title: 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.
authors.affiliation: Janssen-Cilag GmbH, Drug Discovery, Neuss, Germany.
authors.forename: D K
authors.initials: DK
authors.lastname: Scheller
authors.forename: M
authors.initials: M
authors.lastname: De Ryck
authors.forename: J
authors.initials: J
authors.lastname: Kolb
authors.forename: S
authors.initials: S
authors.lastname: Szathmary
authors.forename: J
authors.initials: J
authors.lastname: van Reempts
authors.forename: G
authors.initials: G
authors.lastname: Clincke
authors.forename: F
authors.initials: F
authors.lastname: Tegtmeier
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; D005973:Glutamine; D013654:Taurine; D018698:Glutamic Acid; C097722:lubeluzole