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

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@article{b5fc8db04703411ba7ca013159b399d3,
title = "Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects",
abstract = "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.",
keywords = "Animals, Calcitonin Gene-Related Peptide/metabolism, Central Nervous System/metabolism, Estrogen Receptor alpha/metabolism, Estrogen Receptor beta/metabolism, Female, Humans, Male, Migraine Disorders/physiopathology, Neurons/metabolism, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism, Rats, Rats, Sprague-Dawley, Receptors, Calcitonin Gene-Related Peptide/metabolism, Signal Transduction, Trigeminal Ganglion/metabolism, Immunohistochemistry, Myography, Brain, PACAP, Estrogen receptors, MCA, Trigeminal ganglion, CGRP",
author = "Karin Warfvinge and Krause, {Diana N} and Aida Maddahi and Edvinsson, {Jacob C A} and Lars Edvinsson and Haanes, {Kristian A}",
year = "2020",
month = dec,
doi = "10.1186/s10194-020-01197-0",
language = "English",
volume = "21",
pages = "131",
journal = "Journal of Headache and Pain",
issn = "1129-2369",
publisher = "Springer Italia Srl",
number = "1",

}

RIS

TY - JOUR

T1 - Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

AU - Warfvinge, Karin

AU - Krause, Diana N

AU - Maddahi, Aida

AU - Edvinsson, Jacob C A

AU - Edvinsson, Lars

AU - Haanes, Kristian A

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

KW - Animals

KW - Calcitonin Gene-Related Peptide/metabolism

KW - Central Nervous System/metabolism

KW - Estrogen Receptor alpha/metabolism

KW - Estrogen Receptor beta/metabolism

KW - Female

KW - Humans

KW - Male

KW - Migraine Disorders/physiopathology

KW - Neurons/metabolism

KW - Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Calcitonin Gene-Related Peptide/metabolism

KW - Signal Transduction

KW - Trigeminal Ganglion/metabolism

KW - Immunohistochemistry

KW - Myography

KW - Brain

KW - PACAP

KW - Estrogen receptors

KW - MCA

KW - Trigeminal ganglion

KW - CGRP

UR - http://www.scopus.com/inward/record.url?scp=85095719933&partnerID=8YFLogxK

U2 - 10.1186/s10194-020-01197-0

DO - 10.1186/s10194-020-01197-0

M3 - Journal article

C2 - 33167864

VL - 21

SP - 131

JO - Journal of Headache and Pain

JF - Journal of Headache and Pain

SN - 1129-2369

IS - 1

M1 - 131

ER -

ID: 61421485