The Transient Receptor Potential Ankyrin Type 1 Plays a Critical Role in Cortical Spreading Depression

The transient receptor potential ankyrin type-1 (TRPA1) channels have been proposed as a potential target for migraine therapy. Yet the role of cortical TRPA1 channels in migraine mechanism has not been fully understood. Cortical spreading depression (CSD) is known as an underlying cause of migraine aura. The aim of this study is to investigate if cortical TRPA1 activity is required for CSD genesis and propagation. A mouse brain slice CSD model with intrinsic optical imaging was applied for TRPA1 signaling pharmacology. The results showed that the TRPA1 agonist, umbellulone, facilitated the propagation of submaximal CSD. Correspondingly, an anti-TRPA1 antibody and two selective TRPA1 antagonists, A967079 and HC-030031, prolonged the CSD latency and reduced magnitude, indicating a reduced cortical susceptibility to CSD under TRPA1 deactivation. Furthermore, the TRPA1 agonist, allyl-isothiocyanate (AITC), reversed the suppression of CSD by HC-030031, but not by A967079. Interestingly, the inhibitory action of A967079 on CSD was reversed by exogenous calcitonin-gene-related peptide (CGRP). Consistent to TRPA1 deactivation, the prolonged CSD latency was observed by an anti-CGRP antibody in the mouse brain slice, which was reversed by exogenous CGRP. We conclude that cortical TRPA1 is critical in regulating cortical susceptibility to CSD, which involves CGRP. The data strongly suggest that deactivation of TRPA1 channels and blockade of CGRP would have therapeutic benefits in preventing migraine with aura.