Author(s): Obrenovitch TP, Urenjak J
Traumatic brain injury (TBI) increases extracellular levels of the excitatory 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 acid efflux is a major contributor to the development of neuronal damage subsequent to traumatic injury. However, as with stroke, the hypothesis that high extracellular glutamate is the key to excitotoxicity in TBI conflicts with important data. For example, the initial increase in extracellular glutamate is cleared within 5 min after moderate TBI, whereas antagonists of glutamate receptors and the so- called presynaptic glutamate release inhibitors remain effective when administered 30 min after insult. In this article, we argue that the current concept of excitotoxicity in TBI, centered on high extracellular glutamate, does not withstand scientific scrutiny. As alternatives to explain the beneficial actions of glutamate antagonists in experimental TBI, we propose abnormalities of glutamatergic neurotransmission, such as deficient Mg2+ block of NMDA-receptor ionophore complexes, and phenomena such as spreading depression, which requires activation of glutamate receptors 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. Indeed, glutamate-receptor blockade may be protective by reducing the energy demand required to counterbalance Na+ influx associated with glutamatergic synaptic transmission. In other words, glutamate receptor antagonists (and blockers of voltage-gated Na+-channels) may help nervous tissue to cope with increased permeability of the cellular membrane to ions and reduced efficacy of Na+ extrusion, and thus prevent the decay of transmembrane ionic concentrations gradients.
Referred From: https://www.ncbi.nlm.nih.gov/pubmed/9383088
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