Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
Abstract 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 occurren...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02849-z |
| _version_ | 1797769342163615744 |
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| author | Changliang Liu Jiahui Wu Ming Li Rui Gao Xueying Zhang Shixin Ye-Lehmann Jiangning Song Tao Zhu Chan Chen |
| author_facet | Changliang Liu Jiahui Wu Ming Li Rui Gao Xueying Zhang Shixin Ye-Lehmann Jiangning Song Tao Zhu Chan Chen |
| author_sort | Changliang Liu |
| collection | DOAJ |
| description | Abstract 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 Smad7fl/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. |
| first_indexed | 2024-03-12T21:07:38Z |
| format | Article |
| id | doaj.art-04065c7e759c42439480489af114dcf5 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-12T21:07:38Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-04065c7e759c42439480489af114dcf52023-07-30T11:21:06ZengBMCJournal of Neuroinflammation1742-20942023-07-0120111810.1186/s12974-023-02849-zSmad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgeryChangliang Liu0Jiahui Wu1Ming Li2Rui Gao3Xueying Zhang4Shixin Ye-Lehmann5Jiangning Song6Tao Zhu7Chan Chen8Department of Anesthesiology, West China Hospital, Sichuan UniversityDepartment of Anesthesiology, West China Hospital, Sichuan UniversityDepartment of Anesthesiology, West China Hospital, Sichuan UniversityDepartment of Anesthesiology, West China Hospital, Sichuan UniversityDepartment of Anesthesiology, West China Hospital, Sichuan UniversityDiseases and Hormones of the Nervous System, University of Paris-Scalay Bicêtre Hosptial Bât. Grégory PincusMonash Biomedicine Discovery Institute and Monash Data Futures Institute, Monash UniversityDepartment of Anesthesiology, West China Hospital, Sichuan UniversityDepartment of Anesthesiology, West China Hospital, Sichuan UniversityAbstract 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 Smad7fl/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.https://doi.org/10.1186/s12974-023-02849-zPostoperative cognitive dysfunctionSmad7TGF-βInflammationApoptosis |
| spellingShingle | Changliang Liu Jiahui Wu Ming Li Rui Gao Xueying Zhang Shixin Ye-Lehmann Jiangning Song Tao Zhu Chan Chen Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery Journal of Neuroinflammation Postoperative cognitive dysfunction Smad7 TGF-β Inflammation Apoptosis |
| 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 | Postoperative cognitive dysfunction Smad7 TGF-β Inflammation Apoptosis |
| url | https://doi.org/10.1186/s12974-023-02849-z |
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