Sumatriptan modifies cortical free radical release during cortical spreading depression. A novel antimigraine action for sumatriptan?
Increases in concentration of brain NO are proposed to initiate and mediate migraine headache. Triggered by focal depolarisation, spreading depression (SD) represents a suitable mechanism for eliciting widespread release of nitric oxide. The current study examines the effect of sumatriptan, a 5-HT(1B/1D) agonist and effective antimigraine therapy, on free radical release (nitric oxide and superoxide) in SD in the simple and complex cortices of the rat and cat. Following initiation of SD, sumatriptan pretreatment (300 microg kg(-1) i.v., 15 min prior to SD) modulated all phases of nitric oxide release associated with each SD in both cats and rats. As a result, superoxide levels were observed to significantly (ANOVA, post hoc LSD) increase versus vehicle treated animals (saline 1 ml kg(-1) i.v. 15 min prior to SD) during specific phases of each SD depolarisation. Averaged over all SD depolarisations, mean peak SD nitric oxide levels per depolarisation were 0.73+/-0.23 microM (n=29) in cats, and 0.42+/-0.09 microM (n=34) in rats. Sumatriptan significantly (Students t-test, P<0.05, two tailed hypothesis, P<0.05) modulated this increase in cortical nitric oxide concentrations to 0.32+/-0.06 microM (n=25) and 0. 22+/-0.07 microM (n=37) in cats and rats. Sumatriptan appears to decrease the amplitude of nitric oxide release but enhances extracellular superoxide concentrations in both lissencephalic and gyrencephalic cortices during SD.
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Neuroscience Research, SmithKline Beecham Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, Essex, UK.
Parsons
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D000818:Animals; D002415:Cats; D002540:Cerebral Cortex / Q000378:metabolism*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D005609:Free Radicals / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008881:Migraine Disorders / Q000188:drug therapy*; D010100:Oxygen / Q000378:metabolism; D010313:Partial Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D018170:Sumatriptan / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D005609:Free Radicals; D017366:Serotonin Receptor Agonists; D013481:Superoxides; D018170:Sumatriptan; D010100:Oxygen