Steiner Joseph P, Bachani Muznabanu, Wolfson-Stofko Brett, Lee Myoung-Hwa, Wang Tongguang, Li Guanhan, Li Wenxue, Strayer David, Haughey Norman J, Nath Avindra
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA,
Neurotherapeutics. 2015 Jan;12(1):200-16. doi: 10.1007/s13311-014-0315-9.
There are severe neurological complications that arise from HIV infection, ranging from peripheral sensory neuropathy to cognitive decline and dementia for which no specific treatments are available. The HIV proteins secreted from infected macrophages, gp120 and Tat, are neurotoxic. The goal of this study was to screen, identify and develop neuroprotective compounds relevant to HIV-associated neurocognitive disorders (HAND). We screened more than 2000 compounds that included FDA approved drugs for protective efficacy against oxidative stress-mediated neurodegeneration and identified selective serotonin reuptake inhibitors (SSRIs) as potential neuroprotectants. Numerous SSRIs were then extensively evaluated as protectants against neurotoxicity as measured by changes in neuronal cell death, mitochondrial potential, and axodendritic degeneration elicited by HIV Tat and gp120 and other mitochondrial toxins. While many SSRIs demonstrated neuroprotective actions, paroxetine was potently neuroprotective (100 nM potency) against these toxins in vitro and in vivo following systemic administration in a gp120 neurotoxicity model. Interestingly, the inhibition of serotonin reuptake by paroxetine was not required for neuroprotection, since depletion of the serotonin transporter had no effect on its neuroprotective properties. We determined that paroxetine interacts selectively and preferentially with brain mitochondrial proteins and blocks calcium-dependent swelling but had less effect on liver mitochondria. Additionally, paroxetine induced proliferation of neural progenitor cells in vitro and in vivo in gp120 transgenic animals. Therefore, SSRIs such as paroxetine may provide a novel adjunctive neuroprotective and neuroregenerative therapy to treat HIV-infected individuals.
HIV感染会引发严重的神经并发症，范围从周围感觉神经病变到认知能力下降和痴呆，而针对这些并发症尚无特效治疗方法。受感染巨噬细胞分泌的HIV蛋白gp120和Tat具有神经毒性。本研究的目的是筛选、鉴定和开发与HIV相关神经认知障碍（HAND）相关的神经保护化合物。我们筛选了2000多种化合物，其中包括美国食品药品监督管理局（FDA）批准的药物，以评估其对氧化应激介导的神经退行性变的保护作用，并确定选择性5-羟色胺再摄取抑制剂（SSRI）为潜在的神经保护剂。随后，通过HIV Tat和gp120以及其他线粒体毒素引起的神经元细胞死亡、线粒体电位和轴突树突退变的变化，对多种SSRI作为神经毒性保护剂进行了广泛评估。虽然许多SSRI都表现出神经保护作用，但在gp120神经毒性模型中，系统给药后，帕罗西汀在体外和体内对这些毒素均具有强效神经保护作用（效力为100 nM）。有趣的是，帕罗西汀对5-羟色胺再摄取的抑制作用并非神经保护所必需，因为5-羟色胺转运体的缺失对其神经保护特性没有影响。我们确定帕罗西汀选择性且优先地与脑线粒体蛋白相互作用，并阻断钙依赖性肿胀，但对肝线粒体的影响较小。此外，帕罗西汀在体外和体内均可诱导gp120转基因动物神经祖细胞的增殖。因此，像帕罗西汀这样的SSRI可能为治疗HIV感染个体提供一种新型的辅助神经保护和神经再生疗法。
