Peripheral neuropathic pain is one of the most common and debilitating complications of diabetes. Several genes have been shown to be effective in reducing neuropathic pain in animal models of diabetes after transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)1-based vectors, yet there has never been a comparative analysis of their efficacy. We compared four different HSV1-based vectors engineered to produce one of two opioid receptor agonists (enkephalin or endomorphin), or one of two isoforms of glutamic acid decarboxylase (GAD65 or GAD67), alone and in combination, in the streptozotocin-induced diabetic rat and mouse models. Our results indicate that a single subcutaneous hindpaw inoculation of vectors expressing GAD65 or GAD67 reduced diabetes-induced mechanical allodynia to a degree that was greater than daily injections of gabapentin in rats. Diabetic mice that developed thermal hyperalgesia also responded to GAD65 or endomorphin gene delivery. The results suggest that either GAD65 or GAD67 vectors are the most effective in the treatment of diabetic pain. The vector combinations, GAD67+endomorphin, GAD67+enkephalin or endomorphin+enkephalin also produced a significant antinociceptive effect but the combination did not appear to be superior to single gene treatment. These findings provide further justification for the clinical development of antinociceptive gene therapies for the treatment of diabetic peripheral neuropathies.

译文

周围神经病理性疼痛是糖尿病最常见和使人衰弱的并发症之一。使用基于复制缺陷型单纯疱疹病毒 (HSV)1的载体转移到背根神经节后,几种基因已被证明可有效减轻糖尿病动物模型中的神经病理性疼痛,但从未对其功效进行比较分析。我们在链脲佐菌素诱导的糖尿病大鼠和小鼠模型中比较了四种不同的HSV1-based载体,这些载体单独或组合产生两种阿片受体激动剂 (脑啡肽或内啡肽) 之一,或谷氨酸脱羧酶 (GAD65或GAD67) 的两种同工型之一。我们的结果表明,单次皮下后爪接种表达GAD65或GAD67的载体可将糖尿病诱导的机械性异常性疼痛降低到比每天注射加巴喷丁更大的程度。发生热痛觉过敏的糖尿病小鼠也对GAD65或内吗啡基因递送有反应。结果表明,GAD65或GAD67载体在治疗糖尿病疼痛中最有效。载体组合GAD67内吗啡,GAD67脑啡肽或内吗啡脑啡肽也产生了显着的抗伤害感受作用,但该组合似乎并不优于单基因治疗。这些发现为抗伤害感受基因疗法治疗糖尿病周围神经病的临床发展提供了进一步的理由。

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