Brain extracellular levels of
glutamate,
aspartate,
GABA and
glycine increase rapidly following the onset of
ischemia, remain at an elevated level during the
ischemia, and then decline over 20-30 min following reperfusion. The elevated levels of the excitotoxic
amino acids,
glutamate and
aspartate, are thought to contribute to
ischemia-evoked neuronal injury and death.
Calcium-evoked exocytotic release appears to account for the initial (1-2 min) efflux of
neurotransmitter-type
amino acids following the onset of
ischemia, with non-vesicular release responsible for much of the subsequent efflux of these and other
amino acids, including
taurine and
phosphoethanolamine. Extracellular Ca(2+)-independent release is mediated, in part by Na(+)-dependent
amino acid transporters in the plasma membrane operating in a reversed mode, and by the opening of swelling-induced
chloride channels, which allow the passage of
amino acids down their concentration gradients. Experiments on cultured neurons and astrocytes have suggested that it is the astrocytes which make the primary contribution to this
amino acid efflux. Inhibition of
phospholipase A(2) attenuates
ischemia-evoked release of both amino and
free fatty acids from the rat cerebral cortex indicating that this group of
enzymes is involved in
amino acid efflux, and also accounting for the consistent
ischemia-evoked release of
phosphoethanolamine. It is, therefore, possible that disruption of membrane integrity by
phospholipases plays a role in
amino acid release. Recovery of
amino acid levels to preischemic levels requires their uptake by high affinity Na(+)-dependent transporters, operating in their normal mode, following restoration of energy metabolism, cell resting potentials and ionic gradients.