Statins Improve Outcome in Murine Models of Intracranial Hemorrhage and Traumatic Brain Injury: A Translational Approach
Statins Improve Outcome in Murine Models of Intracranial Hemorrhage and Traumatic Brain Injury: A Translational Approach
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DOI：
10.1089/neu.2011.2117
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发表时间：
2012-05-01
影响因子：
4.2
通讯作者：
Laskowitz, Daniel T.
中科院分区：
文献类型：
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作者：
Indraswari, Fransisca;Wang, Haichen;Laskowitz, Daniel T.
在美国，创伤性脑损伤（TBI）和脑出血（ICH）是导致神经系统死亡和残疾的主要原因。然而，治疗选择有限，临床管理在很大程度上仍然是支持性的。HMG-CoA还原酶抑制剂（他汀类药物）在急性脑损伤中具有多种作用机制，并已被证明可以改善脑出血和脑外伤的临床前模型。为了便于转化为临床实践，我们现在在脑出血和脑外伤小鼠模型中描述了最佳的他汀类药物和给药模式。在TBI的临床前模型中，小鼠在撞击后5天内分别接受1mg/kg和5mg/kg剂量的载药、辛伐他汀和瑞舒伐他汀。评估免疫组织化学、差异基因表达和功能结果（rotarod和Morris水迷宫测试）来衡量治疗反应。TBI后，给予瑞舒伐他汀1mg /kg与功能结局的最大改善相关。瑞舒伐他汀治疗与tbi后24小时神经元变性减少，tbi后第7天小胶质瘤减少，损伤后35天CA3区神经元密度保持相关。TBI后给予瑞舒伐他汀也与脑内炎症基因表达下调有关。脑出血后，辛伐他汀1mg/kg治疗与功能结局的最大改善相关，这种效果与出血量无关。急性脑损伤的临床相关模型可用于定义诸如最佳他汀类药物和剂量范例等变量，以促进临床试验的合理设计。
Traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) are leading causes of neurological mortality and disability in the U.S.. However, therapeutic options are limited and clinical management remains largely supportive. HMG-CoA reductase inhibitors (statins) have pleiotropic mechanisms of action in the setting of acute brain injury, and have been demonstrated to improve outcomes in preclinical models of ICH and TBI. To facilitate translation to clinical practice, we now characterize the optimal statin and dosing paradigm in murine models of ICH and TBI. In a preclinical model of TBI, mice received vehicle, simvastatin, and rosuvastatin at doses of 1mg/kg and 5mg/kg for 5 days after the impact. Immunohistochemistry, differential gene expression, and functional outcomes (rotarod and Morris water maze testing) were assessed to gauge treatment response. Following TBI, administration of rosuvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes. Rosuvastatin treatment was associated with histological evidence of reduced neuronal degeneration at 24 h post-TBI, reduced microgliosis at day 7 post-TBI, and preserved neuronal density in the CA3 region at 35 days post-injury. Administration of rosuvastatin following TBI was also associated with downregulation of inflammatory gene expression in the brain. Following ICH, treatment with simvastatin 1mg/kg was associated with the greatest improvement in functional outcomes, an effect that was independent of hemorrhage volume. Clinically relevant models of acute brain injury may be used to define variables such as optimal statin and dosing paradigms to facilitate the rational design of pilot clinical trials.