The incidence of mild blast traumatic brain injuryhas risen due tothe increased use of improvised explosive devices (IEDs) in militaryconflicts. Mild blast TBI (mbTBI) is especially relevant due to its lack of acutely observable symptoms, and to its association with long-term neurodegenerative and neuropsychiatric disorders. Predominantly, TBI patients often suffer from chronic stress, neuropathic pain and headaches, which greatly compromise the health and quality of life of these individuals. Treatments for neuropathic pain have been empirically found and produce little effect in lessening neuropathic pain, likely due to the lack of targeted therapies. This highlights the need for better understanding of the molecular mechanisms underlying neuropathicpain, TBI and chronic stress that could lead to mechanistic therapeutic targets. Oxidative stress is an important mechanism of the pathophysiology of neuropathic pain, TBI and chronic stress. We hypothesize that acrolein, an endogenously formed neurotoxin, is able to stay active in the body for up to 10 days, is involved in the pathophysiology of neuropathic pain in TBI and chronic stress. This study aims to correlate acrolein elevation in the body with neuropathic pain, deepen the understanding of underlying mechanisms of pain in TBI and chronic stress, and mitigate this pain with acrolein scavenging. The ultimate goal of this research is to provide therapies for TBI and chronic stress patients that can eliminate pain and significantly improve their healthand quality of life

With an estimated incidence of 1.5 million each year, traumatic brain injury (TBI) is a major cause of mortality and morbidity in the United States. Opening of the mitochondrial permeability transition pore (mPTP) is a key event contributing to TBI pathology. Cyclophilin D (CypD), a matrix peptidyl-prolyl cis-trans isomerase, is believed to be the regulating component of the mPTP. Cyclosporin A, an immunosuppressant drug, inhibits CypD and blocks mPTP formation and has been shown to be neuroprotective following TBI. However, it is unclear if CsA’s neuroprotective mechanism is due to inhibition of CypD and/or immuno-suppression. Therefore to directly assess the contribution of CypD to TBI pathology, CypD knockout mice were subjected to a controlled cortical impact model of TBI. CypD ablation resulted in increased tissue sparing, hippocampal protection, and improved mitochondrial complex I driven respiration. Next a dose-response study of the Cyclophilin D inhibitor, NIM811, was performed. NIM811 administration following TBI resulted in improved cognition, increased tissue sparing, and improved mitochondrial function. These results suggest a major role for CypD in TBI pathology and validate CypD as a potential therapeutic target for TBI. TBI has been proposed to be the signature injury of the current Middle Eastern conflicts with an estimated prevalence of 15-60 % among combat soldiers. Although the brain does appear to be vulnerable to blast, the exact mechanisms underlying the injury remain unclear. Adult male Sprague-Dawley rats were exposed to a moderate level of blast overpressure. Following blast, blood brain barrier disruption was evident at 3 and 24 h post-exposure, oxidative damage increased at 3 h post-exposure, and microglia were activated in the hippocampus at 5 and 10 days post-exposure. This may widen future neuroprotective avenues for blast since blast brain injury appears to share similar mechanisms of injury with other TBI models.