Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models

Haanes, Kristian Agmund; Labastida-Ramírez, Alejandro; Blixt, Frank W; Rubio‐Beltrán, Eloísa; Dirven, Clemens; Danser, A.H. Jan; Edvinsson, Lars; MaassenVanDenBrink, Antoinette

doi:10.1177/0333102419851810

Cited by 25 publications

(42 citation statements)

References 38 publications

(56 reference statements)

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“…The current mechanism of action of triptans, ditans and potentially new anti-migraine compounds, e.g. agonists aimed at the P2Y 13 receptor, have been linked to inhibiting CGRP release through receptors coupling to G i proteins [12,22,45,46]. In the current paper, we show an effect of triptans in TG regions that contain neuronal cell bodies, but not in fiber-rich areas devoid of somas.…”

Section: Possible Mechanism Of Sensitizationmentioning

confidence: 53%

“…The Danish Animal Experimentation Inspectorate approved all procedures. The protocol is described in detail elsewhere [21,22]. TGs were dissected and immersed in 10 ml synthetic interstitial fluid (SIF, composition: 108 mM NaCl, 3.5 mM KCl, 3.5 mM MgSO 4 , 26 mM NaHCO 3 , NaH 2 PO 4 , 1.5 mM CaCl 2 , 9.6 mM NaGluconate, 5.6 mM glucose and 7.6 mM sucrose; pH 7.4.)…”

Section: Cgrp Releasementioning

confidence: 99%

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C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

et al. 2019

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Background: Monoclonal antibodies (mAbs) towards CGRP or the CGRP receptor show good prophylactic antimigraine efficacy. However, their site of action is still elusive. Due to lack of passage of mAbs across the bloodbrain barrier the trigeminal system has been suggested a possible site of action because it lacks blood-brain barrier and hence is available to circulating molecules. The trigeminal ganglion (TG) harbors two types of neurons; half of which store CGRP and the rest that express CGRP receptor elements (CLR/RAMP1). Methods: With specific immunohistochemistry methods, we demonstrated the localization of CGRP, CLR, RAMP1, and their locations related to expression of the paranodal marker contactin-associated protein 1 (CASPR). Furthermore, we studied functional CGRP release separately from the neuron soma and the part with only nerve fibers of the trigeminal ganglion, using an enzyme-linked immunosorbent assay. Results: Antibodies towards CGRP and CLR/RAMP1 bind to two different populations of neurons in the TG and are found in the C-and the myelinated Aδ-fibers, respectively, within the dura mater and in trigeminal ganglion (TG). CASPR staining revealed paranodal areas of the different myelinated fibers inhabiting the TG and dura mater. Double immunostaining with CASPR and RAMP1 or the functional CGRP receptor antibody (AA58) revealed co-localization of the two peptides in the paranodal region which suggests the presence of the CGRP-receptor. Double immunostaining with CGRP and CASPR revealed that thin C-fibers have CGRP-positive boutons which often localize in close proximity to the nodal areas of the CGRP-receptor positive Aδ-fibers. These boutons are pearl-like synaptic structures, and we show CGRP release from fibers dissociated from their neuronal bodies. In addition, we found that adjacent to the CGRP receptor localization in the node of Ranvier there was PKA immunoreactivity (kinase stimulated by cAMP), providing structural possibility to modify conduction activity within the Aδ-fibers. Conclusion: We observed a close relationship between the CGRP containing C-fibers and the Aδ-fibers containing the CGRP-receptor elements, suggesting a point of axon-axon interaction for the released CGRP and a site of action for gepants and the novel mAbs to alleviate migraine.

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Section: Possible Mechanism Of Sensitizationmentioning

confidence: 53%

Section: Cgrp Releasementioning

confidence: 99%

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

et al. 2019

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“…All these procedures are approved by the Danish Animal Experimentation Inspectorate. The protocol is described in detail elsewhere [26,27]. Rats were anaesthetized by CO 2 inhalation and decapitated.…”

Section: Cgrp/pacap Release In Males and Femalesmentioning

confidence: 99%

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

et al. 2020

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Background Migraine occurs 2–3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17β-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes. Methods Immunohistochemistry was used for detection and localization of proteins, release of CGRP and PACAP investigated by ELISA and myography/perfusion arteriography was performed on rat and human arterial segments. Results ERα was found throughout the whole brain, and in several migraine related structures. ERβ was mainly found in the hippocampus and the cerebellum. In trigeminal ganglion (TG), ERα was found in the nuclei of neurons; these neurons expressed CGRP or the CGRP receptor in the cytoplasm. G-protein ER (GPER) was observed in the cell membrane and cytoplasm in most TG neurons. We compared TG from males and females, and females expressed more ER receptors. For neuropeptide release, the only observable difference was a baseline CGRP release being higher in the pro-estrous state as compared to estrous state. In the middle cerebral artery (MCA), we observed similar dilatory ER-responses between males and females, except for vasodilatory ERβ which we observed only in female arteries. Conclusion These data reveal significant differences in ER receptor expression between male and female rats. This contrasts to CGRP and PACAP release where we did not observe discernable difference between the sexes. Together, this points to a hypothesis where estrogen could have a modulatory role on the trigeminal neuron function in general rather than on the acute CGRP release mechanisms and vasomotor responses.

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“…Seventeen rats were anaesthetized by CO 2 inhalation and decapitated around 13.00 pm. The protocol is described in detail elsewhere (33,34). The skull was cut mid-sagittally and the brain halves were carefully removed while the cranial dura was left attached to the skull, and the TG was dissected out.…”

Section: Cgrp/pacap Releasementioning

confidence: 99%

Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system

et al. 2020

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Background Several neurotransmitters are expressed in the neurons of the trigeminal ganglion. One such signalling molecule is the pituitary adenylate cyclase-activating peptide (PACAP). PACAP signalling has been suggested to have a possible role in the pathophysiology of primary headaches. Objective The present study was designed to investigate the relationship between PACAP and calcitonin gene-related peptide, currently the two most relevant migraine peptides. Methods In the current study, we used ELISA to investigate PACAP and calcitonin gene-related peptide release in response to 60 mM K+ or capsaicin using a rat hemi-skull model. We combined this analysis with qPCR and immunohistochemistry to study the expression of PACAP and calcitonin gene-related peptide receptors and ligands. Results Calcitonin gene-related peptide (CGRP) is released from the trigeminal ganglion and dura mater. In contrast, PACAP is only released from the trigeminal ganglion. We observed a weak correlation between the stimulated release of the two neuropeptides. PACAP-38 immunoreactivity was expressed alone and in a subpopulation of neurons in the trigeminal ganglion that also store calcitonin gene-related peptide. The receptor subtype PAC1 was mainly expressed in the satellite glial cells (SGCs), which envelop the neurons in the trigeminal ganglion, in some neuronal processes, inside the Aδ-fibres and in the outermost layer of the myelin sheath that envelopes the Aδ-fibres. Conclusion Unlike CGRP, PACAP is only released within the trigeminal ganglion. This raises the question of whether a migraine therapy aimed at preventing peripheral PACAP signalling would be as successful as the CGRP signalling targeted treatments.

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Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models

Cited by 25 publications

References 38 publications

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system

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