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Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases
The role of astrocytes in major depressive disorder has received great attention. Increasing evidence indicates that decreased astrocyte numbers in the hippocampus may be associated with depression, but the role of necroptosis in depression is unknown. Here, in a chronic unpredictable mild stress (C...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847570/ https://www.ncbi.nlm.nih.gov/pubmed/36686688 http://dx.doi.org/10.3389/fphar.2022.1060954 |
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author | Zeb, Salman Ye, Huan Liu, Yuan Du, Hua-Ping Guo, Yi Zhu, Yong-Ming Ni, Yong Zhang, Hui-Ling Xu, Yuan |
author_facet | Zeb, Salman Ye, Huan Liu, Yuan Du, Hua-Ping Guo, Yi Zhu, Yong-Ming Ni, Yong Zhang, Hui-Ling Xu, Yuan |
author_sort | Zeb, Salman |
collection | PubMed |
description | The role of astrocytes in major depressive disorder has received great attention. Increasing evidence indicates that decreased astrocyte numbers in the hippocampus may be associated with depression, but the role of necroptosis in depression is unknown. Here, in a chronic unpredictable mild stress (CUMS) mouse model and a corticosterone (Cort)-induced human astrocyte injury model in vitro, we found that mice treated with chronic unpredictable mild stress for 3–5 weeks presented depressive-like behaviors and reduced body weight gain, accompanied by a reduction in astrocytes and a decrease in astrocytic brain-derived neurotropic factors (BDNF), by activation of necroptotic kinases, including RIPK1 (receptor-interacting protein kinase 1)/p-RIPK1, RIPK3 (receptor-interacting protein kinase 3)/p-RIPK3 and MLKL (mixed lineage kinase domain-like protein)/p-MLKL, and by upregulation of inflammatory cytokines in astrocytes of the mouse hippocampus. In contrast, necroptotic kinase inhibitors suppressed Cort-induced necroptotic kinase activation, reduced astrocytes, astrocytic necroptosis and dysfunction, and decreased Cort-mediated inflammatory cytokines in astrocytes. Treatment with fluoxetine (FLX) for 5 weeks improved chronic unpredictable mild stress-induced mouse depressive-like behaviors; simultaneously, fluoxetine inhibited depression-induced necroptotic kinase activation, reversed the reduction in astrocytes and astrocytic necroptosis and dysfunction, decreased inflammatory cytokines and upregulated brain-derived neurotropic factors and 5-HT1A levels. Furthermore, fluoxetine had no direct inhibitory effect on receptor-interacting protein kinase 1 phosphorylation. The combined administration of fluoxetine and necroptotic kinase inhibitors further reduced corticosterone-induced astrocyte injury. In conclusion, the reduction in astrocytes caused by depressive-like models in vivo and in vitro may be associated with the activation of necroptotic kinases and astrocytic necroptosis, and fluoxetine exerts an antidepressive effect by indirectly inhibiting receptor-interacting protein kinase 1-mediated astrocytic necroptosis. |
format | Online Article Text |
id | pubmed-9847570 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98475702023-01-19 Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases Zeb, Salman Ye, Huan Liu, Yuan Du, Hua-Ping Guo, Yi Zhu, Yong-Ming Ni, Yong Zhang, Hui-Ling Xu, Yuan Front Pharmacol Pharmacology The role of astrocytes in major depressive disorder has received great attention. Increasing evidence indicates that decreased astrocyte numbers in the hippocampus may be associated with depression, but the role of necroptosis in depression is unknown. Here, in a chronic unpredictable mild stress (CUMS) mouse model and a corticosterone (Cort)-induced human astrocyte injury model in vitro, we found that mice treated with chronic unpredictable mild stress for 3–5 weeks presented depressive-like behaviors and reduced body weight gain, accompanied by a reduction in astrocytes and a decrease in astrocytic brain-derived neurotropic factors (BDNF), by activation of necroptotic kinases, including RIPK1 (receptor-interacting protein kinase 1)/p-RIPK1, RIPK3 (receptor-interacting protein kinase 3)/p-RIPK3 and MLKL (mixed lineage kinase domain-like protein)/p-MLKL, and by upregulation of inflammatory cytokines in astrocytes of the mouse hippocampus. In contrast, necroptotic kinase inhibitors suppressed Cort-induced necroptotic kinase activation, reduced astrocytes, astrocytic necroptosis and dysfunction, and decreased Cort-mediated inflammatory cytokines in astrocytes. Treatment with fluoxetine (FLX) for 5 weeks improved chronic unpredictable mild stress-induced mouse depressive-like behaviors; simultaneously, fluoxetine inhibited depression-induced necroptotic kinase activation, reversed the reduction in astrocytes and astrocytic necroptosis and dysfunction, decreased inflammatory cytokines and upregulated brain-derived neurotropic factors and 5-HT1A levels. Furthermore, fluoxetine had no direct inhibitory effect on receptor-interacting protein kinase 1 phosphorylation. The combined administration of fluoxetine and necroptotic kinase inhibitors further reduced corticosterone-induced astrocyte injury. In conclusion, the reduction in astrocytes caused by depressive-like models in vivo and in vitro may be associated with the activation of necroptotic kinases and astrocytic necroptosis, and fluoxetine exerts an antidepressive effect by indirectly inhibiting receptor-interacting protein kinase 1-mediated astrocytic necroptosis. Frontiers Media S.A. 2023-01-04 /pmc/articles/PMC9847570/ /pubmed/36686688 http://dx.doi.org/10.3389/fphar.2022.1060954 Text en Copyright © 2023 Zeb, Ye, Liu, Du, Guo, Zhu, Ni, Zhang and Xu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Zeb, Salman Ye, Huan Liu, Yuan Du, Hua-Ping Guo, Yi Zhu, Yong-Ming Ni, Yong Zhang, Hui-Ling Xu, Yuan Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases |
title | Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases |
title_full | Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases |
title_fullStr | Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases |
title_full_unstemmed | Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases |
title_short | Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases |
title_sort | necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847570/ https://www.ncbi.nlm.nih.gov/pubmed/36686688 http://dx.doi.org/10.3389/fphar.2022.1060954 |
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