TREATMENT OF TRAUMATIC BRAIN INJURY WITH SIMVASTATIN

用辛伐他汀治疗创伤性脑损伤

• 批准号: 7098926
• 负责人: DUNYUE LU
• 金额: $ 29.16万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098926
• 关键词: astrocytes; brain disorder chemotherapy; brain injury; confocal scanning microscopy; dentate gyrus; enzyme linked immunosorbent assay; immunocytochemistry; laboratory rat; learning; neural plasticity; neurogenesis; neuropharmacology; neuroregulation; nonhuman therapy evaluation; oligodendroglia; oral administration; simvastatin; thrombosis; trauma

DESCRIPTION (provided by applicant): This project is designed to investigate the therapeutic effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, on the endogenous neuroplasticity that occurs after traumatic brain injury (TBI) in young adult male Wistar rats. The final goal is to develop a safe and efficacious treatment for TBI, which will reduce neurological defects. Young adult male rats will be subjected to TBI and then treated orally with different doses of simvastatin at various times after TBI. Spatial learning of the rat will be measured using the Morris Water Maze Test. Neurogenesis in the ipsilateral dentate gyrus will be evaluated (Specific Aim 1). The efficacy of simvastatin treatment will be tested and determined based on functional testing and the changes in neurogenesis. In Specific Aim 2, we will employ immunohistochemical staining, laser cofocal microscopy and enzyme- linked immunosorbent assay (ELISA) to study the dynamic changes of neurogenesis, astrogliogenesis and oligogliogenesis in the dentate gyrus from day 15 to 12 months after TBI. Our observations will provide detailed profiles of the effect of simvastatin treatment on neurogenesis, astrogliogenesis and oligogliogenesis after TBI (A). The microenvironment that regulates neurogenesis in the dentate gyrus will be further investigated after TBI and simvastatin treatment, including angiogenesis, cellular (astrocytes and oligodendrocytes) and molecular (growth factors) regulation (B), as well as intravascular thrombosis and vascular structure (C). These studies will provide insight into the underlying changes in the injured brain induced by statin treatment that contributes to its neurorestorative effect. The ultimate goal of this application is to develop a new treatment for TBI using a statin that will enhance endogenous neuroplasticity in the dentate gyrus, especially neurogenesis, and thereby improving spatial learning after TBI.

描述(申请人提供)：本项目旨在研究3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂辛伐他汀对年轻成年雄性Wistar大鼠创伤性脑损伤后内源性神经可塑性的治疗作用。最终目标是开发一种安全有效的脑外伤治疗方法，减少神经缺陷。幼年成年雄性大鼠接受颅脑损伤后，在伤后不同时间给予不同剂量的辛伐他汀治疗。使用Morris水迷宫测试来测量大鼠的空间学习能力。将评估同侧齿状回的神经发生(具体目标1)。辛伐他汀治疗的疗效将根据功能测试和神经再生的变化进行测试和确定。在特定目的2中，我们将利用免疫组织化学染色、激光共聚焦显微镜和酶联免疫吸附试验(ELISA)研究脑损伤后15~12个月海马齿状回神经发生、星形胶质形成和寡糖形成的动态变化。我们的观察将提供辛伐他汀治疗对脑外伤(A)后神经发生、星形胶质细胞形成和寡糖形成的影响的详细资料。在脑创伤和辛伐他汀治疗后，将进一步研究调控齿状回神经发生的微环境，包括血管生成、细胞(星形胶质细胞和少突胶质细胞)和分子(生长因子)调节(B)，以及血管内血栓和血管结构(C)。这些研究将深入了解他汀类药物治疗对神经恢复作用的潜在影响。这项应用的最终目标是开发一种使用他汀类药物治疗脑损伤的新方法，这种药物将增强齿状回的内源性神经可塑性，特别是神经发生，从而改善脑损伤后的空间学习。