Elevation of Neuroactive Substances in the Cortex of Cats during Prolonged Focal Ischemia

Abstract

Sustained accumulation of excitatory amino acids and other neuroactive substances may contribute to the delayed progression of infarction in focal ischemia. Following occlusion of the left middle cerebral artery (MCAO), extracellular amino acid and purine catabolite concentrations as well as local CBF were repeatedly monitored for up to 15 h in auditory (A) and somatosensory (SF) cortices of seven halothane-anesthetized cats using microdialysis/HPLC and hydrogen clearance. MCAO resulted in persistent reduction of local CBF, which was more severe in A (n = 6) than in SF (n = 6). Accordingly, higher transmitter amino acid and purine catabolite concentrations were found in A than in SF during ischemia. Aspartate, glutamate, and γ-aminobutyrate (GABA) as well as hypoxanthine and inosine reached maximum levels 1–2 h after onset of ischemia (15-, 7-, 31-, 8-, and 14-fold increases, respectively). Maximum levels remained almost constant, with the exception of inosine, which decreased subsequently. Glycine seemed to increase with prolonged ischemia and reached maximum levels (10-fold) 15 h after occlusion. Adenosine peaked 30 min after occlusion (54-fold) and decreased thereafter to control levels within 1–2 h. One hour after occlusion, CBF thresholds for amino acid elevation were lower (glutamate and GABA ∼20 ml 100 g⁻¹ min⁻¹ and glycine ∼10 ml 100 g⁻¹ min⁻¹) than 6 and 15 h after occlusion (thresholds for all amino acids at ∼30 ml 100 g⁻¹ min⁻¹). These results indicate that in prolonged ischemia, excitotoxicity is an important factor, particularly in border zones of ischemic foci. It may be enhanced by an increase of glycine and the early disappearance of adenosine, which are considered to facilitate and inhibit, respectively, the deleterious effects of excitatory amino acids.