IPA: Targeting Brain Capillary-Specific Mitochondrial Function Following Mild Blast Traumatic Brain Injury

This proposal delves into the pressing issue of mild blast-induced traumatic brain injury (mbTBI) among U.S. service members and Veterans, stemming from both training and combat exposures. Notably, over 450,000 individuals within this group have been diagnosed with TBI, with approximately 80% classified as mild cases. mbTBI has distinct characteristics, which typically do not involve overt neuronal death but rather sublethal cellular changes. These changes include mitochondrial dysfunction, oxidative stress, and vascular damage, ultimately leading to compromised neuronal function. The central focus of the research is the potential use of sildenafil, an FDA-approved drug, to target the adverse effects of mbTBI on brain capillaries. We believe this approach is innovative and a promising approach. Notably, we seek to address oxidative damage and mitochondrial dysfunction in brain capillaries, an aspect that has not been extensively explored in TBI and mitochondria research. Sildenafil, a PDE5 inhibitor, is hypothesized to have a beneficial impact after mbTBI by targeting these specific mechanisms. The proposal outlines three specific aims to address this hypothesis. Aim 1 assesses sildenafil therapy for acute capillary-specific mitochondrial dysfunction after repeated mbTBI (rmbTBI). This aim seeks to investigate how sildenafil, when administered immediately after rmbTBI, affects acute capillary-specific bioenergetics and mitochondrial morphology in the context of rmbTBI. Aim 2 evaluates the impact of sildenafil on long-lasting capillary-specific mitochondrial and oxidative damage deficits following rmbTBI. This aim examines the long-term effects of rmbTBI on capillary- specific bioenergetics and oxidative stress. Additionally, it explores whether sildenafil, when administered 30 days after injury, can ameliorate these deficits. Aim 3 determines the effect of sildenafil in treating neurovascular dysfunction and long-term neurological impairment after rmbTBI. This aim focuses on the broader outcomes, specifically assessing how sildenafil treatment impacts behavioral outcomes, cerebral blood flow, and pathological vascular outcomes in animals subjected to rmbTBI using both acute and chronic initiation of sildenafil treatment. The research aims to illuminate the role of sildenafil in addressing mitochondrial mechanisms within the cerebral vasculature in response to blast injury. It underscores the possibility that even after the initial "golden hour" of treatment, injured brain capillaries may retain the potential for recovery, and sildenafil could facilitate this recovery. Such findings hold great promise for improving the health and well-being of Veterans suffering from the neurological consequences of blast injuries, an issue of utmost importance and significance.