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: 6445210
• 负责人: STUART A LIPTON
• 金额: $ 14.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6445210
• 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的神经学表现影响一二和二 三分之一的成年人患有艾滋病患者。 这些并发症中包括 产生认知，运动和可能视觉的痴呆症形式 在缺乏神经元病毒感染的情况下，功能障碍在不存在的情况下 机会性超级感染，在没有HIV相关的情况下 中枢神经系统的恶性肿瘤。 最近的进展已在实验室取得 调查这种形式的痴呆症的基础（称为艾滋病 痴呆症复合物，或最近，与HIV相关的运动/认知 复杂的）。 来自世界各地各种实验室的证据 表明在大脑中观察到的至少一部分神经元丧失 艾滋病患者可能与最终的常见途径有关 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 几种急性和退化性神经系统疾病，范围从中风 对于亨廷顿氏病的创伤和癫痫病，可能有类似的基础 用于神经元损伤。 面对兴奋性氨基的过度刺激 酸受体，离子通道允许钙离子过多涌入 随之而来的神经细胞损伤。 虽然神经元的确切机制 钙超负荷受伤仍然是严格调查的问题， 当前的辩论，许多实验室发现，限制涌入 在这些条件下的钙离子可以保护神经元形成损伤。 为了 例如，使用体外和体内动物的实验室研究 模型表明，可渗透到钙的离子通道的阻断 离子可能会防止受HIV感染的巨噬细胞造成的神经细胞损伤 或HIV-1外套蛋白GP120刺激的巨噬细胞。 至少两个 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。 为了这 原因，提出了这些通道的临床耐受性拮抗剂 与最佳可用抗逆转录病毒一起研究 治疗，即齐多夫丁（ZDV）或核苷，例如二乙基氨酸 （DDI）。 第二项研究将用于对这些抗的辅助疗法 逆转录病毒，另一种著名的药物纪念药，最近是 被认为是有效的NMDA开放通道阻滞剂 衰减与暴露于GP120相关的神经元损伤 P.I.的实验室。