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Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways

ABSTRACT: The present study elucidates the neuroprotective mechanisms of the PPARγ (peroxisome proliferator-activated receptor γ) agonist pioglitazone in survival of ischemic neurons following middle cerebral artery occlusion with reperfusion (MCAO). Intracerebroventricular infusion of pioglitazone...

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Autores principales: Zhao, Yi, Lützen, Ulf, Gohlke, Peter, Jiang, Ping, Herdegen, Thomas, Culman, Juraj
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313471/
https://www.ncbi.nlm.nih.gov/pubmed/33864097
http://dx.doi.org/10.1007/s00109-021-02065-3
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author Zhao, Yi
Lützen, Ulf
Gohlke, Peter
Jiang, Ping
Herdegen, Thomas
Culman, Juraj
author_facet Zhao, Yi
Lützen, Ulf
Gohlke, Peter
Jiang, Ping
Herdegen, Thomas
Culman, Juraj
author_sort Zhao, Yi
collection PubMed
description ABSTRACT: The present study elucidates the neuroprotective mechanisms of the PPARγ (peroxisome proliferator-activated receptor γ) agonist pioglitazone in survival of ischemic neurons following middle cerebral artery occlusion with reperfusion (MCAO). Intracerebroventricular infusion of pioglitazone over 5 days before and 24 or 48 h after MCAO alleviated neurological impairments, inhibited apoptosis 24 h, and activated the PI3K/Akt pathway along with increased phosphorylation of Akt (ser473) and GSK-3β (ser9) in the peri-infarct cortical areas 48 h after MCAO. In primary cortical neurons, pioglitazone suppressed the glutamate-induced release of lactate dehydrogenase by a PPARγ-dependent mechanism. This protective effect was reversed after co-treatment with PI3K and Akt inhibitors, LY294002 and SH-6, respectively. Pioglitazone enhanced the expression of the antioxidative transcription factor Nrf2 and its target gene protein, heme oxidase-1, in the peri-infarct area. Pioglitazone also increased activation of the antioxidant response element (ARE) in neuronal PC12 cells transfected with the pNQO1-rARE plasmid. We demonstrate in primary cortical neurons from Nrf2 knockout mice that the lack of Nrf2 completely abolished the neuroprotective effects of pioglitazone against oxidative and excitotoxic damage. Our results strongly suggest that the neuroprotective effects of PPARγ in peri-infarct brain tissues comprise the concomitant activation of the PI3K/Akt and Nrf2/ARE pathways. KEY MESSAGES: Pioglitazone inhibits apoptosis in ischemic brain tissue. . Pioglitazone acting on PPARγ activates PI3K/Akt pathway in ischemic brain tissue. Pioglitazone activates via Nrf2 the antioxidant defense pathway in injured neurons. Pioglitazone activates the antioxidant response element in neuronal PC12 cells. Pioglitazone fails to protect primary neurons lacking Nrf2 against oxidative damage. Activation of PPARγ supports the survival of viable neurons in peri-infarct regions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00109-021-02065-3.
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spelling pubmed-83134712021-08-16 Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways Zhao, Yi Lützen, Ulf Gohlke, Peter Jiang, Ping Herdegen, Thomas Culman, Juraj J Mol Med (Berl) Original Article ABSTRACT: The present study elucidates the neuroprotective mechanisms of the PPARγ (peroxisome proliferator-activated receptor γ) agonist pioglitazone in survival of ischemic neurons following middle cerebral artery occlusion with reperfusion (MCAO). Intracerebroventricular infusion of pioglitazone over 5 days before and 24 or 48 h after MCAO alleviated neurological impairments, inhibited apoptosis 24 h, and activated the PI3K/Akt pathway along with increased phosphorylation of Akt (ser473) and GSK-3β (ser9) in the peri-infarct cortical areas 48 h after MCAO. In primary cortical neurons, pioglitazone suppressed the glutamate-induced release of lactate dehydrogenase by a PPARγ-dependent mechanism. This protective effect was reversed after co-treatment with PI3K and Akt inhibitors, LY294002 and SH-6, respectively. Pioglitazone enhanced the expression of the antioxidative transcription factor Nrf2 and its target gene protein, heme oxidase-1, in the peri-infarct area. Pioglitazone also increased activation of the antioxidant response element (ARE) in neuronal PC12 cells transfected with the pNQO1-rARE plasmid. We demonstrate in primary cortical neurons from Nrf2 knockout mice that the lack of Nrf2 completely abolished the neuroprotective effects of pioglitazone against oxidative and excitotoxic damage. Our results strongly suggest that the neuroprotective effects of PPARγ in peri-infarct brain tissues comprise the concomitant activation of the PI3K/Akt and Nrf2/ARE pathways. KEY MESSAGES: Pioglitazone inhibits apoptosis in ischemic brain tissue. . Pioglitazone acting on PPARγ activates PI3K/Akt pathway in ischemic brain tissue. Pioglitazone activates via Nrf2 the antioxidant defense pathway in injured neurons. Pioglitazone activates the antioxidant response element in neuronal PC12 cells. Pioglitazone fails to protect primary neurons lacking Nrf2 against oxidative damage. Activation of PPARγ supports the survival of viable neurons in peri-infarct regions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00109-021-02065-3. Springer Berlin Heidelberg 2021-04-16 2021 /pmc/articles/PMC8313471/ /pubmed/33864097 http://dx.doi.org/10.1007/s00109-021-02065-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Zhao, Yi
Lützen, Ulf
Gohlke, Peter
Jiang, Ping
Herdegen, Thomas
Culman, Juraj
Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways
title Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways
title_full Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways
title_fullStr Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways
title_full_unstemmed Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways
title_short Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways
title_sort neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by pi3k/akt and nrf2/are pathways
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313471/
https://www.ncbi.nlm.nih.gov/pubmed/33864097
http://dx.doi.org/10.1007/s00109-021-02065-3
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