Human Immunodeficiency Virus (HIV)-Induced Neurotoxicity: Roles for the NMDA Receptor Subtypes

摘要: Neuronal damage in human immunodeficiency virus type 1 (HIV-1) infection the brain is thought to occur at least part through NMDA receptor (NMDAR) excitation initiated by soluble neurotoxins from HIV-infected macrophages. Furthermore, regions enriched NMDAR-2A (NR2A) and NMDAR-2B (NR2B) subunits, such as hippocampus, are particularly vulnerable. Using cultured rat hippocampal cells HIV-1-infected monocyte-derived macrophages (HIV/MDM), we examined role of NR2A NR2B HIV/MDM-induced neuronal death. We used primary HIV-1 strain Jago derived CSF an individual with HIV-associated dementia that robustly replicates MDM. found following: (1) susceptibility HIV/MDM excitotoxins varies according developmental expression patterns NR2B; (2) NMDAR activation results calpain activation, which death; (3) selective antagonists homomeric NR2B/NR2B- heteromeric NR2A/NR2B-containing NMDARs, well inhibitor activity, afford neuroprotection against HIV/MDM. These studies establish a clear link between macrophage HIV infection, calpain-mediated They further suggest dominant for determining brain. Antagonists subunits inhibitors offer attractive neuroprotective approaches both developing mature