NIMODIPINE AND MEMANTINE FOR THE NEUROLOGICAL MANIFESTATIONS OF HIV-1

尼莫地平和美金刚治疗 HIV-1 的神经表现

• 批准号: 6302833
• 负责人: STUART A LIPTON
• 金额: $ 27.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302833
• 关键词: 2'3' dideoxyinosine; AIDS dementia complex; AIDS therapy; NMDA receptors; calcium channel blockers; clinical trials; combination chemotherapy; drug adverse effect; drug screening /evaluation; human subject; human therapy evaluation; inhibitor /antagonist; macrophage; membrane channels; nervous system disorder chemotherapy; neurologic manifestations; neuropsychological tests; zidovudine

The neurological manifestations of HIV-1 affect between one and two- thirds of adults patients with AIDS. Included in these complications are a form of dementia producing cognitive, motor, and possible visual dysfunction in the absences of viral infection of neurons, in the absence of opportunistic superinfections, and in the absence of HIV-associated malignancies of the CNS. Recent progress has been made in the laboratory investigation of the basis for this form of dementia (termed the AIDS dementia complex, or more recently, HIV-associated motor/cognitive complex). Evidence from a variety of laboratories around the world suggests that at least part of the neuronal loss observed in the brains of patients with AIDS may be related to a final common pathway invoking excessive stimulation of excitatory amino acid receptors such as the N- methyl-D-aspartate (NMDA)subtype of these receptors. These findings are in the mainstream of current neuroscience research which has found that several acute and degenerative neurologic disorders, ranging from stroke to trauma and epilepsy to Huntington's disease, may have a similar basis for neuronal injury. In the face of overstimulation of excitatory amino acid receptors, ion channels permit excessive influx of calcium ions and consequent nerve cell injury. Although the exact mechanism for neuronal injury by calcium overload is still a matter of intense investigation and current debate, many laboratories have found that limiting the influx of calcium ions under these conditions can protect neurons form injury. For example, laboratory investigation using in vitro and in vivo animal models has suggested that blockade of ion channels permeable to calcium ions may prevent nerve cell damage engendered by HIV-infected macrophages or macrophages stimulated by the HIV-1 coat protein, gp120. At least two types of ion channels contribute to this form of injury, L-type voltage- dependent calcium channels and NMDA receptor-coupled channels. For this reason, clinically-tolerated antagonists of these channels are proposed to be studied in conjunction with the best available anti-retroviral therapy, i.e. zidovudine (ZDV) or nucleosides such as dideoxyinosine (ddI). A second study will be used an adjunctive therapy to these anti- retroviral another well-known drug, memantine, which has recently been recognized to be a potent NMDA open-channel blocker capable of attenuating neuronal injury associated with exposure to gp120 by the P.I.'s laboratory.

HIV-1的神经系统表现影响一到两种- 三分之一的成年艾滋病患者。 这些并发症包括 一种导致认知、运动和可能的视觉障碍的痴呆症 神经元缺乏病毒感染时的功能障碍， 机会性重叠感染，在没有艾滋病毒相关的 CNS的恶性肿瘤。 最近在实验室里取得了进展 调查这种形式的痴呆症（称为艾滋病）的基础 痴呆综合症，或最近，艾滋病毒相关的运动/认知 复合物）。 来自世界各地不同实验室的证据 表明在大脑中观察到的至少部分神经元缺失 艾滋病患者的死亡可能与最终的共同途径有关， 过度刺激兴奋性氨基酸受体，如N- 甲基-D-天冬氨酸（NMDA）亚型。这些发现 在当前神经科学研究的主流中， 几种急性和退行性神经系统疾病， 外伤和癫痫到亨廷顿病，可能有相似的基础 神经元损伤 面对兴奋性氨基的过度刺激 酸受体、离子通道允许钙离子的过度流入， 神经细胞损伤。 虽然神经元的确切机制 钙超载损伤仍然是一个深入研究的问题， 目前的争论，许多实验室发现，限制流入的 在这些条件下的钙离子可以保护神经元免受损伤。 为 例如，使用体外和体内动物的实验室研究 模型表明，阻断钙离子通道 离子可以防止由HIV感染的巨噬细胞引起的神经细胞损伤 或由HIV-1外壳蛋白gp 120刺激的巨噬细胞。 至少两 离子通道的类型有助于这种形式的损伤，L型电压- 依赖性钙通道和NMDA受体偶联通道。 为此 因此，提出了这些通道的临床耐受拮抗剂 与最好的抗逆转录病毒药物一起研究 治疗，即齐多夫定（ZDV）或核苷如双脱氧肌苷 （ddI）。 第二项研究将用于对这些抗- 逆转录病毒是另一种著名的药物，美金刚，最近被 被认为是一种有效的NMDA开放通道阻滞剂， 减轻与暴露于gp 120相关的神经元损伤 P.I.的实验室。