Department of Psychiatry, HIV Neurobehavioral Research Center, University of California, San Diego, California 92093-0603, USA.
J Neurovirol. 2009 Sep;15(5-6):434-8. doi: 10.1080/13550280903168131.
Glycogen synthase kinase-3beta (GSK3beta) role in human immunodeficiency virus(HIV)-associated neurodegeneration has been evidenced by previous investigations. In this study, we investigated the specificity of two GSK3beta-specific inhibitors, AR-A014418 (A) and B6B30 (B) to prevent direct neurotoxicity in primary human neurons exposed to HIV (BaL). Neurons were exposed to HIV (500 pg/ml) for 12-h and 6-day periods in the presence and absence of A (1 microM, 100 nM, 10 nM) and B (50 nM, 5 nM, 500 pM) to investigate acute and ongoing mechanisms of HIV neurotoxicity. Using an lactate dehydrogenase (LDH) assay to assess cytotoxicity, we observed a significant neurotoxic effect of HIV from control values (P < .01) that was not restored via coexposures of all concentrations of A and B. Additionally, no change in LDH levels were observed after 6 days. However, activity of the acute proapoptotic markers caspases 3 and 7 using a luminescence assay were measured and found to be increased by exposure to HIV (BaL) compared to controls (P = .022). This effect was ameliorated via coexposure to all concentrations of A and 50 nM B after 12 h (P < .01) and to all concentrations of A and B after 6 days (P < .01). Overall, the results from this study provide further evidence for the ability of GSK3beta inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK3beta as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder.
先前的研究证实，糖原合酶激酶-3β（GSK3β）在人类免疫缺陷病毒（HIV）相关神经退行性变中起作用。在这项研究中，我们研究了两种 GSK3β 特异性抑制剂 AR-A014418（A）和 B6B30（B）的特异性，以防止暴露于 HIV（BaL）的原代人神经元发生直接神经毒性。神经元在存在和不存在 A（1μM、100 nM、10 nM）和 B（50 nM、5 nM、500 pM）的情况下分别暴露于 HIV（500 pg/ml）12 小时和 6 天，以研究 HIV 神经毒性的急性和持续机制。通过乳酸脱氢酶（LDH）测定法评估细胞毒性，我们观察到 HIV 从对照值（P <.01）产生显著的神经毒性作用，而 A 和 B 的所有浓度的共同暴露均不能恢复。此外，6 天后 LDH 水平没有变化。然而，使用发光测定法测量急性促凋亡标记物 caspase 3 和 7 的活性，发现与对照相比，暴露于 HIV（BaL）会增加（P =.022）。这种作用通过在 12 小时后与 A 的所有浓度和 50 nM B 共同暴露（P <.01）以及在 6 天后与 A 和 B 的所有浓度共同暴露而得到改善（P <.01）。总的来说，这项研究的结果提供了进一步的证据，表明 GSK3β 抑制通过减少与 HIV 相关的前半胱氨酸酶诱导来对抗 HIV 相关神经毒性具有神经保护作用。这些数据支持 GSK3β 作为潜在治疗靶点的作用，并且可能对治疗 HIV 相关神经认知障碍具有重要的临床意义。
