Giulian D, Yu J, Li X, Tom D, Li J, Wendt E, Lin S N, Schwarcz R, Noonan C
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Neurosci. 1996 May 15;16(10):3139-53. doi: 10.1523/JNEUROSCI.16-10-03139.1996.
Although there is growing evidence that neurotoxic molecules produced by HIV-1-infected mononuclear phagocytes damage neurons, the precise mechanisms of neuronal attack remain uncertain. One class of cytotoxin involves neuronal injury mediated via the NMDA receptor. We examined blood monocytes and brain mononuclear cells isolated at autopsy from HIV-1-infected individuals for the ability to release NMDA-like neuron-killing factors. We found that a neurotoxic amine, NTox, was produced by blood monocytes and by brain mononuclear phagocytes infected with retrovirus. In vivo injections of minute quantities of NTox produced selective damage to hippocampal pyramidal neurons. NTox can be extracted directly from brain tissues infected with HIV-1 and showed structural features similar to wasp and spider venoms. In contrast to NTox, HIV-1 infection did not increase the release of the NMDA excitotoxin quinolinic acid (QUIN) from mononuclear cells. Although we found modest elevations of QUIN in the CSF of HIV-1-infected individuals, the increases were likely attributable to entry through damaged blood-brain barrier. Taken together, our data pinpoint NTox, rather than QUIN, as a major NMDA receptor-directed toxin associated with neuro-AIDS.
尽管越来越多的证据表明，HIV-1感染的单核吞噬细胞产生的神经毒性分子会损害神经元，但神经元受攻击的确切机制仍不明确。一类细胞毒素涉及通过NMDA受体介导的神经元损伤。我们检测了从HIV-1感染个体尸检中分离出的血液单核细胞和脑单核细胞释放NMDA样神经元杀伤因子的能力。我们发现，一种神经毒性胺类物质NTox由血液单核细胞和感染逆转录病毒的脑单核吞噬细胞产生。在体内注射微量NTox会对海马锥体神经元造成选择性损伤。NTox可直接从感染HIV-1的脑组织中提取，其结构特征与黄蜂和蜘蛛毒液相似。与NTox不同，HIV-1感染并未增加单核细胞释放NMDA兴奋性毒素喹啉酸（QUIN）。尽管我们发现HIV-1感染个体的脑脊液中QUIN有适度升高，但这种升高可能是由于通过受损的血脑屏障进入所致。综上所述，我们的数据表明，与神经艾滋病相关的主要NMDA受体导向毒素是NTox，而非QUIN。
