Neuroregenerative Effects of Simvastatin in TBI

描述(由申请人提供)： 创伤性脑损伤(TBI)已成为在阿富汗和伊拉克战争中服役的美军部队的标志性损伤。在作战情况下，由于几个原因，患有脑外伤的退伍军人的治疗经常被延误，包括瞬间无法识别/误诊，在受伤后几天/几周/几个月出现症状，因此在微妙的脑创伤问题得到解决之前，患有脑外伤的士兵极有可能返回战场。退伍军人与退伍军人管理局提供者的第一次互动可能发生在实际的TBI事件几个月甚至几年之后，这些退伍军人中的相当一部分人可能直到从战斗中返回并过渡到退伍军人身份后几个月甚至几年才寻求退伍军人管理局的照顾。此外，创伤性脑损伤的一些症状，如易怒和失眠，可能与其他情况重叠，如创伤后应激障碍(PTSD)，因此可能被误诊。因此，相当多的颅脑损伤病例可能直到实际受伤后很长一段时间才“未被诊断”和“未治疗”，这增加了颅脑损伤本身日益增长的异质性。目前的治疗策略确实帮助脑外伤患者恢复了一定程度的功能，但仍有迫切需要研究候选药物作为脑损伤后的“晚期”治疗效果，这是大多数退伍军人目前面临的问题。鉴于创伤性脑损伤的多因素异质性，时间跨度从几天到几个月甚至数年不等，而且越来越多的退伍军人已经患有脑损伤，但面临着“未诊断”和“未治疗”的状态，容易出现长期的脑损伤异质性，因此需要针对多个治疗目标进行治疗，而不是单一治疗。在这方面，已知的辛伐他汀的多效性，包括其神经营养、神经再生、突触营养和抗炎特性，独立于其降胆固醇特性，是值得注意的。特别是关于辛伐他汀，到目前为止报道的研究表明辛伐他汀对脑损伤后的即时疗效，并没有解决目前对脑损伤退伍军人的晚期治疗的需要。本项目将通过分析神经-轴突-树突状细胞的再生长和连接，神经营养因子的表达，神经再生和突触的关键参与神经再生和突触的表达，来检验辛伐他汀后急性治疗将有效地恢复脑损伤小鼠模型神经元和突触的完整性和改善功能结局的假设。 神经递质标记物关键参与学习和记忆，并通过评估脑损伤后辛伐他汀治疗后更慢性阶段的功能结果。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) has emerged as a Signature injury among U.S. forces serving in Afghanistan and Iraq wars. In the combat situation, treatment for Veterans sustaining TBI is often delayed due to several reasons including instant un-/mis-identification, appearance of symptoms days/weeks/months after injury, and hence soldiers sustaining TBI are highly likely to be returned to the battlefield before subtle TBI problems are resolved. A Veteran's first interaction with the VA provider may occur months or even years after actual TBI event, and significant number of these Veterans might not seek care from VA until several months or even years after their return from the combat and their transition to Veteran status. Furthermore, some of the symptoms of TBI, such as irritability and insomnia, may overlap with other conditions, such as post-traumatic stress disorder (PTSD), and hence may be mis-treated. Therefore, considerable cases of TBI may go "undiagnosed" and "untreated" until much later after actual injury that adds to the growing heterogeneity of TBI injury per se. Current therapeutic strategies do help TBI patients to regain some degree of function, but there remains a compelling need for investigating therapeutic efficacy of candidate drugs as a "late stage" treatment after TBI, that most Veterans are currently facing. Given the multifactorial heterogeneous nature of TBI spanning over an extended period of time from days-months-years, and given the increasing number of returning war Veterans already sustaining TBI but facing "undiagnosed" and "untreated" status, pre-disposed to long term TBI heterogeneity, calls for a treatment aimed at multiple therapeutic targets rather than mono- treatment. In that regard, known pleiotropy of Simvastatin including its neurotrophic, neuroregenerative, synaptotrophic and anti-inflammatory properties, independent of its cholesterol-lowering properties, are remarkable. With particular reference to Simvastatin, studies reported this far have shown immediate treatment effects of Simvastatin after TBI, and did not address current need for "late treatment of TBI Veterans. This project will test the hypothesis that Post-acute treatment with Simvastatin will effectively restore neuronal and synaptic integrity and improve functional outcome in the CCI mouse model of TBI by analyzing neuro-axonal- dendritic re-growth and connectivity, expression of neurotrophic factors critically involved in neuroregeneration, synaptic neurotransmitter markers critically involved in learning and memory, and by evaluating functional outcome after Simvastatin treatment at a more chronic stage after TBI.