Bench to Bedside: Current Challenges in TBI Research Lauren Jones, Gerene Denning, and Christopher Buresh University of Iowa Hospitals and Clinics, Emergency Medicine Department, University of Iowa Put Picture here Goals of Project Challenge 2: Neuroprotective Agent Challenge 3: Study Design The goal of this project was to conceptualize an animal TBI model that is clinically relevant to humans and a multi-modal drug therapy targeting key pathologies in TBI. Our long-term goal is to translate basic research results into clinical research and treatment. Many drugs are neuroprotective in animal models but fail in clinical trials. Interestingly, all of these drugs have U-shaped dose response curves (examples below). Higher concentrations can not only lead to loss of treatment effects but may increase adverse consequences. Multicenter phase III clinical trials have failed to show improvements in TBI patients. Wrong Experimental Model? Animal models and injury severity may not reflect clinical situations. Wrong Treatment Target? Neuroprotective agents may target only one mechanism of injury. Background and Significance Global Mechanism: Increase Ischemic Tolerance Wrong Pharmacological Approach? Study must employ clinically relevant time window and route of administration. Drug dose must be optimal. Traumatic brain injury (TBI) affects ~1.7 million people each year and results in over 52,000 deaths.   To date, TBI research has been relatively unsuccessful in translating laboratory results to patient care. The three major challenges are: Selecting animal models that mimic human TBI Identifying narrow therapeutic windows for neuro-protective agents. Selecting therapeutic targets (e.g., metabolic pathway) and pharmacological approaches (e.g., time and route of administration). Ischemic-reperfusion (IR) injury results from transient oxygen/glucose deprivation. IR leads to focal and/or diffuse cellular damage. Activating GABA receptors reduces cellular metabolism and protects cells from IR injury. IR itself can inactivate GABA receptors. Diazepam protects cells by allosterically enhancing GABA receptor activation. Conclusions TBI model: Comparing the FPI and blast model will improve the generalizability and relevance of our results. Neuroprotective agent: Erythropoietin (Epo), a compound that is both anti-inflammatory and increases ischemic tolerance, may prove more effective than agents that target only one mechanisms of injury. Study design: Treatment will begin1 hr after injury to more closely model pre-hospital care. Optimal drug doses will be employed. Multiple outcomes will be measured. Challenge 1: Animal Model Graph A. Diazepam protects neurons from oxygen/glucose deprivation (ischemia) and reperfusion.   Controlled Cortical Injury Weight Drop Injury *Fluid Percussion Injury (FPI) Rotational Acceleration Injury Blast Injury Instrument Air-driven piston Metal weight (gravity) Pendulum, (water) Impactor Chamber with force wave Exposure of Brain Exposed dura Exposed skull Closed head, free to rotate Closed head Type of injury Most focal More diffuse than FPI and CCI Focal and diffuse (mixed) Diffuse axonal injury  All mimic some but not all aspects of human TBI *Only fluid percussion injury has delayed development of epilepsy in some animals Global Mechanism: Decrease Inflammation Inflammatory mediators contribute to brain injury, including breakdown of the blood brain barrier. Inflammation can activate cellular death cascades. Pranlukast is an anti-inflammatory that antagonizes the effects of pro-inflammatory lipids (leukotrienes). Reduces both necrosis and apoptosis of neurons. Acknowledgments Funding for these studies was provided by the University of Iowa Department of Emergency Medicine. Fluid Percussion Model Blast Model We would also like to thank the Iowa Center for Research by Undergraduates (ICRU) for providing student support. Graph B. Pranlukast protects neurons by reducing inflammation.