Abstract
The release of the neuropeptide CGRP from the trigeminal ganglion neurons (TGNs) plays a central role in migraine. Whereas CGRP can activate NO release from ganglionic glial cells, NO in turn enhances CGRP release. However, it remains unclear how NO promotes CGRP release. Here, we report that the NO donor SNAP triggered CGRP release from cultured primary TGNs. This event was associated with GSK-3β activation and Akt inactivation. Immunofluorescent staining revealed that GSK-3β primarily located in neurons. Furthermore, GSK-3β inhibition resulted in a marked reduction in expression of CGRP as well as other migraine-related factors, including substance P, cholecystokinin, and prostaglandin E2. Last, exposure to SNAP also activated NF-κB, while NF-κB inhibition prevented the induction of CGRP by SNAP. Interestingly, this event was blocked by GSK-3β inhibition, in association with inhibition of NF-κB/p65 expression and nuclear translocation. Together, these findings argue that NO could stimulate TGNs to release of CGRP as well as other migraine-related factors, likely by activating GSK-3β, providing a novel mechanism underlying a potential feed-forward loop between NO and CGRP in migraine. They also raise a possibility that GSK-3β might act to trigger migraine through activation of NF-κB, suggesting a link between neuroinflammation and migraine.
Highlights
Migraine is a complex neurological disease, which represents the second largest cause of disability in the world
The neuropeptide calcitonin gene-related peptide (CGRP) with a potent vasodilating property represents a link between the neurons within the trigeminal ganglion and the meningeal vascular system, which plays a central role in the onset of migraine [2]
While CGRP is abundant in trigeminal ganglion neurons (TGNs), it is released from the end of the trigeminal afferents once stimulated
Summary
Migraine is a complex neurological disease, which represents the second largest cause of disability in the world. The introduction of the trigeminovascular hypothesis, which proposed a central role of the trigeminal nerve and its vasoactive neuropeptidecontaining axonal projections to the meninges and its www.aging-us.com blood vessels, has led to a fundamental paradigm shift - from the classic vascular disorder to a neural disease, in mechanistic understanding and clinical management of migraine [2]. There are at least three this kind of neuropeptides that have been identified so far, including substance P (SP), calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) These neuropeptides share a common property of powerful vasodilation as well as all have been found within the trigeminal afferents innervating the meninges, CGRP is the only one that has been proven as a therapeutic target for the treatment of migraine to date [2, 9, 10]. The CGRP-targeted therapies, including monoclonal antibodies against
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