KSCHIRT: Pharmacological Intervention Targeting Mitochondrial Respiration for the Treatment of Traumatic Brain Injury

ABSTRACT. Traumatic brain injury (TBI) is a major cause of long-term disabilities, linked to increased risk for neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, dementia, and chronic traumatic encephalopathy. There are no effective therapies for the clinical treatment of TBI and its associated chronic neurodegeneration in survivors of TBI. Thus, the development of novel pharmacologic agents to treat TBI and restore the blood-brain barrier (BBB) is urgently needed. Recently, we have shown that AuPhos, a gold-based small molecule is neuroprotective following TBI and that its mechanism of action may be directly related to its interactions with mitochondrial complex I. Consistent with these ideas, our preliminary results indicate that AuPhos enhances mitochondrial biogenesis, cognitive index, and is neuroprotective following TBI. The central hypothesis of this proposal is that AuPhos can afford neuroprotection following TBI by directly interacting with mitochondrial complex I to enhance mitochondrial biogenesis and to elucidate the mechanism(s) underlying neuroprotection. To test this hypothesis, we propose two specific aims that include the use of innovative tools and multidisciplinary techniques that employ relevant mouse models and synthetic chemistry. In Specific Aim 1, we will determine the optimal dosage and therapeutic window of opportunity for AuPhos to maintain enhanced mitochondrial biogenesis post-injury (PI) and optimize AuPhos via synthetic chemistry to obtain an improved drug candidate to treat TBI. These studies will, for the first time, examine pharmacologic induction of mitochondrial biogenesis in synaptic and nonsynaptic mitochondria in the injury core and penumbra of individual animals. We will then measure the degree of cortical sparing, motor and serial cognitive behavioral endpoints and behavior improvements that are mediated through AuPhos treatment after TBI using the optimal dosage and therapeutic window. We will use T2 weighted and DTI MRI to longitudinally assess changes in cortical and hippocampal morphology at -3, 3, 7, and 28 days PI followed by unbiased stereology at 30 days PI. Additionally, we will expand structure activity relationship studies to obtain AuPhos derivatives with improved pharmacokinetics & safety, enhanced cerebral metabolism, and efficacious neuroprotection through rigorous synthetic chemistry. Specific Aim 2 will determine the mechanism by which AuPhos affords neuroprotection by testing the hypothesis that the therapeutic benefit of AuPhos is mediated through interactions with mitochondrial complex I that enhances mitochondrial biogenesis. Mitochondrial bioenergetics will be measured at 24 hours and behavioral outcome and tissue sparing will be measured 15 days following TBI. Key markers of mitochondrial biogenesis in the brain including PGC- 1α, NRF2 activation pathways will be evaluated. The transformative outcome of these studies will not only shed light on the fundamental processes involved in TBI neuropathology but the proposed experiments may pinpoint potentially novel interventions and targets for the treatment of TBI and beyond.