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Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms

1
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, Spain
2
Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
3
Faculty of Health, Camilo José Cela University of Madrid (UCJC), 28692 Madrid, Spain
4
Neuropsychopharmacology Unit, “Hospital 12 de Octubre” Research Institute, 28041 Madrid, Spain
5
Laboratory of Medicinal Chemistry, Institute of Organic Chemistry (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
6
Instituto de Investigación en Neuroquímica, Universidad Complutense de Madrid, Ciudad Universitaria, 28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
Current address: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
Antioxidants 2020, 9(6), 545; https://doi.org/10.3390/antiox9060545
Received: 27 April 2020 / Revised: 13 June 2020 / Accepted: 18 June 2020 / Published: 22 June 2020
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. View Full-Text
Keywords: apoptosis; autophagy; brain ischemia; cell signaling; natural antioxidants; neuroprotection; phytoestrogens apoptosis; autophagy; brain ischemia; cell signaling; natural antioxidants; neuroprotection; phytoestrogens
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Abbruzzese, G.; Morón-Oset, J.; Díaz-Castroverde, S.; García-Font, N.; Roncero, C.; López-Muñoz, F.; Marco Contelles, J.L.; Oset-Gasque, M.J. 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 2020, 9, 545.

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