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的标志性损伤。在战斗情况下，对患有TBI的退伍军人的治疗通常由于几个原因而被延迟，包括即时未识别/错误识别，受伤后几天/几周/几个月出现症状，因此患有TBI的士兵很可能在微妙的TBI问题得到解决之前返回战场。退伍军人与VA提供者的第一次互动可能发生在实际TBI事件后数月甚至数年，并且这些退伍军人中的相当数量可能直到他们从战斗中返回并过渡到退伍军人状态后数月甚至数年才寻求VA的护理。此外，TBI的一些症状，如易怒和失眠，可能与其他病症，如创伤后应激障碍（PTSD）重叠，因此可能被错误治疗。因此，相当多的TBI病例可能会“未诊断”和“未治疗”，直到实际损伤后很久，这增加了TBI损伤本身日益增长的异质性。目前的治疗策略确实有助于TBI患者恢复一定程度的功能，但仍然迫切需要调查候选药物作为TBI后“晚期”治疗的治疗效果，这是大多数退伍军人目前面临的问题。考虑到TBI跨越从数天-数月-数年的延长时间段的多因素异质性性质，并且考虑到已经患有TBI但面临“未诊断”和“未治疗”状态、倾向于长期TBI异质性的越来越多的返回的退伍军人，需要针对多个治疗靶点的治疗而不是单一治疗。在这方面，辛伐他汀的已知多效性，包括其神经营养、神经再生、突触营养和抗炎特性，与其降胆固醇特性无关，是显著的。特别是关于辛伐他汀，迄今为止报道的研究已经显示了辛伐他汀在TBI后的即时治疗效果，并且没有解决目前对“TBI退伍军人的晚期治疗”的需求。该项目将通过分析神经轴突树突的再生长和连接、神经再生中关键参与的神经营养因子的表达、突触的形成和突触的形成，来检验辛伐他汀急性后治疗能有效恢复TBI CCI小鼠模型中神经元和突触的完整性并改善功能结果的假设。 神经递质标记物的关键参与学习和记忆，并通过评估功能的结果后，辛伐他汀治疗后，在更长期的阶段TBI。

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.