Neuroregenerative Effects of Simvastatin in TBI

辛伐他汀对 TBI 的神经再生作用

• 批准号: 8974190
• 负责人: NEELIMA CHAUHAN
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974190
• 关键词: Acute; Address; Afghanistan; Aftercare; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Appearance; Axon; Biochemical; Brain Concussion; Brain Injuries; Brain-Derived Neurotrophic Factor; Caring; Cholesterol; Chronic; Coenzyme A; Cognition; Cognitive deficits; Complex; Dendrites; Epidemic; Etiology; Event; Exposure to; Functional disorder; Growth; Heterogeneity; Hippocampus (Brain); Injury; Investigation; Iraq; Learning; Life; Memory; Modeling; Molecular; Mono-S; Multiple Trauma; Nature; Nerve Degeneration; Nerve Regeneration; Neurons; Neuroprotective Agents; Neurotransmitters; Orthopedics; Outcome; Oxidoreductase; Patients; Physiological; Post-Traumatic Stress Disorders; Property; Provider; Rattus; Reporting; Research Priority; Services; Severities; Signal Pathway; Simvastatin; Sleeplessness; Soldier; Staging; Symptoms; Synapses; Testing; Therapeutic; Time; Traumatic Brain Injury; Treatment Efficacy; Uncertainty; Up-Regulation; Veterans; War; angiogenesis; astrogliosis; axon injury; behavioral outcome; care seeking; cognitive disability; combat; controlled cortical impact; disability; drug candidate; functional outcomes; high risk; improved; inhibitor/antagonist; instrument; interest; member; mouse model; neurogenesis; neuroinflammation; neurotrophic factor; open wound; pleiotropism; screening; targeted treatment; therapeutic target; treatment effect

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.

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国军队中的签名伤害。在战斗情况下，由于几个原因，包括即时未识别/识别的症状出现，受伤后的症状/几周/几个月的出现，以及维持TBI的士兵很可能很可能会返回战场，然后在解决微妙的TBI问题之前将其返回战场。退伍军人与VA提供商的第一次互动可能发生在实际TBI事件发生后的几个月甚至几年，这些退伍军人可能要等到他们从战斗返回几个月甚至几年后才能从VA寻求护理，并过渡到退伍军人身份。此外，TBI的某些症状（例如烦躁和失眠）可能与其他疾病重叠，例如创伤后应激障碍（PTSD），因此可能会误处理。因此，大量TBI病例可能“未经诊断”和“未经治疗”，直到实际受伤后很久以后增加了TBI损伤本身的异质性。当前的治疗策略确实可以帮助TBI患者恢复一定程度的功能，但仍有迫切需要研究候选药物作为TBI之后的“后期”治疗的治疗功效，大多数退伍军人目前都面临。鉴于TBI的多因素异质性质在很长一段时间内从天数开始延长，并且鉴于越来越多的返回的退伍军人数量已经维持了TBI，但面对“未经诊断”和“未经诊断”的“未经诊断”和“未经治疗的”状态，预先识别为长期的TBI杂种，而不是治疗目标。在这方面，辛伐他汀的已知多效性（包括其神经营养，神经增生，突触营养和抗炎特性，与降低胆固醇的特性无关）是显着的。特别是提及辛伐他汀，研究报告了这一遥远的研究表明，TBI后辛伐他汀的立即治疗作用，也没有解决当前对“ TBI退伍军人的晚期治疗的需求”。该项目将检验以下假设：急性后，用Simvastatin急性治疗将有效地恢复神经元和突触良好，并在CCI Models中有效地恢复了cci Modal of CCI Models的功能性成果。重新发展和连通性，神经营养因子的表达与神经变成，突触 神经递质标记物与学习和记忆非常重要，并通过评估辛伐他汀治疗后在TBI后更慢性的阶段评估功能结果。