Neuroprotective Effects of Minocycline in Lentiviral Inf

米诺环素对慢病毒感染的神经保护作用

基本信息

批准号：
6852662
负责人：
M CHRISTINE ZINK
金额：
$ 58.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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、促炎细胞因子的产生增加、促凋亡和神经毒性介质的表达增加以及神经元损失相关。目前正在研究多种神经保护疗法，但尚未出现任何单一药物可以解决 HIV 在中枢神经系统中的炎症和神经退行性影响。最近发现四环素衍生物米诺环素是一种有效的抗炎和神经保护药物，还可以抑制巨噬细胞、小胶质细胞和星形胶质细胞中的 HIV 复制，因此需要对这种现成的仿制药作为 HIV 感染的神经保护剂进行检查。我们开发了一种 HIV CNS 疾病的加速、一致的 SIV/猕猴模型 (SIV-AC)，其中超过 90% 的受感染动物出现脑炎并伴有神经变性，B-APP 和 B-淀粉样蛋白表达增加以及神经元变性证据证明了这一点/脑脊液和大脑中的细胞凋亡。该模型以高度可重复的时间安排概括了人类 HIV 感染的急性、无症状和终末期特征。我们最近使用该模型的研究表明，SIV 脑炎的发生与抗凋亡 ERK 信号通路与促凋亡 JNK 和 p38 信号通路之间的不平衡相一致，代表中枢神经系统无法维持稳态平衡。我们的假设是，米诺环素将在 SIV 感染的猕猴中发挥双重神经保护作用：a）通过抑制 p38 的病理激活，从而重建促凋亡途径和抗凋亡途径之间的平衡，b）通过抑制 SIV 复制，从而抑制病毒神经毒性物质的产生。中枢神经系统中的蛋白质。本申请提出综合体内和体外研究来检查米诺环素对中枢神经系统发挥其姑息作用的机制。在目标 1 中，我们建议测量米诺环素对病毒复制以及 SIV 感染猕猴中中枢神经系统炎症和神经退行性变化的影响。在目标 2 和 3 中，我们将确定米诺环素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 SIV/HIV 复制的机制。鉴于米诺环素不仅可以作为神经保护剂，而且可以作为中枢神经系统中的病毒抑制剂，这些机制研究非常重要。