Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits

Colonna, David M.; Wang, Meng; Deal, Dwight D.; Busija, David W.

doi:10.1152/ajpheart.1994.266.3.h1095

Cited by 43 publications

(55 citation statements)

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“…In vivo animal models have shown that CGRP is released by dilatation of cortical arterioles during CSD (35,36). In the present study, we have demonstrated a calcium-dependent CGRP release in cortical slices during the application of extracellular K + at elevated concentrations able to trigger CSD.…”

Section: Discussionsupporting

confidence: 65%

Critical role of calcitonin gene-related peptide receptors in cortical spreading depression

Tozzi

Iure

Filippo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

117

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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 topiramate, 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.M igraine is a common episodic headache disorder characterized by attacks that include various combinations of headache and neurologic, gastrointestinal, and autonomic symptoms. It is among the most common neurologic conditions, affecting ∼12-20% of the population. The International Headache Society classifies migraine into migraine without aura and migraine with aura, with aura defined as the complex of focal neurologic symptoms that most often precedes or accompanies an attack (1-3).Cortical spreading depression (CSD) is thought to represent a key pathogenetic step in migraine with aura (4, 5). First reported by Leão in 1944 (6), CSD is a wave of electrical activity (excitation followed by depression) that moves across the cerebral cortex after electrical or chemical stimulation. The pivotal event in the generation and propagation of CSD is a marked decrease in neuronal membrane resistance associated with massive increases in extracellular K + and neurotransmitters, as well as increases in intracellular Na + and Ca 2+ (7-9). Genetic and environmental factors modulate individual susceptibility by lowering the CSD threshold, and cortical excitation can cause sufficient elevation in extracellular K + and glutamate to initiate CSD (5,7,8,(10)(11)(12)(13)(14). Conversely, the CSD threshold also may be increased by factors that re...

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Section: Discussionsupporting

confidence: 65%

Critical role of calcitonin gene-related peptide receptors in cortical spreading depression

Tozzi

Iure

Filippo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

117

View full text Add to dashboard Cite

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“…An increase in vascular endothelial shear stress may be a stimulant for increased NO synthesis and release. 33 Third, similar to one proposed mechanism promoting CGRP release during CSD, 3 the increase in [K + ] e observed during CSD 1 may perhaps be sufficient to depolarize NO-containing perivascular nitroxidergic nerve fibers. Nitroxidergic fibers investing parenchymal brain blood vessels may release NO when they are depolarized.…”

Section: Discussionmentioning

confidence: 70%

“…3 In those experiments, application of a CGRP receptor antagonist (the 8-37 fragment of human CGRP) before CSD attenuated the pial arteriolar dilation by approximately 40%, without changing the speed of CSD propagation. However, it is clear that other mechanisms promoting pial arteriolar dilation must come into play during CSD.…”

Section: See Editorial Comment Page 2470mentioning

confidence: 93%

“…Two small brass screws were then implanted into the skull over each hemisphere for continuous monitoring of the electroencephalogram (EEG). Since depression is typically observed in the EEG amplitude when a depolarization wave passes near an EEG electrode 3 during CSD, we used the presence of EEG changes as one of our criteria to demonstrate the presence of CSD. Two burr holes were drilled through the skull just anterior to the craniectomy.…”

Section: Animal Preparationmentioning

confidence: 99%

“…One hole was the site for insertion of a short length of PE-50 tubing as a guide for the microapplication of 10 /iL of 5% KC1 to initiate CSD. A Ag-AgCl electrode (World Precision Instruments, Inc) was placed into the second burr hole down to the level of the dura to demonstrate the slow DC potential change that is characteristic of CSD, 3 -6 the other criterion for demonstrating the presence of CSD. Both the EEG tracings and the DC slow potential tracing were continuously recorded on the Grass polygraph.…”

Section: Animal Preparationmentioning

confidence: 99%

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Nitric oxide promotes arteriolar dilation during cortical spreading depression in rabbits.

Colonna

Meng

Deal

et al. 1994

Stroke

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Background and Purpose Pial arterioles transiently dilate during cortical spreading depression (CSD), although the mechanisms are unclear. We tested the hypothesis that increased production of nitric oxide (NO) promotes arteriolar dilation.Methods Urethane-anesthetized rabbits were equipped with cranial windows, and the diameter (reported in micrometers) of a pial arteriole was determined via intravital microscopy. In each rabbit, a baseline CSD was elicited by microapplication of KC1 onto the cortex, and resultant pial arteriolar dilation was measured. Either 100 fimolfL iV"-nitro-L-arginine methyl ester (L-NAME) or 50 /imol/L iV

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Meningeal mast cells, inflammation and migraine pain

Levy

2007

Drug Development Research

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Migraine is a debilitating, throbbing headache that afflicts about 15% of the Western population. While the underlying cause of migraine is still a matter of speculation, the intracranial throbbing pain of migraine is largely attributed to an episode of local sterile meningeal inflammation that promote activation of trigeminal mechanosensitive nociceptive afferents that supply the meninges. The key players responsible for triggering such nociceptive neuronal events remain poorly defined, however. Mast cells, resident inflammatory cells that populate the meninges, particularly the dura mater, were implicated in the pathophysiology of migraine more than 50 years ago. Additional clinical and preclinical data that further support their role in migraine have recently emerged. This review highlights these findings, examines the evidence of a neuroimmune interaction between meningeal nociceptors and mast cells, in particular their involvement in promoting the activation and sensitization of the trigeminovascular systems, and will finally discuss the notion that in some migraine attacks, mast cells serve as an intermediate between various migraine triggers and the persistent activation of meningeal nociceptors. Drug Dev Res 68: 412-418, 2007.

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Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits

Cited by 43 publications

References 0 publications

Critical role of calcitonin gene-related peptide receptors in cortical spreading depression

Critical role of calcitonin gene-related peptide receptors in cortical spreading depression

Nitric oxide promotes arteriolar dilation during cortical spreading depression in rabbits.

Meningeal mast cells, inflammation and migraine pain

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