title: SB-220453, a potential novel antimigraine agent, inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat.
abstract: Profound nitric oxide release associated with cortical spreading depression (SD), has been implicated in stroke, traumatic brain injury and migraine pathophysiology. SB-220453 represents a mechanistically novel, well-tolerated class of compounds which may have therapeutic potential in the treatment of conditions associated with neuronal hyperexcitability and inflammation. The aim of the present study was to investigate the effects of SB-220453 on the nitric oxide (NO) release associated with SD in the anaesthetized cat. In vehicle treated animals, KCl application for 6 min to the cortical suface produced repeated changes in extracellular direct current field potential with associated NO release. This activity was sustained for a median duration of 55 min (25-75% range, 32-59 min) and 59 min (25-75% range, 34-59 min), respectively. SB-220453 (1, 3 and 10 mg/kg i.p.) produced a dose-related inhibition of this activity and at the highest dose tested, the median duration of changes in extracellular field potential and NO release were reduced to 4 min (25-75% range, 4-5 min) and 5 min (25-75% range, 5-5 min), respectively. No effect was observed on basal systemic haemodynamic parameters or resting cerebral laser Doppler blood flux at any of the doses of SB-220453 tested. SB-220453 therefore represents a novel compound to assess the potential benefit of inhibiting SD associated nitric oxide release in neurological disease.
authors.affiliation: Neuroscience Research, Smithkline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Read
authors.forename: M I
authors.initials: MI
authors.lastname: Smith
authors.forename: A J
authors.initials: AJ
authors.lastname: Hunter
authors.forename: N
authors.initials: N
authors.lastname: Upton
authors.forename: A A
authors.initials: AA
authors.lastname: Parsons
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002415:Cats; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology; D006221:Halothane / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D000700:Analgesics; D018685:Anesthetics, Inhalation; D001549:Benzamides; D001578:Benzopyrans; C118706:tonabersat; D009569:Nitric Oxide; D006221:Halothane