Neurotrophin mimetic therapeutics for HIV-associated neural dysfunction

描述(申请人提供)：人类免疫缺陷病毒(HIV)迅速渗透并感染中枢神经系统(CNS)。HIV与神经系统中的巨噬细胞和小胶质细胞相互作用引起的炎症活动导致不同程度的神经损伤和神经元丢失。虽然随着高效抗逆转录病毒疗法的出现，疾病的严重性已经降低，但中枢神经系统疾病仍然存在，随着艾滋病毒患者的寿命延长，预计将造成越来越严重的损失。目前还没有有效控制炎症相互作用的治疗方法，这些炎症相互作用使神经元失效和破坏。一些研究表明，神经营养素受体的激活和随后通过蛋白激酶B(俗称Akt)的信号转导具有治疗HIV相关性中枢神经系统疾病的巨大潜力。然而，由于多肽对大脑的渗透性差，以及难以控制神经保护和促凋亡神经营养素信号之间的平衡，开发这一潜力一直是困难的。最近发现的穿过血脑屏障并模拟神经营养因子作用的非肽小分子为开发神经营养因子-Akt信号通路的治疗潜力提供了重要机会。这些化合物针对p75神经营养素受体(P75NTR)或受体酪氨酸激酶B(TrkB)的特定表位，从而允许比内源性配体更大程度地控制信号。早期的研究表明，这些化合物具有强大的神经保护特性。拟议的研究将使用原代神经培养来评估其中三种化合物的治疗潜力。将大鼠神经培养物暴露于暴露于HIV-1包膜蛋白gp120的巨噬细胞的条件培养液中，以测试对早期神经元损伤的保护作用。钙稳态和微管相关蛋白免疫反应性的改变将被用作神经元功能障碍的敏感指标。此外，将通过测量小胶质细胞和巨噬细胞培养中的细胞因子、趋化因子和生长因子的分泌来评估每种化合物的直接抗炎特性。检测的目的是产生从培养实验到临床前整体动物研究所需的基本药理学数据。拟议的研究将建立神经营养素模拟物治疗开发所需的剂量指南、机制信息和细胞靶向配置文件。与公共卫生相关：非肽类神经营养素类化合物代表了一类全新的化合物，它们有效地渗透到大脑中，并提供了逆转与艾滋病毒感染相关的神经损害的进行性发展的希望。通过模仿高效的天然神经营养因子的神经保护和修复过程，这些化合物可能不仅为HIV相关的神经退行性疾病提供一种安全有效的新疗法，而且还可能为广泛的神经退行性疾病提供一种新的治疗方法。拟议的研究将通过建立剂量反应指南并提供负责保护的潜在分子和细胞途径的详细信息，使这些化合物更接近治疗用途。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) rapidly penetrates into and infects the central nervous system (CNS). Inflammatory activity resulting from the interaction of HIV with macrophages and microglia in the nervous system leads to varying levels of neurological impairment and neuronal loss. While disease severity has been reduced with the advent of highly active antiretroviral therapy, CNS disease persists and is expected to exert an increasingly heavy toll as patients with HIV live longer. Currently there are no therapeutic treatments that effectively control the inflammatory interactions that disable and destroy neurons. Several studies have indicated that neurotrophin receptor activation and subsequent signaling through protein kinase B (commonly known as Akt) has substantial therapeutic potential for the treatment of HIV-associated CNS disease. However, it has been difficult to exploit this potential due to the poor penetration of peptides into the brain and difficulties in controlling the balance between neuroprotective and pro-apoptotic neurotrophin signaling. The recent identification of small, non-peptide molecules that cross the blood-brain barrier and mimic the actions of neurotrophins offers an important opportunity to develop the therapeutic potential of the neurotrophin-Akt signaling pathway. These compounds are targeted to specific epitopes of the p75 neurotrophin receptor (p75NTR) or receptor tyrosine kinase B (TrkB), thereby allowing a greater degree of control over signaling than seen with the endogenous ligands. Early work has shown that these compounds have potent neuroprotective properties. The proposed studies will use primary neural cultures to evaluate the therapeutic potential of three of these compounds. Protection against early neuronal damage will be tested by exposing rat neural cultures to conditioned medium from macrophages exposed to the HIV-1 envelope protein, gp120. Alterations in calcium homeostasis and microtubule-associated protein immunoreactivity will be used as sensitive indices of neuronal dysfunction. In addition, the direct anti- inflammatory properties of each compound will be assessed by measuring cytokine, chemokine and growth factor secretion in microglial and macrophage cultures. Assays are designed to generate basic pharmacological data needed to progress from culture experiments to pre-clinical whole animal studies. The proposed studies will establish dosing guidelines, mechanistic information and cellular targeting profiles necessary for therapeutic development of the neurotrophin mimetics. PUBLIC HEALTH RELEVANCE: Non-peptide neurotrophin mimetics represent a completely new class of compounds which penetrate effectively into the brain and offer the hope of reversing the progressive development of neural damage associated with HIV infection. By mimicking the neuroprotective and repair processes of natural neurotrophins with high potency, these compounds may offer a safe and powerful new therapy not only for HIV-associated neurodegeneration but also for a broad range of neurodegenerative diseases. The proposed studies will move these compounds closer to therapeutic use by establishing dose-response guidelines and providing detailed information on the underlying molecular and cellular pathways responsible for protection.