Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system.
Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system.
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抗逆转录病毒药物会引起中枢神经系统的氧化应激和神经元损伤。
DOI：
10.1007/s13365-013-0227-1
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发表时间：
2014-02
影响因子：
3.2
通讯作者：
Jordan-Sciutto KL
中科院分区：
文献类型：
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作者：
Akay C;Cooper M;Odeleye A;Jensen BK;White MG;Vassoler F;Gannon PJ;Mankowski J;Dorsey JL;Buch AM;Cross SA;Cook DR;Peña MM;Andersen ES;Christofidou-Solomidou M;Lindl KA;Zink MC;Clements J;Pierce RC;Kolson DL;Jordan-Sciutto KL
HIV 相关神经认知障碍 (HAND) 的特点是广泛的行为、认知和运动功能障碍，尽管联合抗逆转录病毒药物治疗 (cART) 在外围取得了成功，但仍继续影响约 50% 的 HIV(+) 患者。值得注意的是，抗逆转录病毒药物对中枢神经系统 (CNS) 的潜在毒性仍未得到充分研究，这可能是导致 CART 时代 HAND 持续存在的原因。先前的研究表明，抗逆转录病毒药物（ARV）对体内周围神经系统和体外周围神经元具有神经毒性。脂质和蛋白质代谢的改变、线粒体损伤和氧化应激都在外周抗逆转录病毒神经毒性中发挥作用。我们假设抗逆转录病毒药物也会引起中枢神经系统的细胞应激，最终导致神经元损伤，并导致 cART 时代 HIV 阳性患者的临床和病理情况发生变化。在本报告中，我们证明抗逆转录病毒药物对猪尾猕猴和大鼠体内的中枢神经系统具有神经毒性。此外，在体外，抗逆转录病毒药物会导致活性氧（ROS）的积累，并最终诱导神经元损伤和死亡。单独的抗逆转录病毒药物在体外会引起内源性抗氧化反应的一些激活，而富马酸酯、富马酸单甲酯 (MMF) 会增强这种反应，阻断抗逆转录病毒药物诱导的 ROS 生成和神经元损伤/死亡。这些发现表明氧化应激是抗逆转录病毒引起的神经毒性的潜在机制的一个因素，并将为辅助治疗提供一个切入点，以补充抗逆转录病毒治疗并减少该患者群体的神经毒性。
HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.
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影响因子：
2
作者：
Kageyama, M;Namiki, H;Takada, K
通讯作者：
Takada, K
影响因子：
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作者：
Manda, Vamshi K.;Mittapalli, Rajendar K.;Lockman, Paul R.
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Lockman, Paul R.
影响因子：
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作者：
Linker, Ralf A.;Lee, De-Hyung;Gold, Ralf
通讯作者：
Gold, Ralf
影响因子：
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作者：
Dore, GJ;Correll, PK;Brew, BJ
通讯作者：
Brew, BJ
影响因子：
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作者：
Letendre, Scott;Marquie-Beck, Jennifer;Ellis, Ronald J.
通讯作者：
Ellis, Ronald J.