Retinoids as Novel Treatment of Ischemic Stroke

类维生素A作为缺血性中风的新型治疗方法

• 批准号: 7108051
• 负责人: Jean-Baptiste O Roullet
• 金额: $ 13.05万
• 依托单位: ACRYMED, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108051
• 关键词: apoptosis; brain; inflammation; oxygen; retinoids; stroke; tissues

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the U.S. and a major source of disability. Ischemic stroke, the most common type, is associated with a dramatic increase in calcium influx in brain tissue, an increased production in reactive oxygen species (ROS), cell death and inflammation. Studies by the PI have shown that retinoids block neuronal voltage-gated calcium channels. Studies by others suggest that retinoids reduce tissue levels of reactive oxygen species and prevents cellular apoptosis, increase tissue plasminogen activator, favorably modify the balance of pro-inflammatory and inflammatory cytokines and attenuate inflammation in vivo. Together, the data suggest that retinoids might be neuroprotective and potentially useful in the treatment of ischemic stroke. Our goal is to demonstrate that retinoids have neuroprotective activity in vivo. Specifically, we propose to demonstrate that treatment with retinoids: 1) attenuates post-stroke motor deficits using a mouse model of permanent focal cerebral ischemia (middle cerebral artery occlusion), 2) reduces cerebral infarct size, and 3) reduces the expression of the biochemical markers of apoptosis, ROS production and inflammation in the ischemic brain. The project will provide a rationale for the development of retinoid-based formulations to treat ischemic stroke and for the screening of retinoid libraries in search of more potent compounds.

描述（由申请人提供）：中风是美国第三大死亡原因，也是残疾的主要来源。缺血性中风是最常见的类型，与脑组织中钙内流的急剧增加、活性氧（ROS）产生的增加、细胞死亡和炎症有关。PI的研究表明，类维生素A阻断神经元电压门控钙通道。其他人的研究表明，类维生素A降低活性氧的组织水平并防止细胞凋亡，增加组织纤溶酶原激活剂，有利地改变促炎和炎性细胞因子的平衡并减轻体内炎症。总之，这些数据表明，类维生素A可能具有神经保护作用，并可能用于治疗缺血性卒中。我们的目标是证明维甲酸在体内具有神经保护活性。具体而言，我们建议证明类维生素A治疗：1）使用永久性局灶性脑缺血（大脑中动脉闭塞）的小鼠模型减轻中风后运动缺陷，2）减少脑梗死面积，3）减少缺血脑中细胞凋亡、ROS产生和炎症的生化标志物的表达。该项目将为开发基于维甲酸的制剂以治疗缺血性中风和筛选维甲酸文库以寻找更有效的化合物提供理论基础。