Excessive increases in intracellular calcium appear to be a critical pathophysiologic event in many histopathological sequelae of traumatic brain injury. Although considerable attention has been recently given to the potential neuroprotective effects of pharmacologic antagonists of the N-methyl-D-aspartate (NMDA) receptor (Which act by reducing calcium influx into neurons via glutamate receptor-associated ion channels), it is unlikely that these agents will be singularly efficacious in all types of brain injury. Moreover, since the neurochemical cellular and molecular sequelae of TBI are diverse and varied, it is likely that some form of combined (cocktail) therapy will be optimally effective in reversing the secondary consequences of CNS trauma. Using a coordinated set of laboratory models, and our experience with pharmacologic intervention, we propose to evaluate novel pharmacologic compounds that can affect calcium-induced cell death and examine the following hypotheses: 1) that neuronal damage following axonal injury primarily involves cytoskeletal degradation and will be optimally protected by therapeutic agents that attenuate or prevent cytoskeletal injury and proteolysis (specific inhibitors of calcium-activated neutral proteases (CANPs), including the calpain inhibitor Ceph 1190 and calpastatin), 2) that the neuronal damage following isolated cortical injury involves receptor-mediated dysfunction and may therefore be more amenable to pharmacotherapies targeted at receptor systems (NMDA, non-NMDA and calcium-channel) believed to be involved in post-traumatic calcium influx (the non-NMDA antagonist GYK152466, the competitive NMDA antagonist LY233053, the presynaptic glutamate release blocker BW619C89, or novel calcium-channel/serotonin antagonist (s)-emopamil); and 3) that experimental models of mixed axonal/cortical injury, such as lateral fluid-percussion brain injury, will maximally benefit from a combination (cocktail) of both types of pharmacotherapies.
Showing the most recent 10 out of 71 publications
