Cortical spreading depression produces increased cGMP levels in cortex andbrain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan

Migraine headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms for eliciting increases in brain NO concentration in migraineur s have not yet been identified, although, animal models highlight cortical spreading depression (CSD) as a potential candidate. These studies have foc used on CSD-associated NO release at highly acute time points (min-hours) a nd have not employed markers of NO metabolism with direct clinical applicat ion e.g. cGMP. The current study evaluated changes in plasma cGMP concentra tions 3 h, 24 h and 3 days post-CSD and compared these to cortical and brai nstem cGMP concentrations at 3 days. Moreover, this study also examined the effect of sumatriptan, a clinically effective antimigraine agent, and tona bersat (SB-220453) a potential novel antimigraine agent, on any observed ch anges in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan (300 b kg-l i.v, n=3) or tonabersat (SB-220453 10 mg kg(-1) i.p., n=3), CSD was evoked in anaesthetised rats by a 6-min KCI application to the parietal co rtex. In the vehicle-treated group a median of eight depolarisations, were observed. Sumatriptan had no effect on the number of depolarisations, where as tonabersat significantly reduced the number of events (median=2). No dep olarisation events were observed throughout the recording period in the sha m group. Following KC1 application plasma cGMP concentrations were reduced up to 24 h post-CSD, but not significantly different from sham animals at 3 days. CSD in vehicle-treated animals produced a highly significant elevati on in cGMP concentration in the brain stem 3 days after application of KC1, cGMP concentration increased 2.3-fold from 68+/-8 fmol/mg in sham animals (n=3) to 158+/-28 fmol/mg in the vehicle group. This increase in brain stem cGMP was abolished by tonabersat pre-treatment but not by sumatriptan. (C) 2001 Elsevier Science BN. All rights reserved.