Human immunodeficiency virus (HIV)-induced neurotoxicity: Roles for the NMDA receptor subtypes 2A and 2B and the calcium-activated protease calpain by a CSF-derived HIV-1 strain
Human immunodeficiency virus (HIV)-induced neurotoxicity: Roles for the NMDA receptor subtypes 2A and 2B and the calcium-activated protease calpain by a CSF-derived HIV-1 strain
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DOI：
10.1523/jneurosci.4617-05.2006
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发表时间：
2006-01-18
影响因子：
5.3
通讯作者：
Kolson, DL
中科院分区：
文献类型：
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作者：
O'Donnell, LA;Agrawal, A;Kolson, DL
人类免疫缺陷病毒1型(HIV-1)感染脑内的神经元损伤被认为至少部分是通过HIV感染的脑巨噬细胞中的可溶性神经毒素引起的NMDAR兴奋而发生的。此外，富含NMDAR-2A(NR2A)和NMDAR-2B(NR2B)亚单位的大脑区域，如海马体，尤其脆弱。利用培养的大鼠海马细胞和HIV-1感染的人单核细胞来源的巨噬细胞(HIV/MDM)，我们研究了NR2A和NR2B在HIV/MDM诱导的海马神经元死亡中的作用。我们使用了主要的HIV-1毒株Jago，该毒株来自一名HIV相关性痴呆患者的脑脊液，并在MDM中强劲复制。我们发现：(1)海马神经元对HIV/MDM兴奋性毒素的敏感性因NR2A和NR2B的发育表达模式而异；(2)由HIV/MDM激活的NMDAR导致神经元Calain激活，从而导致神经元死亡；(3)含同构体NR2B/NR2B-和异构体NR2A/NR2B的NMDARs的选择性拮抗剂以及Calain活性的抑制剂对HIV/MDM具有神经保护作用。这些研究建立了巨噬细胞HIV感染、神经元NR2A和NR2B激活以及钙蛋白酶介导的海马神经元死亡之间的明确联系。他们进一步表明，NR2A和NR2B在确定HIV感染的大脑中的神经元敏感性方面发挥了主导作用。NR2A和NR2B亚基的拮抗剂以及钙蛋白酶激活的抑制剂在发育中和成熟的大脑中都提供了诱人的神经保护方法来对抗艾滋病毒。
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.