Common Mechanisms of Neuronal Cell Death after Exposure to Diverse Environmental Insults: Implications for Treatment

摘要

Neuronal cell death after exposure to neurotoxins or after central nervous system (CNS) injury is the major cause of devastating neurological pathologies associated with military combat-related morbidity and mortality. An understanding of the cellular and molecular mechanisms contributing to neuronal cell death is critical to development of appropriate treatment strategies. Although the environmental causes of CNS injury are diverse (e.g., penetrating injuries, concussive injuries, neurotoxin exposure, etc), we hypothesize that regardless of the injury mechanisms, a relatively small subset of cellular and molecular events is responsible for the vast majority of cell death. The research results contained in this annual report summarize the findings of the second year of supported research on this grant. We have made great progress in implementing the proposed studies and have generated a wealth of data that supports both our broad and specific hypotheses. Importantly, our research indicates that the calcium activated family of cysteine proteases-the calpains- are rapidly activated in response to a variety of cellular insults while the cysteine protease caspase-3 is only activated in response to more specific cellular signals. These results suggest that inhibition of both calpain and caspase may provide greater neuroprotection than either inhibitor given alone.