Neuroregenerative Effects of Simvastatin in TBI

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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.