Lubeluzole blocks increases in extracellular glutamate and taurine in the peri-infarct zone in rats

Abstract

A microdialysis probe was positioned inside the peri-infarct zone of a photochemically induced neocortical infarct in rats. Extracellular glutamate rose within 20 min after the start of infarct induction and continued to increase during the 5 h observation period to 5.5-fold the pre-infarct baseline value of 0.8 +/- 0.4 micromol/l. Glutamine increased only 1.4-fold. Changes in peri-infarct glutamate were preceded by steep rises in taurine (a 3.9-fold increase from the baseline value of 2.8 +/- 0.7 micromol/l), which coincided with spreading depressions during infarct induction. Post-treatment with lubeluzole ((S)-4-(2-benzothiazolylmethylamino)-alpha-[(3,4-difluoro-phenoxy) methyl]-1-piperidineethanol, 1.25 mg/kg i.v.), a new cerebroprotective drug, blocked the peri-infarct increases of glutamate and taurine, whereas the R-enantiomer was ineffective. Since lubeluzole has previously been shown to stereospecifically decrease glutamate-activated nitric oxide (NO) toxicity in vitro, the present in vivo stereospecific effect of lubeluzole may be related to modulation of the cascade of NO toxicity, thus preventing NO toxicity-mediated increases in extracellular glutamate. Blockade of the peri-infarct taurine response suggests that lubeluzole also may have reduced cellular osmotic stress in the peri-infarct zone.