Stroke/Traumatic Brain and Spinal Cord Injuries

Abstract

Stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) represent three of the most devastating occurrences that a human being can encounter. However, much of the injury that occurs in the nervous system and the resulting disability following these acute neurological insults is not due to the primary ischemic, hemorrhagic of mechanical insult, but rather is caused by a secondary cascade of biochemical, physiological, and neurodegenerative events that takes place within the neural tissue during the first minutes, hours, and days. Over the past 25 years significant progress has been made in understanding the secondary injury process(es), revealing several molecular targets for pharmacological neuroprotection. Three of the key targets are glutamate-mediated excitotoxicity; intracellular calcium overload, and reactive oxygen species (ROS)-induced oxidative damage. Agents effective against these three mechanisms have been examined in clinical trials for the treatment stroke, TBI, and SCI with largely negative results and only a few indications of a significant effect in certain subsets of stroke, TBI, and SCI patients. However, this first generation of neuroprotective drug discovery and associated clinical trials has provided a valuable learning experience that has identified several deficiencies that should be avoidable in future efforts. The present chapter reviews: the understanding of secondary CNS injury; a brief history of past clinical trials; the principal animal models of stroke, TBI, and SCI; issues relevant to future neuroprotective drug evaluation in animal and human trials; and several relatively new pharmacologic neuroprotective approaches that may allow the development of clinically effective drugs in the future, to mitigate the effects of acute neurological disorders in many patients. Furthermore, the potential for neurorestorative drug discovery based upon evolving knowledge of the potential of the nervous system for structural and functional plasticity and regeneration, and some of the molecular mechanisms that might be pharmacologically targeted, are also briefly considered.