HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a.
HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a.
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作者：
Kanda H;Kanao M;Liu S;Yi H;Iida T;Levitt RC;Candiotti KA;Lubarsky DA;Hao S
人类免疫缺陷病毒（HIV）相关的神经性疼痛是一种严重且持续的使人衰弱的慢性疾病。尽管进行了广泛的研究，但确切的神经病理机制仍然未知，这阻碍了我们开发有效治疗方法的能力。GABA能张力的丧失可能在神经病理性疼痛状态中起重要作用。谷氨酸脱羧酶67（GAD 67）是催化GABA合成的同工酶之一。在这里，我们使用重组单纯疱疹病毒（HSV-1）载体，编码gad 1基因，以评估GAD 67在外周HIV gp 120诱导的大鼠神经病理性疼痛的治疗潜力。我们发现1）皮下接种表达GAD 67的HSV载体减轻了HIV gp 120诱导的神经病理性疼痛模型中的机械性异常性疼痛，2）GAD 67的抗异常性疼痛作用被GABA-A和-B受体拮抗剂降低，3）表达GAD 67的HSV载体逆转了降低的GABA-IR表达，表达GAD 67的HSV载体抑制脊髓背角线粒体超氧化物和Wnt 5a的上调。综上所述，我们的研究支持这样的概念，即通过HSV载体恢复GABA能张力可以通过抑制线粒体超氧化物和Wnt 5a来逆转HIV相关的神经病理性疼痛。我们的研究为HSV介导的GAD 67基因治疗HIV相关神经病理性疼痛提供了验证。
Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may play an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that 1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, 2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, 3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression, and 4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain.