Neuroprotective and anti-inflammatory actions of novel growth factor mimetics

描述（由申请人提供）：人类免疫缺陷病毒（HIV）迅速渗透并感染中枢神经系统（CMS）。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疗法的出现，疾病的严重程度有所减轻，但CMS疾病仍然存在，预计随着艾滋病毒患者的寿命延长，CMS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。一些研究表明，蛋白激酶B（通常称为Akt）的神经营养因子受体活化对于治疗HIV相关CMS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。最近鉴定的小的非肽分子，其穿过血脑屏障并模拟神经营养因子对p75神经营养因子受体（p75 NTR）或受体酪氨酸激酶B（Trk B）的作用，为开发神经营养因子-Akt信号传导途径的治疗潜力提供了重要的机会。这些神经营养因子模拟物代表了一类新的化合物，其似乎具有优异的神经保护和抗炎特性，无毒且具有良好的口服利用度。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。将使用细胞死亡的常规措施以及新开发的评估钙稳态改变的技术，评估对大鼠神经培养物暴露于HIV-1包膜蛋白或猫神经培养物暴露于猫免疫缺陷病毒（FIV）所产生的炎症和损伤的保护作用。此外，将通过测量混合和纯化的小胶质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抗炎性质。拟议的研究将确定非肽神经营养因子模拟物在专门设计的试验中的基本药理学和治疗潜力，以最大限度地提高筛选效率并允许快速转化为体内模型。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) rapidly penetrates into and infects the central nervous system (CMS). 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, CMS 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 of protein kinase B (commonly known as Akt) has substantial therapeutic potential for the treatment of HIV-associated CMS 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 at the p75 neurotrophin receptor (p75NTR) or receptor tyrosine kinase B (TrkB) offers an important opportunity to develop the therapeutic potential of the neurotrophin-Akt signaling pathway. These neurotrophin mimetics represent a new class of compounds that appear to have excellent neuroprotective and anti-inflammatory properties, are non-toxic and have good oral availability. The proposed studies will use primary neural cultures to evaluate the therapeutic potential of three of these compounds. Protection against inflammation and damage generated by exposing rat neural cultures to HIV-1 envelope proteins or feline neural cultures to feline immunodeficiency virus (FIV) will be assessed using conventional measures of cell death as well as newly developed techniques to assess alterations in calcium homeostasis. In addition, the anti-inflammatory properties of each compound will be assessed by measuring cytokine, chemokine and growth factor secretion in both mixed and purified microglial cultures. The proposed studies will determine the basic pharmacology and therapeutic potential of the non-peptide neurotrophin mimetics in assays specifically designed to maximize the efficiency of screening and allow rapid translation to in vivo models.