The objective of this particular proposal is to characterize the stability, brain availability, and pharmacokinetic/pharmacodynamic profiles of an intranasally administered selective calpain inhibitor-based therapeutic for moderate to severe TBI . The projects central hypothesis is that TBI causes overexpression and hyperactivation of calpain-1/2 that contribute to traumatic axonal injury and blood-brain barrier (BBB) compromise via multiple molecular and/or cellular pathways. Thus, selective pharmacological inhibition of the target protease would result in brain tissue protection and improvement of functional outcome. We have formulated this hypothesis based on available published data and preliminary findings from our laboratory which collectively support the idea that selective inhibition of calpain-1/2 may not only have neuroprotective effect but also enhance neuronal plasticity and repair and in this way improve functional outcome after TBI.
