Combo therapy to curtail oxidative stress after TBI

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DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) leads to long-term neurological dysfunction. The extent of secondary neuronal death (mediated synergistically by pathophysiologic events that include but not limited to inflammation, oxidative stress, ER stress and ionic imbalance) dictates the functional outcome after TBI. The present proposal wishes to evaluate if controlling oxidative stress and the interconnected inflammation can minimize the secondary brain damage leading to improved neurological recovery in rodents subjected to TBI. We will test apocynin that inhibits NADPH oxidase subunit NOX2 and thus curtails reactive oxygen species (ROS) formation, and TBHQ that potentiates the transcription factor Nrf2 which is upstream to many antioxidant genes and thus efficiently neutralizes ROS. Our preliminary data provided the proof-of-principle for the efficacy of these 2 drugs in a rodent TBI model. In this proposal we will identify the minimal efficacious dose and the window of opportunity for the 2 drugs. As secondary brain damage after TBI is multifactorial, a combination therapy to achieve neuroprotection by targeting multiple interactive pathways might be more efficacious than mono-therapies that target single pathways. To efficiently control oxidative stress, it is essential to curtail the formation of ROS and at the same time increase the disposal of ROS. Hence, we will test if a combination of apocynin and TBHQ curtails neuronal death and neurological dysfunction after TBI more effectively.