Secondary Elevation of Extracellular Neurotransmitter Amino Acids in the Reperfusion Phase following Focal Cerebral Ischemia

Abstract

The purpose of this study was to evaluate amino acid neurotransmitter dynamics in the reperfusion phase after transient cerebral ischemia. In vivo microdialysis was used to measure extracellular amino acid levels in a rabbit model of focal ischemia. During 30 min of transient ischemia (n = 5), small but significant (p < 0.05) increases in glutamate, aspartate, gamma-aminobutyric acid (GABA), and taurine were noted. These elevations rapidly returned to baseline levels upon recirculation and remained constant for up to 5.5 h of reperfusion. In rabbits subjected to 2 h of transient ischemia (n = 5), two phases of amino acid release were seen. During ischemia, large (5- to 50-fold) elevations in glutamate, aspartate, GABA, and taurine occurred, as expected. These elevations rapidly normalized upon unocclusion. However, significant (p < 0.05) secondary elevations in glutamate, aspartate, and GABA occurred after 2-4 h of reperfusion. Regression analysis demonstrated significant correlations between primary (ischemic) and secondary (reperfusion) efflux. In permanent ischemia (n = 5), amino acid levels remained elevated throughout the entire experiment. Secondary elevations in excitatory amino acids may further contribute to the excitotoxic cascade during reperfusion.

Glutamate release by an Na+ load and oxidative stress in nerve terminals: relevance to ischemia/reperfusion

“…In vivo studies showed a recovery of glutamate release to the baseline during reperfusion (Torp et al 1993); however, in other studies a transient further increase in the release of glutamate was found in the initial phase (Taguchi et al 1996;Caragine et al 1998) or after hours of reperfusion (Matsumoto et al 1996;Yang et al 2001). In addition, in vivo neuroprotection exerted by NMDA and non-NMDA receptor antagonists, even when added after the initiation of a transient ischemia (Park et al 1988;Sheardown et al 1990;Nellgard and Wieloch 1992) suggested that glutamate neurotransmission could also be important after the ischemic attack, during reperfusion (see also Nishizawa 2001).…”

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

“…We did not explore the therapeutic window for DCPIB, yet further studies would be useful to establish the actual therapeutic window to show this correlates only with inhibition of the early transient increased EAAs, or a broader therapeutic window is found consistent with later smaller secondary increases in EAAs seen after reperfusion (Matsumoto et al, 1996).…”

Relationship between Cerebral Interstitial Levels of Amino Acids and Phosphorylation Potential during Secondary Energy Failure in Hypoxic-Ischemic Newborn Piglets

“…The secondary rise in cortical glutamate concentration corresponds to that in the level of seizure activity. Matsumoto et al (30) reported that the large secondary elevation in concentrations of transmitter amino acids occurred in the reperfusion phase after 2 h of transient focal ischemia in a rabbit model. They found correlations between primary (ischemic) and secondary (reperfusion) transmitter interstitial levels, suggesting that secondary elevations are 278 related to the severity of the primary insult.…”