Proceedings of the National Academy of Sciences - PNAS, 2012-11, Vol.109 (46), p.18985-18990
2012
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- Autor(en) / Beteiligte
- Titel
- Critical role of calcitonin gene-related peptide receptors in cortical spreading depression
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2012-11, Vol.109 (46), p.18985-18990
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Cortical spreading depression (CSD) is a key pathogenetic step in migraine with aura. Dysfunctions of voltage-dependent and receptor-operated channels have been implicated in the generation of CSD and in the pathophysiology of migraine. Although a known correlation exists between migraine and release of the calcitonin gene-related peptide (CGRP), the possibility that CGRP is involved in CSD has not been examined in detail. We analyzed the pharmacological mechanisms underlying CSD and investigated the possibility that endogenous CGRP contributes to this phenomenon. CSD was analyzed in rat neocortical slices by imaging of the intrinsic optical signal. CSD was measured as the percentage of the maximal surface of a cortical slice covered by the propagation of intrinsic optical signal changes during an induction episode. Reproducible CSD episodes were induced through repetitive elevations of extracellular potassium concentration. AMPA glutamate receptor antagonism did not inhibit CSD, whereas NMDA receptor antagonism did inhibit CSD. Blockade of voltage-dependent sodium channels by TTX also reduced CSD. CSD was also decreased by the antiepileptic drug top-iramate, but not by carbamazepine. Interestingly, endogenous CGRP was released in the cortical tissue in a calcium-dependent manner during CSD, and three different CGRP receptor antagonists had a dose-dependent inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. Our findings show that both glutamate NMDA receptors and voltage-dependent sodium channels play roles in CSD. They also demonstrate that CGRP antagonism reduces CSD, supporting the possible use of drugs targeting central CGRP receptors as antimigraine agents.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1215435109Titel-ID: cdi_jstor_primary_41830137
- Format
- –
- Schlagworte
- Animals, Anticonvulsants - pharmacology, Biological Sciences, Calcitonin gene related peptide receptors, Calcitonin Gene-Related Peptide - pharmacokinetics, Calcitonin Gene-Related Peptide - pharmacology, Calcitonin Gene-Related Peptide Receptor Antagonists, Carbamazepine - pharmacology, Cerebral Cortex - metabolism, Cerebral Cortex - pathology, Cerebral Cortex - physiopathology, Cortical Spreading Depression - drug effects, Depressive disorders, Dose-Response Relationship, Drug, Fructose - analogs & derivatives, Fructose - pharmacology, Genetic variation, Headache, Imaging, Instructional materials, Male, Migraine, Migraine Disorders - drug therapy, Migraine Disorders - metabolism, Migraine Disorders - pathology, Migraine Disorders - physiopathology, N methyl D aspartate receptors, Neuropsychology, Pain, Pathology, Peptides, Rats, Rats, Wistar, Receptors, AMPA - antagonists & inhibitors, Receptors, AMPA - metabolism, Receptors, Calcitonin Gene-Related Peptide - metabolism, Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors, Receptors, N-Methyl-D-Aspartate - metabolism, Rodents, Signal transduction, Topiramate, Voltage-Gated Sodium Channels