Excitotoxicity and Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major health problem in the industrialized world where survivors suffer major physical, psychological and economical consequences. Despite numerous clinical trials investigating pharmaceutical compounds with promising pre-clinical efficacy, no pharmacological treatment has been developed with proven clinical efficacy. The present chapter reviews the pathophysiology of TBI with focus on the evidence of and mechanisms for glutamate-mediated excitotoxicity, which is considered to be a major contributor to the secondary injury process following both experimental and clinical TBI. Furthermore, we review the numerous pharmacological approaches targeting excitotoxicity employed in experimental TBI, and address the controversies that exist with regard to the importance of glutamate-mediated mechanisms following TBI. The impressive reductions in functional and structural impairment observed following experimental TBI after administration of compounds designed to attenuate glutamate excitotoxicity raised high expectations for improvement of outcome following clinical TBI, and we summarize the phase III clinical trials conducted thus far with glutamate receptor antagonists following clinical TBI. Finally, we address possible future directions in the search of a clinically useful treatment for human head injury.