Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: implications for gender differences i
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RESEARCH ARTICLE
Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: implications for gender differences in migraine Ayhan Cetinkaya1 · Erkan Kilinc1 · Cagri Camsari2 · Muhammed Nur Ogun3 Received: 19 March 2020 / Accepted: 5 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Neurogenic inflammation including calcitonin gene-related peptide (CGRP) and substance-P (SP) release plays a pivotal role in migraine pathogenesis. Prevalence of migraine is ~ 3 folds higher in women than in men, but its underlying mechanisms remained unclear. We investigated the effects of female sex hormones estrogen and progesterone on CGRP and SP in in-vivo and ex-vivo in rats of both sexes. For in-vivo experiments, male, female and ovariectomized rats were separated into four groups (n = 7) as control, estrogen, progesterone and estrogen + progesterone, respectively. Groups received daily intraperitoneal vehicle, 17β-estradiol, progesterone and 17β-estradiol + progesterone for 5 days, respectively. For ex-vivo experiments in both sexes, isolated trigeminal ganglia and hemiskull preparations were divided into four groups (n = 6 or 8), respectively, as in-vivo groups, and administered the same test substances. CGRP and SP contents in plasma and superfusates were determined using ELISA. In in-vivo experiments, 17β-estradiol decreased CGRP levels in males and SP levels in ovariectomized rats. Progesterone increased both CGRP and SP levels in females. Their combination decreased both CGRP and SP levels in males, and only SP levels in ovariectomized rats. In ex-vivo experiments, 17β-estradiol reduced CGRP release in males and SP release in females in trigeminal ganglia. While progesterone increased CGRP release in trigeminal ganglia, it reduced SP release from hemiskulls in both sexes. Their combination restored progesterone-mediated changes in neuropeptides releases in both trigeminal ganglia and hemiskulls in both sexes. Estrogen alleviates neurogenic inflammation through modulation of CGRP and SP release. Progesterone has dual effects on these neuropeptides in different sites associated with migraine pain. Keywords Gender difference · Migraine · Neurogenic inflammation · Trigeminovascular system · Calcitonin gene-related peptide · Substance-P
Communicated by Thomas Deller. Presentation at a conference: This study has been accepted to present as oral presentation at the 4th International Congress of Turkish Neuroendocrinology Society on April 10–12, 2020, in Istanbul, Turkey. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00221-020-05923-7) contains supplementary material, which is available to authorized users. * Erkan Kilinc [email protected] 1
Department of Physiology, Medical Faculty, Bolu Abant Izzet Baysal University, Bolu, Turkey
2
Innovative Food Technologies Development Application Research Center, Bolu Abant Izzet Baysal University, Bolu, Turkey
3
Department of Neurology, Bolu Abant Izzet Baysa
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