Neurotrophin mimetic therapeutics for HIV-associated neural dysfunction

描述（由申请方提供）：人类免疫缺陷病毒（HIV）迅速渗透并感染中枢神经系统（CNS）。由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性导致不同水平的神经损伤和神经元损失。虽然随着高效抗逆转录病毒治疗的出现，疾病的严重程度有所降低，但CNS疾病仍然存在，并且随着HIV患者的寿命延长，预计CNS疾病将造成越来越严重的死亡。目前还没有有效控制使神经元丧失和破坏的炎症相互作用的治疗方法。几项研究表明，神经营养因子受体活化和随后通过蛋白激酶B（通常称为Akt）的信号传导对于治疗HIV相关CNS疾病具有显著的治疗潜力。然而，由于肽对脑的渗透性差以及难以控制神经保护和促凋亡神经营养因子信号传导之间的平衡，难以利用这种潜力。最近鉴定出的小的非肽分子可以穿过血脑屏障并模拟神经营养因子的作用，这为开发神经营养因子-Akt信号通路的治疗潜力提供了重要的机会。这些化合物靶向p75神经营养因子受体（p75 NTR）或受体酪氨酸激酶B（Trk B）的特异性表位，从而允许比内源性配体更大程度地控制信号传导。早期的研究表明，这些化合物具有有效的神经保护作用。拟议的研究将使用原代神经培养物来评估其中三种化合物的治疗潜力。将通过将大鼠神经培养物暴露于来自暴露于HIV-1包膜蛋白gp 120的巨噬细胞的条件培养基来测试对早期神经元损伤的保护。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物中的细胞因子、趋化因子和生长因子分泌来评估每种化合物的直接抗炎性质。试验旨在生成从培养实验进展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的治疗开发所需的给药指南、机制信息和细胞靶向特征。

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.