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个- 三分之一的成年患者患有艾滋病。 这些并发症包括 一种产生认知、运动和可能视觉的痴呆症 在没有神经元病毒感染的情况下，在没有病毒感染的情况下，功能障碍 机会性重复感染，并且在没有艾滋病毒相关的情况下 中枢神经系统恶性肿瘤。 实验室近期取得进展 对这种形式的痴呆症（称为艾滋病）的基础的调查 复杂性痴呆，或者最近的艾滋病毒相关运动/认知 复杂的）。 来自世界各地多个实验室的证据 表明至少在大脑中观察到部分神经元损失 艾滋病患者的患病率可能与最终的共同途径有关 过度刺激兴奋性氨基酸受体，例如 N- 这些受体的甲基-D-天冬氨酸 (NMDA) 亚型。这些发现是 在当前神经科学研究的主流中发现 几种急性和退行性神经系统疾病，包括中风 外伤、癫痫、亨廷顿病，可能有相似的基础 用于神经元损伤。 面对兴奋性氨基酸的过度刺激 酸受体、离子通道允许钙离子过量流入 随之而来的神经细胞损伤。 尽管神经元的确切机制 钙超载造成的损伤仍然是一个深入研究的问题 当前的争论中，许多实验室发现限制 这些条件下的钙离子可以保护神经元免受损伤。 为了 例如，使用体外和体内动物进行实验室研究 模型表明，阻断钙可渗透的离子通道 离子可以防止艾滋病毒感染的巨噬细胞引起的神经细胞损伤 或由 HIV-1 外壳蛋白 gp120 刺激的巨噬细胞。 至少两个 类型的离子通道导致这种形式的损伤，L型电压- 依赖性钙通道和 NMDA 受体偶联通道。 为了这 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 疗法，即齐多夫定 (ZDV) 或双脱氧肌苷等核苷 （ddI）。 第二项研究将用于这些抗药物的辅助治疗 逆转录病毒 另一种众所周知的药物美金刚，最近被 被认为是一种有效的 NMDA 开放通道阻断剂，能够 减轻与暴露于 gp120 相关的神经元损伤 P.I.的实验室。