Abstract
ObjectivesThe transient receptor potential ankyrin A 1 (TRPA1) channel and calcitonin gene-related peptide (CGRP) are targets for migraine prophylaxis. This study aimed to understand their mechanisms in migraine by investigating the role of TRPA1 in cortical spreading depression (CSD) in vivo and exploring how reactive oxygen species (ROS)/TRPA1/CGRP interplay in regulating cortical susceptibility to CSD.MethodsImmunohistochemistry was used for detecting TRPA1 expression. CSD was induced by K+ on the cerebral cortex, monitored using electrophysiology in rats, and intrinsic optical imaging in mouse brain slices, respectively. Drugs were perfused into contralateral ventricle of rats. Lipid peroxidation (malondialdehyde, MDA) analysis was used for indicating ROS level.ResultsTRPA1 was expressed in cortical neurons and astrocytes of rats and mice. TRPA1 deactivation by an anti-TRPA1 antibody reduced cortical susceptibility to CSD in rats and decreased ipsilateral MDA level induced by CSD. In mouse brain slices, H2O2 facilitated submaximal CSD induction, which disappeared by the antioxidant, tempol and the TRPA1 antagonist, A-967079; Consistently, TRPA1 activation reversed prolonged CSD latency and reduced magnitude by the antioxidant. Further, blockade of CGRP prolonged CSD latency, which was reversed by H2O2 and the TRPA1 agonist, allyl-isothiocyanate, respectively.ConclusionsROS/TRPA1/CGRP signaling plays a critical role in regulating cortical susceptibility to CSD. Inhibition ROS and deactivation of TRPA1 channels may have therapeutic benefits in preventing stress-triggered migraine via CGRP.
Highlights
Migraine is a complex disabling neurovascular disorder, which has unmet therapeutic need due to its complicated mechanism that is not yet fully understood
reactive oxygen species (ROS)/transient receptor potential ankyrin A 1 (TRPA1)/calcitonin gene-related peptide (CGRP) signaling plays a critical role in regulating cortical susceptibility to Cortical spreading depression (CSD)
Deactivation of TRPA1 reduces the likelihood for CSD occurrence in rats, which coincides with lower level of lipid peroxidation induced by CSD
Summary
Migraine is a complex disabling neurovascular disorder, which has unmet therapeutic need due to its complicated mechanism that is not yet fully understood. Cortical spreading depression (CSD) is a key pathophysiological basis of migraine aura [1,2,3]. One common factor for almost all migraine triggers is reactive oxygen species (ROS) [7]. Increased ROS is associated with migraine [8, 9] and with CSD in the trigeminal nociceptive system [10]. This is supported by that the antioxidant, tempol, strongly reduces the CSD occurrence in vivo [11]; while the lowered-CSD threshold level is considered
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