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

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Abbruzzese, Giuseppe and Morón Oset, Javier and Díaz Castroverde, Sabela and García Font, Nuria and Roncero Romero, Cesáreo and López Muñoz, Francisco and Marco Contelles, José Luis and Oset Gasque, María Jesús (2020) 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, 9 (6). p. 545. ISSN 2076-3921

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Official URL: https://doi.org/10.3390/antiox9060545




Abstract

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 50 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.


Item Type:Article
Uncontrolled Keywords:apoptosis; autophagy; brain ischemia; cell signaling; natural antioxidants; neuroprotection; phytoestrogens
Subjects:Medical sciences > Medicine > Neurosciences
Medical sciences > Pharmacy > Cytology
Medical sciences > Pharmacy > Biochemistry
ID Code:67559
Deposited On:30 Aug 2021 08:31
Last Modified:06 Sep 2021 09:14

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