A New Drug for the Treatment of Traumatic Brain Injury

Project Summary AbstractTraumatic Brain InjuryTBIcontributes to a third of injury related deaths in the US and is among the leading causes of death and disability in people underand overRecent statistics show that TBI annually causesdeathshospital admissionscarries an average lifetime expense of $patientand an annual economic burden conservatively estimated at $billionThe lack of any approved drugs that preventminimizeor reverse the brain damage and deficits caused by moderate to severe TBI is a critical unmet needWe propose to test a novel class of vasopressinaV areceptor antagonists as a new treatment to meet this needThere is a strong scientific rationale for V a receptor antagonism as a disease modifying pharmacotherapy for moderate to severe TBIBrain edema following TBI is associated with poor prognosisFollowing TBIincreased vasopressinAVPexpressionacting through the V a receptoris a major driver of cerebral edemaWe recently found thatdays of treatment with one of Azevanandapos s novelblood brain barrierBBBpenetrating V a antagonists beginninghr after moderate TBI was induced using the momentum exchange model significantly reduced cerebral edema and eliminated cognitive deficits in concussed animalsThe proposed studies will confirm and build on these encouraging preliminary findingsUsing the momentum exchange model to induce moderate TBI in female and male rats with a single head strikefour candidate compounds will be screened in physiologicalimagingbehavioraland pharmacokinetic experimentsThe compounds will be tested to characterize their effects onedema and resting state functional connectivity using MRIplasma biomarkersSbGFAPUCH lin the firsthours post injury that are known to reflect injury severity in rats and humansandcognitive function based on performance on the Novel Object Recognition task and Barnes Maze testFinallywe will measure plasma levels of thecandidate compounds after intravenousintraperitonealand oral gavage administrationSerial sampling of blood will allow calculation of pharmacokineticPKparametersThese data will help inform planning for studies to help optimize route of administration and formulations for use in treating moderate to severe TBIThe two compounds that most effectively reduce edemaimprove rsFCeliminate cognitive deficits on both testsand exhibit the best PK profilese gIV and oral availabilitytAUCwill be designated for continued development in Phasewhere further IND enabling workmechanistic studiesformulationsafety andamptoxicologywill be undertaken Project Narrative Traumatic Brain InjuryTBIis a contributing factor to a third of all injury related deaths in the United Statesone of the leading causes of death and disability in persons underand overand a growing global health issueThere are no approved pharmaceutical treatments that can preventminimizeor reverse the brain damage and deficits caused by serious TBIIn the proposed projectvasopressina receptor antagonists will be tested as a potential new disease modifying pharmacotherapy for the treatment of moderate TBI