Cargando…

Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication following anesthesia and surgery. Increasing evidence has demonstrated that neuroinflammation caused by systemic inflammatory responses during the perioperative period is a key factor in the occurrence of PO...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Changliang, Wu, Jiahui, Li, Ming, Gao, Rui, Zhang, Xueying, Ye-Lehmann, Shixin, Song, Jiangning, Zhu, Tao, Chen, Chan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375636/
https://www.ncbi.nlm.nih.gov/pubmed/37507781
http://dx.doi.org/10.1186/s12974-023-02849-z
_version_ 1785079076718903296
author Liu, Changliang
Wu, Jiahui
Li, Ming
Gao, Rui
Zhang, Xueying
Ye-Lehmann, Shixin
Song, Jiangning
Zhu, Tao
Chen, Chan
author_facet Liu, Changliang
Wu, Jiahui
Li, Ming
Gao, Rui
Zhang, Xueying
Ye-Lehmann, Shixin
Song, Jiangning
Zhu, Tao
Chen, Chan
author_sort Liu, Changliang
collection PubMed
description BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication following anesthesia and surgery. Increasing evidence has demonstrated that neuroinflammation caused by systemic inflammatory responses during the perioperative period is a key factor in the occurrence of POCD. In addition, SMAD family member 7 (Smad7) has been confirmed to play vital roles in the pathogenesis and treatment of inflammatory diseases, such as inflammatory bowel disease. However, whether Smad7 participates in the regulatory process of neuroinflammation and apoptosis in the development of POCD is still unknown. METHODS: In this study, a POCD mouse model was constructed by unilateral nephrectomy under anesthesia, and cognitive function was assessed using the fear conditioning test and open field test. The expression of Smad7 at the mRNA and protein levels in the hippocampus 3 days after surgery was examined by qRT-PCR, western blot and immunofluorescence assays. Furthermore, to identify whether the elevation of Smad7 in the hippocampus after unilateral nephrectomy contributes to cognitive impairment, the expression of Smad7 in the hippocampal CA1 region was downregulated by crossing Smad7(fl/fl) conditional mutant mice and CaMKIIα-Cre line T29-1 transgenic mice or stereotaxic injection of shRNA–Smad7. Inflammation and apoptosis in the hippocampus were assessed by measuring the mRNA levels of typical inflammatory cytokines, including TNF-α, IL-1β, IL-6, CCL2, CXCL1, and CXCL2, and the protein levels of apoptotic proteins, including Bax and Bcl2. In addition, apoptosis in the hippocampus postoperation was investigated by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining assay. Finally, western blotting was used to explore how Smad7 mediates inflammation and apoptosis postoperation. RESULTS: The results unequivocally revealed that elevated Smad7 in the hippocampal CA1 region significantly inhibited TGF-β signal transduction by blocking Smad2/3 phosphorylation, which enhanced neuroinflammation and apoptosis in the hippocampus and further led to learning and memory impairment after surgery. CONCLUSIONS: Our results revealed that Smad7 contributes to cognitive impairment after surgery by enhancing neuroinflammation and apoptosis in the hippocampus and might serve as a promising therapeutic target for the treatment of memory impairment after anesthesia surgery. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02849-z.
format Online
Article
Text
id pubmed-10375636
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-103756362023-07-29 Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery Liu, Changliang Wu, Jiahui Li, Ming Gao, Rui Zhang, Xueying Ye-Lehmann, Shixin Song, Jiangning Zhu, Tao Chen, Chan J Neuroinflammation Research BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication following anesthesia and surgery. Increasing evidence has demonstrated that neuroinflammation caused by systemic inflammatory responses during the perioperative period is a key factor in the occurrence of POCD. In addition, SMAD family member 7 (Smad7) has been confirmed to play vital roles in the pathogenesis and treatment of inflammatory diseases, such as inflammatory bowel disease. However, whether Smad7 participates in the regulatory process of neuroinflammation and apoptosis in the development of POCD is still unknown. METHODS: In this study, a POCD mouse model was constructed by unilateral nephrectomy under anesthesia, and cognitive function was assessed using the fear conditioning test and open field test. The expression of Smad7 at the mRNA and protein levels in the hippocampus 3 days after surgery was examined by qRT-PCR, western blot and immunofluorescence assays. Furthermore, to identify whether the elevation of Smad7 in the hippocampus after unilateral nephrectomy contributes to cognitive impairment, the expression of Smad7 in the hippocampal CA1 region was downregulated by crossing Smad7(fl/fl) conditional mutant mice and CaMKIIα-Cre line T29-1 transgenic mice or stereotaxic injection of shRNA–Smad7. Inflammation and apoptosis in the hippocampus were assessed by measuring the mRNA levels of typical inflammatory cytokines, including TNF-α, IL-1β, IL-6, CCL2, CXCL1, and CXCL2, and the protein levels of apoptotic proteins, including Bax and Bcl2. In addition, apoptosis in the hippocampus postoperation was investigated by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining assay. Finally, western blotting was used to explore how Smad7 mediates inflammation and apoptosis postoperation. RESULTS: The results unequivocally revealed that elevated Smad7 in the hippocampal CA1 region significantly inhibited TGF-β signal transduction by blocking Smad2/3 phosphorylation, which enhanced neuroinflammation and apoptosis in the hippocampus and further led to learning and memory impairment after surgery. CONCLUSIONS: Our results revealed that Smad7 contributes to cognitive impairment after surgery by enhancing neuroinflammation and apoptosis in the hippocampus and might serve as a promising therapeutic target for the treatment of memory impairment after anesthesia surgery. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02849-z. BioMed Central 2023-07-28 /pmc/articles/PMC10375636/ /pubmed/37507781 http://dx.doi.org/10.1186/s12974-023-02849-z Text en © The Author(s) 2023 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Liu, Changliang
Wu, Jiahui
Li, Ming
Gao, Rui
Zhang, Xueying
Ye-Lehmann, Shixin
Song, Jiangning
Zhu, Tao
Chen, Chan
Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
title Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
title_full Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
title_fullStr Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
title_full_unstemmed Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
title_short Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
title_sort smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375636/
https://www.ncbi.nlm.nih.gov/pubmed/37507781
http://dx.doi.org/10.1186/s12974-023-02849-z
work_keys_str_mv AT liuchangliang smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT wujiahui smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT liming smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT gaorui smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT zhangxueying smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT yelehmannshixin smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT songjiangning smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT zhutao smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery
AT chenchan smad7inthehippocampuscontributestomemoryimpairmentinagedmiceafteranesthesiaandsurgery