Neuroprotective and anti-inflammatory actions of novel growth factor mimetics

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(CMS)。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CMS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，蛋白激酶B的神经营养素受体激活(俗称Akt)在治疗HIV相关性CMS疾病方面具有很大的治疗潜力。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素在p75神经营养素受体(P75NTR)或受体酪氨酸激酶B(TrkB)上的作用的非肽小分子为开发神经营养素-Akt信号通路的治疗潜力提供了重要的机会。这些神经营养素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，并具有良好的口服利用度。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。通过将大鼠神经培养细胞暴露于HIV-1包膜蛋白或猫神经培养细胞暴露于猫免疫缺陷病毒(FIV)而产生的炎症和损害的保护，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变化的技术来评估。此外，每种化合物的抗炎性能将通过测量混合和纯化的小胶质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。拟议的研究将在专门设计的最大限度提高筛选效率并允许快速转化为体内模型的分析中确定非肽神经营养素模拟物的基本药理学和治疗潜力。

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.