Division of Anatomy, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Neuroscience. 2013 Nov 12;252:512-25. doi: 10.1016/j.neuroscience.2013.07.046. Epub 2013 Jul 30.
Distal sensory polyneuropathy (DSP) with associated neuropathic pain is the most common neurological disorder affecting patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Viral protein R (Vpr) is a neurotoxic protein encoded by HIV-1 and secreted by infected macrophages. Vpr reduces neuronal viability, increases cytosolic calcium and membrane excitability of cultured dorsal root ganglion (DRG) sensory neurons, and is associated with mechanical allodynia in vivo. A clinical trial with HIV/AIDS patients demonstrated that nerve growth factor (NGF) reduced the severity of DSP-associated neuropathic pain, a problem linked to damage to small diameter, potentially NGF-responsive fibers. Herein, the actions of NGF were investigated in our Vpr model of DSP and we demonstrated that NGF significantly protected sensory neurons from the effects of Vpr. Footpads of immunodeficient Vpr transgenic (vpr/RAG1(-/-)) mice displayed allodynia (p<0.05), diminished epidermalinnervation (p<0.01) and reduced NGF mRNA expression (p<0.001) compared to immunodeficient (wildtype/RAG1(-/-)) littermate control mice. Compartmented cultures confirmed recombinant Vpr exposure to the DRG neuronal perikarya decreased distal neurite extension (p<0.01), whereas NGF exposure at these distal axons protected the DRG neurons from the Vpr-induced effect on their cell bodies. NGF prevented Vpr-induced attenuation of the phosphorylated glycogen synthase-3 axon extension pathway and tropomyosin-related kinase A (TrkA) receptor expression in DRG neurons (p<0.05) and it directly counteracted the cytosolic calcium burst caused by Vpr exposure to DRG neurons (p<0.01). TrkA receptor agonist indicated that NGFacted through the TrkA receptor to block the Vpr-mediated decrease in axon outgrowth in neonatal and adult rat and fetal human DRG neurons (p<0.05). Similarly, inhibiting the lower affinity NGF receptor, p75, blocked Vpr's effect on DRG neurons. Overall, NGF/TrkA signaling or p75 receptor inhibition protects somatic sensory neurons exposed to Vpr, thus laying the groundwork for potential therapeutic options for HIV/AIDS patients suffering from DSP.
远端感觉性多发性神经病（DSP）伴发神经性疼痛是影响人类免疫缺陷病毒/获得性免疫缺陷综合征（HIV/AIDS）患者的最常见神经障碍。病毒蛋白 R（Vpr）是 HIV-1 编码并由受感染的巨噬细胞分泌的一种神经毒性蛋白。Vpr 降低神经元活力，增加培养的背根神经节（DRG）感觉神经元的胞浆钙和膜兴奋性，并与体内机械性痛觉过敏有关。一项针对 HIV/AIDS 患者的临床试验表明，神经生长因子（NGF）可减轻与小直径神经纤维损伤相关的 DSP 相关性神经性疼痛的严重程度，而小直径神经纤维可能对 NGF 有反应。在此，我们研究了 Vpr 在 DSP 模型中的作用，并证明 NGF 可显著保护感觉神经元免受 Vpr 的影响。免疫缺陷 Vpr 转基因（vpr/RAG1(-/-)）小鼠的足底表现出痛觉过敏（p<0.05）、表皮神经支配减少（p<0.01）和 NGF mRNA 表达减少（p<0.001），与免疫缺陷（野生型/RAG1(-/-)）同窝对照小鼠相比。分隔培养证实，DRG 神经元胞体中重组 Vpr 的暴露减少了远端轴突的延伸（p<0.01），而这些远端轴突中 NGF 的暴露可保护 DRG 神经元免受 Vpr 对其胞体的影响。NGF 可防止 Vpr 诱导的磷酸化糖原合酶-3 轴突延伸途径和原肌球蛋白相关激酶 A（TrkA）受体表达减弱（p<0.05），并直接抵消 Vpr 暴露于 DRG 神经元引起的胞浆钙爆发（p<0.01）。TrkA 受体激动剂表明，NGF 通过 TrkA 受体发挥作用，阻止 Vpr 介导的新生和成年大鼠及胎人 DRG 神经元的轴突生长减少（p<0.05）。同样，抑制低亲和力 NGF 受体 p75 可阻断 Vpr 对 DRG 神经元的作用。总体而言，NGF/TrkA 信号转导或 p75 受体抑制可保护暴露于 Vpr 的躯体感觉神经元，为 HIV/AIDS 患者 DSP 治疗提供了潜在选择。
