Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms
Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/9/6/545 |
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| author | Giuseppe Abbruzzese Javier Morón-Oset Sabela Díaz-Castroverde Nuria García-Font Cesáreo Roncero Francisco López-Muñoz José Luis Marco Contelles María Jesús Oset-Gasque |
| author_facet | Giuseppe Abbruzzese Javier Morón-Oset Sabela Díaz-Castroverde Nuria García-Font Cesáreo Roncero Francisco López-Muñoz José Luis Marco Contelles María Jesús Oset-Gasque |
| author_sort | Giuseppe Abbruzzese |
| collection | DOAJ |
| description | Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 5′ AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy. |
| first_indexed | 2024-03-10T18:58:27Z |
| format | Article |
| id | doaj.art-9f35bb8ad89f463fbeb72fbca5b32956 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T18:58:27Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-9f35bb8ad89f463fbeb72fbca5b329562023-11-20T04:35:48ZengMDPI AGAntioxidants2076-39212020-06-019654510.3390/antiox9060545Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling MechanismsGiuseppe Abbruzzese0Javier Morón-Oset1Sabela Díaz-Castroverde2Nuria García-Font3Cesáreo Roncero4Francisco López-Muñoz5José Luis Marco Contelles6María Jesús Oset-Gasque7Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, SpainFaculty of Health, Camilo José Cela University of Madrid (UCJC), 28692 Madrid, SpainLaboratory of Medicinal Chemistry, Institute of Organic Chemistry (CSIC), Juan de la Cierva 3, 28006 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, SpainPhytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 5′ AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy.https://www.mdpi.com/2076-3921/9/6/545apoptosisautophagybrain ischemiacell signalingnatural antioxidantsneuroprotection |
| spellingShingle | Giuseppe Abbruzzese Javier Morón-Oset Sabela Díaz-Castroverde Nuria García-Font Cesáreo Roncero Francisco López-Muñoz José Luis Marco Contelles María Jesús Oset-Gasque Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms Antioxidants apoptosis autophagy brain ischemia cell signaling natural antioxidants neuroprotection |
| title | Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms |
| title_full | Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms |
| title_fullStr | Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms |
| title_full_unstemmed | Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms |
| title_short | Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms |
| title_sort | neuroprotection by phytoestrogens in the model of deprivation and resupply of oxygen and glucose in vitro the contribution of autophagy and related signaling mechanisms |
| topic | apoptosis autophagy brain ischemia cell signaling natural antioxidants neuroprotection |
| url | https://www.mdpi.com/2076-3921/9/6/545 |
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