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.
Keywords: 1-β-d-arabinofuranosylcytosine; ACSF; AIDS; ANOVA; AraC; DMEM/F12; DRG; DSP; Dulbecco’s Modified Eagle’s Medium/Ham’s F-12; EDTA; GSK3β; HAART; HIV; NGF; PBS; TrkA; Vpr; acquired immunodeficiency syndrome; analysis of variance; artificial cerebral spinal fluid; distal sensory polyneuropathy; dorsal root ganglion; ethylenediaminetetraacetic acid; glycogen synthase kinase-3 beta; highly active antiretroviral therapy; human immunodeficiency virus; human immunodeficiency virus (HIV); nerve growth factor; nerve growth factor (NGF); neuropathic pain; pGSK3β; phosphate-buffered saline; phosphorylated GSK3β; qRT-PCR; quantitative real-time polymerase chain reaction; tropomyosin-related kinase A; tropomyosin-related kinase A (TrkA); viral protein R; viral protein R (Vpr).
Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.