期刊
JOURNAL OF NEUROSCIENCE
卷 26, 期 3, 页码 981-990出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4617-05.2006
关键词
HIV-1; NMDA receptor; calpain; hippocampus; virus; neurotoxicity; macrophage
资金
- NIAID NIH HHS [P30 AI045008, T32 AI007632, T32 AI07632] Funding Source: Medline
- NINDS NIH HHS [R01 NS043994, NS043994, NS27405, NS45956, P01 NS027405] Funding Source: Medline
Neuronal damage in human immunodeficiency virus type 1 (HIV-1) infection in the brain is thought to occur at least in part through NMDA receptor ( NMDAR) excitation initiated by soluble neurotoxins from HIV-infected brain macrophages. Furthermore, brain regions enriched in NMDAR-2A (NR2A) and NMDAR-2B (NR2B) subunits, such as the hippocampus, are particularly vulnerable. Using cultured rat hippocampal cells and HIV-1-infected human monocyte-derived macrophages (HIV/MDM), we examined the role of NR2A and NR2B in HIV/MDM-induced hippocampal neuronal death. We used the primary HIV-1 strain Jago derived from the CSF of an individual with HIV-associated dementia and that robustly replicates in MDM. We found the following: ( 1) hippocampal neuronal susceptibility to HIV/MDM excitotoxins varies according to the developmental expression patterns of NR2A and NR2B; ( 2) NMDAR activation by HIV/MDM results in neuronal calpain activation, which results in neuronal death; and ( 3) selective antagonists of homomeric NR2B/NR2B- and heteromeric NR2A/NR2B-containing NMDARs, as well as an inhibitor of calpain activity, afford neuroprotection against HIV/MDM. These studies establish a clear link between macrophage HIV infection, neuronal NR2A and NR2B activation, and calpain-mediated hippocampal neuronal death. They further suggest a dominant role for NR2A and NR2B in determining neuronal susceptibility in HIV-infected brain. Antagonists of NR2A and NR2B subunits as well as inhibitors of calpain activation offer attractive neuroprotective approaches against HIV in both developing and mature brain.
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