SB-220453, a potential novel antimigraine agent, inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat

Profound nitric oxide release associated with cortical spreading depression (SD), has been implicated in stroke, traumatic brain injury and migraine p athophysiology. SB-220453 represents a mechanistically novel, well-tolerate d 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 surf ace produced repeated changes in extracellular direct current field potenti al with associated NO release. This activity was sustained for a median dur ation of 55 min (25-75% range, 32-59 min) and 59 min (25-75% range, 34-59 m in), respectively. SB-220453 (1, 3 and 10 mg/kg i.p.) produced a dose-relat ed inhibition of this activity and at the highest dose tested, the median d uration of changes in extracellular field potential and NO release were red uced to 9 min (25-75% range, 4-5min) and 5 min (25-75% range, 5-5min), resp ectively. No effect was observed on basal systemic haemodynamic parameters or resting cerebral laser Doppler blood flux at any of the doses of SB-2204 53 tested. SB-220453 therefore represents a novel compound to assess the po tential benefit of inhibiting SD associated nitric oxide release in neurolo gical disease.