IS HIGH EXTRACELLULAR GLUTAMATE THE KEY TO EXCITOTOXICITY IN TRAUMATIC BRAIN INJURY

Traumatic brain injury (TBI) increases extracellular levels of the exc itatory amino acid glutamate and aspartate, and N-methyl-D aspartate ( NMDA)-receptor antagonists protect against experimental TBI, These two findings have led to the prevalent hypothesis that excitatory amino a cid efflux is a major contributor to the development of neuronal damag e subsequent to traumatic injury, However, as with stroke, the hypothe sis that high extracellular glutamate is the key to excitotoxicity in TBI conflicts with important data, For example, the initial increase i n extracellular glutamate is cleared within 5 min after moderate TBI, whereas antagonists of glutamate receptors and the so-called presynapt ic glutamate release inhibitors remain effective when administered 30 min after insult, In this article, we argue that the current concept o f excitotoxicity in TBI, centered on high extracellular glutamate, doe s not withstand scientific scrutiny, As alternatives to explain the be neficial actions of glutamate antagonists in experimental TBI, we prop ose abnormalities of glutamatergic neurotransmission, such as deficien t Mg2+ block of NMDA-receptor ionophore complexes, and phenomena such as spreading depression, which requires activation of glutamate recept ors and is detrimental to neurons in damaged/vulnerable brain regions, Finally, we introduce the notion that beneficial effects of glutamate receptor antagonists in experimental models of neurological disorders do not necessarily imply the occurrence of excitotoxic processes, Ind eed, glutamate-receptor blockade may be protective by reducing the ene rgy demand required to counterbalance Na+ influx associated with gluta matergic synaptic transmission, In other words, glutamate receptor ant agonists (and blockers of voltage-gated Na+-channels) may help nervous tissue to cope with increased permeability of the cellular membrane t o ions and reduced efficacy of Na+ extrusion, and thus prevent the dec ay of transmembrane ionic concentrations gradients.