ABSTRACT Despite advances in care, morbidity following traumatic brain injury (TBI) remains high. Notably, all therapeutics for primary TBI that have shown promise in preclinical animal models have failed to demonstrate efficacy in humans, a lost in translation phenomenon. Treatment of secondary insults to TBI patients while in the intensive care setting provides a unique opportunity for therapeutic interventions. Specifically, patients with TBI in the intensive care setting are at high risk for unavoidable hypoxemia and brain hypoxia due to pulmonary contusions, aspiration, and as a result of required procedural interventions. To explicitly model the contribution of secondary brain hypoxia, we have developed a clinically relevant murine model of TBI with delayed hypoxemia. Our objective is to test therapeutics that may mitigate secondary injury from delayed hypoxemia following TBI. We propose a rigorous preclinical trial funnel design including adequate sample sizes, minimization of bias, validation/replication of results, clinically relevant long term outcomes, and testing of sex and genotype factors, as recommended by NINDS and others, to establish a framework for efficient testing of potential candidate therapeutics. Preliminary screening of several candidate therapeutics in our translational model has identified three FDA approved agents with potential short term efficacy: epoetin alfa (EPO), minocycline (MINO), and N-acetylcysteine (NAC). We hypothesize that targeting brain hypoxia after TBI in the ICU setting will overcome many of the barriers of previous therapeutic failures, permit rapid administration of neuroprotective agents with short temporal windows of efficacy, and improve outcomes. We will first evaluate short term neuroprotective efficacy of three therapeutic candidates (EPO, MINO, and NAC) following brain hypoxia after TBI. We will study 3 different doses and 2 treatment start times for each candidate therapeutic in a randomized, placebo controlled fashion. To assess initial efficacy, we will determine lesion volume and perform rigorous blinded quantification of immunohistochemistry for severity of axonal injury as well as hippocampal neuronal protection using our novel high throughput automated image analysis. In Aim 2 we will evaluate long term neuroprotective efficacy of therapeutic candidates for brain hypoxia after TBI with behavioral testing 6 months after initial injury. We will validate our findings by replicating drug candidate dosing and timing studies in a second laboratory by investigators not involved in the initial studies. Finally in Aim 3, to improve the likelihood of successful translation, we will determine sex-distinct responses to therapeutics. Our approach with an enhanced animal model with a clinically relevant delayed secondary insult and rigorous preclinical study design has excellent potential to yield a high probability of effective translation to success in human studies and rapidly eliminate therapeutic candidates unlikely to ultimately succeed.