120诱导的小胶质细胞神经毒性活性。

甲基苯丙胺（甲基）的滥用不仅增加了人类免疫缺陷病毒1（HIV-1）感染的风险，而且还加剧了与HIV-1相关的神经认知障碍（HAND）。共病效应的潜在机制尚不完全清楚。甲硫氨酸和HIV-1分别与小胶质细胞相互作用，小胶质细胞表达电压门控钾（KV）通道KV1.3。为了了解KV1.3是否对Meth和HIV-1具有交叉点，我们研究了Meth对培养的大鼠小胶质细胞中HIV-1糖蛋白120（gp120）诱导的神经毒性活性的增强作用。尽管单独使用低浓度（亚毒性）的Meth和gp120无法触发小胶质细胞神经毒性活性，但联合使用Meth可以增强gp120诱导的小胶质神经毒性。甲氧通过增强小胶质细胞KV1增强gp120对小胶质细胞的作用。3蛋白表达和KV1.3电流，导致神经毒素产生增加和由此引起的神经元损伤。用特定的KV1.3拮抗剂5-（4-苯氧基丁氧基）补骨脂素（PAP）或广谱KV通道阻滞剂4-氨基吡啶（4-AP）预处理小胶质细胞显着减弱了Meth / gp120处理的小胶质细胞产生的神经毒素和由此产生的神经元损伤，表明KV1.3参与了Meth / gp120诱导的小胶质神经毒性活动。Meth / gp120激活了小胶质细胞中的caspase-3活性并增加了caspase-3 / 7活性，其特异性抑制剂对caspase-3的抑制作用显着降低了小胶质细胞产生的TNF-α和iNOS，并减弱了与小胶质细胞相关的神经毒性。此外，通过特定的阻滞剂对KV1.3的阻滞减弱了Caspase-3 / 7活性的Meth / gp120增强。在一起