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动导致不同程度的神经损伤和神经元损失。虽然随着高活性抗逆转录病毒疗法的出现，疾病的严重程度已经降低，但CMS疾病仍然存在，并且随着艾滋病毒感染者寿命的延长，预计将造成越来越严重的损失。目前还没有治疗方法可以有效地控制炎症相互作用，使神经元丧失功能和破坏。一些研究表明，激活蛋白激酶B（通常称为Akt）的神经营养因子受体对治疗hiv相关CMS疾病具有巨大的治疗潜力。然而，由于多肽对大脑的渗透能力差，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，开发这种潜力一直很困难。最近发现的小的非肽分子可以穿过血脑屏障，模拟神经营养因子在p75神经营养因子受体（p75NTR）或受体酪氨酸激酶B （TrkB）上的作用，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。这些神经营养因子模拟物代表了一类新的化合物，似乎具有良好的神经保护和抗炎特性，无毒并且具有良好的口服有效性。拟议的研究将使用初级神经培养来评估这三种化合物的治疗潜力。将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，将使用传统的细胞死亡测量方法以及新开发的评估钙稳态改变的技术进行评估。此外，每种化合物的抗炎特性将通过测量混合和纯化小胶质细胞培养中细胞因子、趋化因子和生长因子的分泌来评估。拟议的研究将在专门设计的试验中确定非肽神经营养模拟物的基本药理学和治疗潜力，以最大限度地提高筛选效率，并允许快速翻译到体内模型。

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.