The chemokine receptor CXCR4 and not the N-methyl-D-aspartate receptor mediates gp120 neurotoxicity in cerebellar granule cells
The chemokine receptor CXCR4 and not the N-methyl-D-aspartate receptor mediates gp120 neurotoxicity in cerebellar granule cells
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DOI：
10.1002/jnr.10826
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发表时间：
2004-01-01
影响因子：
4.2
通讯作者：
Mocchetti, I
中科院分区：
文献类型：
--
作者：
Bachis, A;Mocchetti, I
人类免疫缺陷病毒1型（HIV-1）糖蛋白gp120导致神经细胞死亡；然而，神经毒性作用的分子机制在很大程度上仍未解决。有研究表明，gp120通过诱导谷氨酸等神经毒素的释放来诱导细胞死亡。这项工作的目的是研究谷氨酸在gp120介导的神经毒性中的作用。我们使用从8日龄大鼠小脑制备的小脑颗粒细胞作为实验工具，其中谷氨酸和gp120都导致细胞死亡。小脑颗粒神经元单独暴露于gp120或谷氨酸，或与谷氨酸受体拮抗剂MK801以及其他抗谷氨酸能化合物联合暴露。通过使用几种细胞死亡和凋亡标志物在不同时间测量细胞活力。MK801在阻断谷氨酸诱导的神经元细胞死亡的浓度下，未能阻止gp120介导的凋亡细胞死亡。此外，白细胞介素-10 （interleukin-10）先前已被证明可以阻断这些神经元中的谷氨酸毒性)对gp120没有神经保护作用。由于gp120的毒性是通过趋化因子受体CXCR4的激活介导的，因此用CXCR4抑制剂AMD3100培养神经元。该化合物可阻止gp120介导的细胞死亡，但不能阻止谷氨酸介导的细胞死亡。这些发现表明，即使在没有病毒的情况下，gp120也对神经元具有毒性，其毒性机制主要涉及CXCR4受体的激活。因此，CXCR4受体拮抗剂可能是抑制HIV-1神经毒性的更合适的化合物。(C) 2003 Wiley-Liss, Inc。
The human immunodeficiency virus type 1 (HIV-1) glycoprotein gp120 causes neuronal cell death; however, the molecular mechanisms of the neurotoxic effect remain largely unresolved. It has been suggested that gp120 evokes cell death by inducing the release of neurotoxins, including glutamate. The objective of this work was to examine the role of glutamate in gp120-mediated neurotoxicity. We used as an experimental tool cerebellar granule cells prepared from 8-day-old rat cerebella, in which both glutamate and gp120 cause cell death. Cerebellar granule neurons were exposed to gp120 or glutamate alone or in combination with the glutamate receptor antagonist MK801 as well as other antiglutamatergic compounds. Cell viability was measured at various times by using several markers of cell death and apoptosis. MK801, at a concentration that blocked glutamate-induced neuronal cell death, failed to prevent gp120-mediated apoptotic cell death. Moreover, interleukin-10, which has previously been shown to block glutamate toxicity in these neurons, was not neuroprotective against gp120. Because gp120 toxicity is mediated by activation of the chemokine receptor CXCR4, neurons were incubated with the CXCR4 inhibitor AMD3100. This compound prevented gp120- but not glutamate-mediated cell death. These findings suggest that gp120 is toxic to neurons even in the absence of the virus and that the toxic mechanism involves primarily activation of CXCR4 receptor. Therefore, antagonists to the CXCR4 receptor may be more suitable compounds for inhibiting HIV-1 neurotoxicity. (C) 2003 Wiley-Liss, Inc.