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Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan.
Brain Res 2001; 891(1-2):69-77BR

Abstract

Migraine headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms for eliciting increases in brain NO concentration in migraineurs have not yet been identified, although, animal models highlight cortical spreading depression (CSD) as a potential candidate. These studies have focused on CSD-associated NO release at highly acute time points (min-hours) and have not employed markers of NO metabolism with direct clinical application e.g. cGMP. The current study evaluated changes in plasma cGMP concentrations 3 h, 24 h and 3 days post-CSD and compared these to cortical and brainstem cGMP concentrations at 3 days. Moreover, this study also examined the effect of sumatriptan, a clinically effective antimigraine agent, and tonabersat (SB-220453) a potential novel antimigraine agent, on any observed changes in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan (300 microg kg(-1) 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 KCl application to the parietal cortex. In the vehicle-treated group a median of eight depolarisations, were observed. Sumatriptan had no effect on the number of depolarisations, whereas tonabersat significantly reduced the number of events (median=2). No depolarisation events were observed throughout the recording period in the sham group. Following KCl 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 elevation in cGMP concentration in the brain stem 3 days after application of KCl. 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.

Authors+Show Affiliations

Neuroscience Research, SmithKline Beecham Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, Essex, UK. simon_read@sbphrd.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11164810

Citation

Read, S J., et al. "Cortical Spreading Depression Produces Increased cGMP Levels in Cortex and Brain Stem That Is Inhibited By Tonabersat (SB-220453) but Not Sumatriptan." Brain Research, vol. 891, no. 1-2, 2001, pp. 69-77.
Read SJ, Hirst WD, Upton N, et al. Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan. Brain Res. 2001;891(1-2):69-77.
Read, S. J., Hirst, W. D., Upton, N., & Parsons, A. A. (2001). Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan. Brain Research, 891(1-2), pp. 69-77.
Read SJ, et al. Cortical Spreading Depression Produces Increased cGMP Levels in Cortex and Brain Stem That Is Inhibited By Tonabersat (SB-220453) but Not Sumatriptan. Brain Res. 2001 Feb 9;891(1-2):69-77. PubMed PMID: 11164810.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan. AU - Read,S J, AU - Hirst,W D, AU - Upton,N, AU - Parsons,A A, PY - 2001/2/13/pubmed PY - 2001/5/22/medline PY - 2001/2/13/entrez SP - 69 EP - 77 JF - Brain research JO - Brain Res. VL - 891 IS - 1-2 N2 - Migraine headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms for eliciting increases in brain NO concentration in migraineurs have not yet been identified, although, animal models highlight cortical spreading depression (CSD) as a potential candidate. These studies have focused on CSD-associated NO release at highly acute time points (min-hours) and have not employed markers of NO metabolism with direct clinical application e.g. cGMP. The current study evaluated changes in plasma cGMP concentrations 3 h, 24 h and 3 days post-CSD and compared these to cortical and brainstem cGMP concentrations at 3 days. Moreover, this study also examined the effect of sumatriptan, a clinically effective antimigraine agent, and tonabersat (SB-220453) a potential novel antimigraine agent, on any observed changes in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan (300 microg kg(-1) 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 KCl application to the parietal cortex. In the vehicle-treated group a median of eight depolarisations, were observed. Sumatriptan had no effect on the number of depolarisations, whereas tonabersat significantly reduced the number of events (median=2). No depolarisation events were observed throughout the recording period in the sham group. Following KCl 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 elevation in cGMP concentration in the brain stem 3 days after application of KCl. 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. SN - 0006-8993 UR - https://www.unboundmedicine.com/medline/citation/11164810/Cortical_spreading_depression_produces_increased_cGMP_levels_in_cortex_and_brain_stem_that_is_inhibited_by_tonabersat__SB_220453__but_not_sumatriptan_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(00)03191-7 DB - PRIME DP - Unbound Medicine ER -