TREATMENT OF TRAUMATIC BRAIN INJURY WITH SIMVASTATIN

描述（由申请人提供）：本项目旨在研究辛伐他汀（一种3-羟基-3-甲基戊二酰（HMG）-CoA还原酶抑制剂）对年轻成年雄性Wistar大鼠创伤性脑损伤（TBI）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TBI治疗方法，以减少神经系统缺陷。年轻的成年雄性大鼠将经受TBI，然后在TBI后的不同时间用不同剂量的辛伐他汀口服治疗。将使用Morris水迷宫测试测量大鼠的空间学习。将评价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发生的变化进行测试和确定。具体目标2：采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）等方法，研究脑外伤后15 ~ 12个月齿状回神经元、星形胶质细胞和寡胶质细胞的动态变化。我们的观察将提供辛伐他汀治疗对TBI后神经发生、星形胶质细胞生成和寡胶质细胞生成的影响的详细概况（A）。在TBI和辛伐他汀治疗后，将进一步研究调节齿状回中神经发生的微环境，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），以及血管内血栓形成和血管结构（C）。这些研究将提供深入了解他汀类药物治疗引起的受损大脑的潜在变化，这些变化有助于其神经恢复作用。本申请的最终目标是开发一种使用他汀类药物的TBI新治疗方法，该方法将增强齿状回中的内源性神经可塑性，特别是神经发生，从而改善TBI后的空间学习。

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.