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Review Int J Mol Sci. 2023 Jul 31;24(15):12268. doi: 10.3390/ijms241512268.

Migraine Treatment: Towards New Pharmacological

Targets
Marcello Silvestro 1 2 , Luigi Francesco Iannone 3 , Ilaria Orologio 1 , Alessandro Tessitore 1 2,

Gioacchino Tedeschi 1 2 , Pierangelo Geppetti 3 , Antonio Russo 2

Affiliations expand
PMID: 37569648 PMCID: PMC10418850 DOI: 10.3390/ijms241512268
Free PMC article

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Abstract
Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few
years ago, preventive migraine treatments were based on molecules with pleiotropic targets,
developed for other indications, and discovered by serendipity to be effective in migraine
prevention, although often burdened by tolerability issues leading to low adherence. However, the
progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as
calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP
monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by
an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent
of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP
family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary
adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors,
such as transient receptor potential (TRP) channels; intracellular downstream determinants, such
as potassium channels, but also the opioid system and the purinergic pathway, have been
suggested to be involved in migraine pathophysiology. The present review provides an overview of
these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative
studies, their potential role as future targets for migraine preventive treatment.

Keywords: BKCa receptor; CGRP; KATP receptor; PACAP; TRP channel; VIP; adrenomedullin;
amylin; purinergic pathway.

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Conflict of interest statement

The authors declare the following potential conflicts of interest with respect to the research,
authorship, and/or publication of this article: M.S. has received speaker honoraria from Novartis,
Teva, and Lilly. L.F.I. has received speaker honoraria from Teva and Lilly. A.T. has received speaker
honoraria from Novartis, Schwarz Pharma/UCB, Lundbeck, Abbvie, and Glaxo and serves as
associate editor of European Journal of Neurology. G.T. has received speaker honoraria from
Sanofi-Aventis, Merck Serono, Bayer Schering Pharma, Novartis, Biogen-Dompe’ AG, Teva, and
Lilly; has received funding for travel from Bayer Schering Pharma, Biogen-Dompe’ AG, Merck
Serono, Novartis, and Sanofi Aventis; and serves as an associate editor of Neurological Sciences.
A.R. has received speaker honoraria from Allergan, Lilly, Novartis, Biogen, and Teva and serves as
an associate editor of Frontiers in Neurology (Headache Medicine and Facial Pain session). The
other authors have nothing to declare.

Figures

Figure 1 Schematic and

simplified graphical
representation…

Cited by
Atogepant: Mechanism of action, clinical and translational science.
Boinpally R, Shebley M, Trugman JM.
Clin Transl Sci. 2024 Jan;17(1):e13707. doi: 10.1111/cts.13707.
PMID: 38266063 Free PMC article. Review.

CGRP Antagonism and Ketogenic Diet in the Treatment of Migraine.

Finelli F, Catalano A, De Lisa M, Ferraro GA, Genovese S, Giuzio F, Salvia R, Scieuzo C, Sinicropi MS, Svolacchia
F, Vassallo A, Santarsiere A, Saturnino C.
Medicina (Kaunas). 2024 Jan 15;60(1):163. doi: 10.3390/medicina60010163.
PMID: 38256423 Free PMC article. Review.

In Search of More Leaps to Realize the Precision Medicine of Migraine.

Shibata M.
Int J Mol Sci. 2023 Dec 12;24(24):17375. doi: 10.3390/ijms242417375.
PMID: 38139204 Free PMC article.

From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine
Treatment.
Tanaka M, Szabó Á, Körtési T, Szok D, Tajti J, Vécsei L.
Cells. 2023 Nov 17;12(22):2649. doi: 10.3390/cells12222649.
PMID: 37998384 Free PMC article. Review.

References
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Show all 197 references

Publication types
Review

MeSH terms
Analgesics, Opioid
Animals
Humans
Migraine Disorders* / drug therapy
Migraine Disorders* / metabolism
Potassium Channels / metabolism
Signal Transduction / drug effects
Vasoactive Intestinal Peptide / therapeutic use

Substances
purine
Vasoactive Intestinal Peptide
Potassium Channels
Analgesics, Opioid

Related information
MedGen
PubChem Compound (MeSH Keyword)

Grants and funding

The APC of this article was partly covered by a grant from the Japanese Headache Society. Tokyo
169-0072, Japan.

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