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Synt Viagra or natural CGRP? Be as it may, they trigger pain “way over your head”

A recent study published in the journal Cephalalgia, the official journal of the International Headache Society, reported a fascinating discovery. The study was conducted by Dr. Samaira Younis and colleagues from the Danish Headache Center, Rigshospitalet Glostrup, University of Copenhagen, Denmark. Previous clinical studies of the same research group using experimental human models have shown that at least two cellular signaling pathways are involved in migraine attacks. One is mediated by increases in cyclic adenosine monophosphate (cAMP), which can be stimulated by intravenous infusion in patients of the peptide related to the calcitonin gene (CGRP), against which indeed there are new anti-migraine drugs (like the eremumab). The other, depends on the cyclic guanosine monophosphate (cGMP), which is upregulated in the actions of the drug sildenafil (Viagra, to define it better), which is an enzyme inhibitor of phosphodiesterase-5 (PDE5), the enzyme that destroys cGMP.

The cyclic AMP is a second cellular messenger that is produced by the energy molecule ATP. It is necessary for the cell to transduce dozens of messages arriving from the outside in the form of hormones, neurotransmitters, drugs and more. The distribution of the regulatory systems of the cyclic AMP is practically present in every type of body cell. Cyclic GMP, on the other hand, derives from GTP which does not have the same functions as ATP, but serves as a cofactor to one of the components that carries the message from the external receptor, the G proteins. Now, these two signaling pathways are usually antagonistic: if one is active the other is silent and vice versa. The research question in this study was whether the activation of these 2 different signaling pathways would have produced distinct migraine attacks regarding their clinical characteristics. What do cAMP and cGMP share to produce the same pathological condition, or migraine?

Dr. Younis studied the clinical features of migraine attacks of 27 participants following intravenous CGRP injections and oral administration of sildenafil. The location and quality of the pain of the attacks, as well as the related symptoms such as photophobia, phonophobia, nausea, stress aggravation and associated triggers were compared between the conditions in a double-blind, randomized, crossover design. Participants received both CGRP and sildenafil on two different days, separated by about 14 days in order to avoid the drug transport effect. CGRP and sildenafil caused migraine attacks in 67% and 89% of patients respectively. In 63% of the participants, both drugs caused migraine attacks. There were no differences in the clinical features of the attacks, which means that both drugs act through a redundant molecular pathway.

Dr. Younis explained a hypothesis of why this double-crossed effect: “The discovery concerning a more effective action of sildenafil in causing migraine attacks could be attributed to its effects further downstream, thus being closer to the determiner common compared to CGRP in migraine that starts the cascade. CGRP stimulates the formation of cAMP, but it is likely that in the late phases of its mechanism it stimulates that of cGMP, which has vasodilator effect on the cerebral arteries, hence the pain. But sildenafil keeps cGMP high immediately (by inhibiting PDE5), without going through the more complex signaling pathway of CGRP. The results of our study will help researchers look for the commonality of the beginning of the migraine attack, as it could prove to be a potential cellular target for new preventive therapies”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Younis S et al. Cephalalgia. 2019 Dec; 39(14):1776-88.

Younis S et al. J Headache Pain. 2018 Jun 18;19(1):44. 

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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