Neuroprotective Effects of Minocycline in Lentiviral Inf

米诺环素对慢病毒感染的神经保护作用

• 批准号: 7035912
• 负责人: M CHRISTINE ZINK
• 金额: $ 58.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035912
• 关键词: AIDS /HIV neuropathy; AIDS therapy; HIV infections; Macaca nemestrina; Retroviridae disease; antiAIDS agent; antibacterial agents; antiviral agents; apoptosis; astrocytes; central nervous system disorders; disease /disorder model; drug screening /evaluation; human fetus tissue; juvenile animal; macrophage; microglia; microorganism disease chemotherapy; neuroprotectants; pharmacokinetics; pharmacology; simian immunodeficiency virus; tetracyclines; tissue /cell culture; virus protein; virus replication

DESCRIPTION (provided by applicant): HIV CNS disease is consistently associated with infiltration and activation of macrophages/microglia, enhanced production of proinflammatory cytokines, increased expression of proapoptotic and neurotoxic mediators, and neuronal loss. A number of neuroprotective therapeutics are being examined, but no single agent has emerged as the solution to the inflammatory and neurodegenerative effects of HIV in the CNS. The recent identification of the tetracycline derivative, minocycline, as a potent anti-inflammatory and neuroprotective drug that also inhibits HIV replication in macrophages, microglial cells, and astrocytes demands the examination of this readily available generic drug as a neuroprotective agent in HIV infection. We have developed an accelerated, consistent SIV/macaque model (SIV-AC) of HIV CNS disease in which over 90% of infected animals develop encephalitis with neurodegeneration as evidenced by increased expression of B-APP and B-amyloid and evidence of neuronal degeneration/apoptosis in the CSF and brain. This model recapitulates the acute, asymptomatic, and terminal characteristics of HIV infection in humans on a highly reproducible time schedule. Our recent studies using this model have demonstrated that the development of SIV encephalitis coincides with an imbalance between the antiapoptotic ERK signaling pathways and the proapoptotic JNK and p38 signaling pathways, representing a failure to maintain a homeostatic balance in the CNS. Our hypothesis is that minocycline will play a dual neuroprotective role in SIV-infected macaques: a) by inhibiting pathologic activation of p38 thus reestablishing a balance between pro-and antiapoptotic pathways, and b) by inhibiting SIV replication and hence the production of viral neurotoxic proteins in the CNS. This application proposes integrated in vivo and in vitro studies to examine the mechanisms by which minocycline exerts its palliative effects on the CNS. In Aim 1 we propose to measure the effects of minocycline on virus replication and on the development of CNS inflammatory and neurodegenerative changes in SIV-infected macaques. In Aims 2 and 3 we will identify the mechanism(s) by which minocycline protects against neurotoxicity and suppresses SIV/HIV replication in macrophages, microglia and astrocytes. Theses mechanistic studies are important given the potential of minocycline to act not only as a neuroprotective agent but also as a viral suppressive agent in the CNS.

描述（由申请人提供）：HIV CNS疾病始终与巨噬细胞/小胶质细胞的浸润和激活相关，促炎细胞因子的产生增强，促凋亡和神经毒性介质的表达增加以及神经元损失。正在检查许多神经保护疗法，但没有任何单一药物作为解决中枢神经系统中HIV的炎症和神经退行性作用的解决方案。最近将四环素衍生物米诺环素鉴定为有效的抗炎和神经保护药物，它也抑制了巨噬细胞，小胶质细胞和星形胶质细胞中的HIV复制，要求检查这种易于使用的通用药物作为HIV Iniv Intection int Iniv Intection toction的神经保护剂。我们已经开发了一种艾滋病毒CNS疾病的加速，一致的SIV/猕猴模型（SIV-AC），其中超过90％的感染动物患有神经退行性的脑炎患有神经退行性的脑炎，这是由B-APP和B-淀粉样蛋白表达的增加以及CSF和脑部神经元转化/凋亡的证据的增加所证明的。该模型在高度可重现的时间表中概括了人类艾滋病毒感染的急性，无症状和终末特征。我们最近使用该模型的研究表明，SIV脑炎的发展与抗凋亡ERK信号通路与促凋亡的JNK和p38信号通路之间的失衡相吻合，这代表了未能维持CNS中稳态平衡的抗抑制作用。我们的假设是，在SIV感染的猕猴中，米诺环素将扮演双重神经保护作用：a）通过抑制p38的病理激活，从而在pro和抗抗凋亡途径之间取得平衡，而b）通过抑制SIV的复制并从而抑制病毒神经毒性蛋白质中的蛋白质。该应用建议在体内和体外研究中整合，以检验米诺环素对中枢神经系统的姑息作用的机制。在AIM 1中，我们建议衡量米诺环素对病毒复制的影响以及对SIV感染猕猴中CNS炎症和神经退行性变化的发展。在目标2和3中，我们将确定米诺环素可以防止神经毒性并抑制巨噬细胞，小胶质细胞和星形胶质细胞中的SIV/HIV复制的机制。鉴于米诺环素不仅可以用作神经保护剂，而且还作为中枢神经系统中的病毒抑制剂，这些机械研究很重要。