nNOS-PSD95 inhibitors as novel treatments for TBI

DESCRIPTION provided by applicant This application andquot nNOS PSD inhibitors as novel treatments for TBIandquot addresses the critical need for an efficacious treatment for traumatic brain injury TBI TBI is the leading cause of death and disability in the most active population andlt years of age in the United States Unfortunately no effective pharmaceutical interventions have been developed Thus there is a critical need to understand the molecular mechanisms underlying functional deficits after TBI as well as to translate this knowledge into the development of new TBI treatments In TBI activation of the NMDA glutamate receptor NMDAR stimulates the enzyme neuronal nitric oxide synthase nNOS and ultimately increases the signaling molecule nitric oxide NO Postsynaptic density protein PSD is necessary to position nNOS close to the NMDAR and is therefore required for NMDAR activation of nNOS This NMDAR PSD nNOS cascade is implicated in the functional deficits following TBI Anagin an Indiana based small business and its research partners at Indiana University School of Medicine have preliminary results suggesting that a small molecule inhibitor of the interaction between nNOS and PSD is neuroprotective in a preclinical model of TBI The specific aim for this Phase I SBIR program is to test the functional benefits of inhibiting nNOS PSD interaction in a preclinical model of TBI by fully characterizing the dose response and therapeutic window of treatment If successful this project will validate a new target and mechanism for intervention for TBI Future Phase II SBIR studies will determine if the new nNOS PSD inhibitors currently being developed by Anagin are potential drug development candidates for the treatment of TBI PUBLIC HEALTH RELEVANCE Traumatic brain injury TBI is the leading cause of death and disability with no effective treatment This proposal seeks to test novel small molecule inhibitor that specifically disrupt a major neuronal signaling pathway in a preclinical model of TBI If successful this project will validate a novel approach for the treatment of TBI