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Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, and current treatment options are unsatisfactory on the long term. Several studies suggest a potential neuroprotective action by female hormones, especially estrogens. The potential role of progestogens, however,...

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Autores principales: Castelnovo, Luca F., Thomas, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036350/
https://www.ncbi.nlm.nih.gov/pubmed/36967764
http://dx.doi.org/10.3389/fendo.2023.1125962
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author Castelnovo, Luca F.
Thomas, Peter
author_facet Castelnovo, Luca F.
Thomas, Peter
author_sort Castelnovo, Luca F.
collection PubMed
description Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, and current treatment options are unsatisfactory on the long term. Several studies suggest a potential neuroprotective action by female hormones, especially estrogens. The potential role of progestogens, however, is less defined, and no studies have investigated the potential involvement of membrane progesterone receptors (mPRs). In the present study, the putative neuroprotective role for mPRs was investigated in SH-SY5Y cells, using two established pharmacological treatments for cellular PD models, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). Our results show that both the physiologic agonist progesterone and the specific mPR agonist Org OD 02-0 were effective in reducing SH-SY5Y cell death induced by 6-OHDA and MPP(+), whereas the nuclear PR agonist promegestone (R5020) and the GABA(A) receptor agonist muscimol were ineffective. Experiments performed with gene silencing technology and selective pharmacological agonists showed that mPRα is the isoform responsible for the neuroprotective effects we observed. Further experiments showed that the PI3K-AKT and MAP kinase signaling pathways are involved in the mPRα-mediated progestogen neuroprotective action in SH-SY5Y cells. These findings suggest that mPRα could play a neuroprotective role in PD pathology and may be a promising target for the development of therapeutic strategies for PD prevention or management.
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spelling pubmed-100363502023-03-25 Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7) Castelnovo, Luca F. Thomas, Peter Front Endocrinol (Lausanne) Endocrinology Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, and current treatment options are unsatisfactory on the long term. Several studies suggest a potential neuroprotective action by female hormones, especially estrogens. The potential role of progestogens, however, is less defined, and no studies have investigated the potential involvement of membrane progesterone receptors (mPRs). In the present study, the putative neuroprotective role for mPRs was investigated in SH-SY5Y cells, using two established pharmacological treatments for cellular PD models, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). Our results show that both the physiologic agonist progesterone and the specific mPR agonist Org OD 02-0 were effective in reducing SH-SY5Y cell death induced by 6-OHDA and MPP(+), whereas the nuclear PR agonist promegestone (R5020) and the GABA(A) receptor agonist muscimol were ineffective. Experiments performed with gene silencing technology and selective pharmacological agonists showed that mPRα is the isoform responsible for the neuroprotective effects we observed. Further experiments showed that the PI3K-AKT and MAP kinase signaling pathways are involved in the mPRα-mediated progestogen neuroprotective action in SH-SY5Y cells. These findings suggest that mPRα could play a neuroprotective role in PD pathology and may be a promising target for the development of therapeutic strategies for PD prevention or management. Frontiers Media S.A. 2023-03-10 /pmc/articles/PMC10036350/ /pubmed/36967764 http://dx.doi.org/10.3389/fendo.2023.1125962 Text en Copyright © 2023 Castelnovo and Thomas https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Castelnovo, Luca F.
Thomas, Peter
Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)
title Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)
title_full Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)
title_fullStr Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)
title_full_unstemmed Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)
title_short Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)
title_sort progesterone exerts a neuroprotective action in a parkinson’s disease human cell model through membrane progesterone receptor α (mprα/paqr7)
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036350/
https://www.ncbi.nlm.nih.gov/pubmed/36967764
http://dx.doi.org/10.3389/fendo.2023.1125962
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