Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Pharmacol Exp Ther. 2012 Dec;343(3):696-703. doi: 10.1124/jpet.112.195701. Epub 2012 Sep 13.
Despite combination antiretroviral therapies (cARTs), a significant proportion of HIV-infected patients develop HIV-associated neurocognitive disorders (HAND). Ongoing viral replication in the central nervous system (CNS) caused by poor brain penetration of cART may contribute to HAND. However, it has also been proposed that the toxic effects of long-term cART may contribute to HAND. A better understanding of the neurotoxic potential of cART is critically needed in light of the use of CNS-penetrating cARTs to contend with the virus reservoir in the brain. The efavirenz (EFV) metabolites 7-hydroxyefavirenz (7-OH-EFV) and 8-hydroxyefavirenz (8-OH-EFV) were synthesized and purified, and their chemical structures were confirmed by mass spectrometry and NMR. The effects of EFV, 7-OH-EFV, and 8-OH-EFV on calcium, dendritic spine morphology, and survival were determined in primary neurons. EFV, 7-OH-EFV, and 8-OH-EFV each induced neuronal damage in a dose-dependent manner. However, 8-OH-EFV was at least an order of magnitude more toxic than EFV or 7-OH-EFV, inducing considerable damage to dendritic spines at a 10 nM concentration. The 8-OH-EFV metabolite evoked calcium flux in neurons, which was mediated primarily by L-type voltage-operated calcium channels (VOCCs). Blockade of L-type VOCCs protected dendritic spines from 8-OH-EFV-induced damage. Concentrations of EFV and 8-OH-EFV in the cerebral spinal fluid of HIV-infected subjects taking EFV were within the range that damaged neurons in culture. These findings demonstrate that the 8-OH metabolite of EFV is a potent neurotoxin and highlight the importance of directly determining the effects of antiretroviral drugs and drug metabolites on neurons and other brain cells.
尽管采用了联合抗逆转录病毒疗法（cART），但相当一部分感染 HIV 的患者仍会出现与 HIV 相关的神经认知障碍（HAND）。cART 对大脑穿透性差导致中枢神经系统（CNS）内持续的病毒复制可能促成 HAND 的发生。然而，也有人提出，长期 cART 的毒性作用可能促成 HAND 的发生。鉴于需要使用穿透中枢神经系统的 cART 来对抗大脑中的病毒储存库，因此迫切需要更好地了解 cART 的神经毒性潜力。
合成并纯化了依非韦伦（EFV）的代谢物 7-羟基依非韦伦（7-OH-EFV）和 8-羟基依非韦伦（8-OH-EFV），并通过质谱和 NMR 确认了它们的化学结构。在原代神经元中测定了 EFV、7-OH-EFV 和 8-OH-EFV 对钙、树突棘形态和存活的影响。EFV、7-OH-EFV 和 8-OH-EFV 均以剂量依赖的方式诱导神经元损伤。然而，8-OH-EFV 的毒性至少比 EFV 或 7-OH-EFV 高一个数量级，在 10 nM 浓度下即可对树突棘造成相当大的损伤。8-OH-EFV 代谢物可诱发神经元内钙流，这主要是由 L 型电压门控钙通道（VOCCs）介导的。阻断 L 型 VOCCs 可保护树突棘免受 8-OH-EFV 诱导的损伤。接受 EFV 治疗的 HIV 感染者脑脊液中的 EFV 和 8-OH-EFV 浓度处于可损伤培养神经元的范围内。这些发现表明 EFV 的 8-OH 代谢物是一种有效的神经毒素，并强调了直接确定抗逆转录病毒药物及其代谢物对神经元和其他脑细胞的影响的重要性。
