Secondary mechanisms in neuronal trauma.
Secondary damage in central nervous system trauma results from toxic effects of a variety of modulators that magnify the initial traumatic damage. These modulators include the excitatory transmitter glutamate, the intracellular messenger calcium, and the intercellular messenger nitric oxide. Glutamate-induced toxicity, called excitotoxicity, occurs from excess glutamate release following trauma. Passage of calcium into the cell through a specific postsynaptic glutamate receptor ion channel, the N-methyl-D-aspartate (NMDA) receptor, is crucial in activating cellular pathways leading to excitotoxic damage. The NMDA receptor requires both glutamate and glycine for activation and is blocked by many drugs that act at either of these sites. It is also blocked by agents that selectively block the ion channel of this receptor. Blocking NMDA receptors at any of these sites decreases the cellular damage mediated by glutamate in neuronal trauma and improves physiological measures associated with traumatic damage. Other strategies to limit secondary damage include blockade of other calcium channels, of calcium-activated enzymes, and of processes that mediate the effects of calcium. Calcium-activated enzymes include nitric oxide synthase and phospholipases, which cause production of free radicals. In combination with NMDA receptor blockade, these sites represent promising areas for therapeutic intervention in secondary traumatic damage.
Lynch
D R
DR
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Dawson
T M
TM
D000818:Animals; D001927:Brain Diseases / Q000503:physiopathology* / Q000517:prevention & control; D001930:Brain Injuries / Q000503:physiopathology* / Q000628:therapy; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D005971:Glutamates / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism; D009569:Nitric Oxide / Q000378:metabolism
D005609:Free Radicals; D005971:Glutamates; D009569:Nitric Oxide; D002118:Calcium