Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models
Gastrointestinal disorders in Parkinson’s disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.898067/full |
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| author | Andrée-Anne Poirier Andrée-Anne Poirier Mélissa Côté Hend Jarras Hend Jarras Nadhir Litim Nadhir Litim Jérôme Lamontagne-Proulx Jérôme Lamontagne-Proulx Sara Al-Sweidi Sara Al-Sweidi Marc Morissette Asmaa Lachhab Asmaa Lachhab Martin Pelletier Martin Pelletier Thérèse Di Paolo Thérèse Di Paolo Denis Soulet Denis Soulet Denis Soulet |
| author_facet | Andrée-Anne Poirier Andrée-Anne Poirier Mélissa Côté Hend Jarras Hend Jarras Nadhir Litim Nadhir Litim Jérôme Lamontagne-Proulx Jérôme Lamontagne-Proulx Sara Al-Sweidi Sara Al-Sweidi Marc Morissette Asmaa Lachhab Asmaa Lachhab Martin Pelletier Martin Pelletier Thérèse Di Paolo Thérèse Di Paolo Denis Soulet Denis Soulet Denis Soulet |
| author_sort | Andrée-Anne Poirier |
| collection | DOAJ |
| description | Gastrointestinal disorders in Parkinson’s disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD. |
| first_indexed | 2024-04-13T03:36:57Z |
| format | Article |
| id | doaj.art-c8da65148103495c9b9e6e7073e55f5d |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T03:36:57Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-c8da65148103495c9b9e6e7073e55f5d2022-12-22T03:04:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-07-011310.3389/fphar.2022.898067898067Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease ModelsAndrée-Anne Poirier0Andrée-Anne Poirier1Mélissa Côté2Hend Jarras3Hend Jarras4Nadhir Litim5Nadhir Litim6Jérôme Lamontagne-Proulx7Jérôme Lamontagne-Proulx8Sara Al-Sweidi9Sara Al-Sweidi10Marc Morissette11Asmaa Lachhab12Asmaa Lachhab13Martin Pelletier14Martin Pelletier15Thérèse Di Paolo16Thérèse Di Paolo17Denis Soulet18Denis Soulet19Denis Soulet20Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Pharmacie, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Pharmacie, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Pharmacie, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Pharmacie, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Pharmacie, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Médecine, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Médecine, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Pharmacie, Université Laval, Québec City, QC, CanadaCentre de Recherche du CHU de Québec-Université Laval, Québec City, QC, CanadaFaculté de Pharmacie, Université Laval, Québec City, QC, CanadaInstitut sur la Nutrition et les Aliments Fonctionnels (INAF), Université Laval, Québec City, QC, CanadaGastrointestinal disorders in Parkinson’s disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.https://www.frontiersin.org/articles/10.3389/fphar.2022.898067/fulldutasterideenteric nervous systemfemale hormonesfinasteridegutinflammation |
| spellingShingle | Andrée-Anne Poirier Andrée-Anne Poirier Mélissa Côté Hend Jarras Hend Jarras Nadhir Litim Nadhir Litim Jérôme Lamontagne-Proulx Jérôme Lamontagne-Proulx Sara Al-Sweidi Sara Al-Sweidi Marc Morissette Asmaa Lachhab Asmaa Lachhab Martin Pelletier Martin Pelletier Thérèse Di Paolo Thérèse Di Paolo Denis Soulet Denis Soulet Denis Soulet Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models Frontiers in Pharmacology dutasteride enteric nervous system female hormones finasteride gut inflammation |
| title | Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models |
| title_full | Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models |
| title_fullStr | Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models |
| title_full_unstemmed | Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models |
| title_short | Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models |
| title_sort | peripheral neuroprotective and immunomodulatory effects of 5α reductase inhibitors in parkinson s disease models |
| topic | dutasteride enteric nervous system female hormones finasteride gut inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.898067/full |
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