S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2
Abstract Depression, a pervasive mental health condition, has increasingly been linked to neuroinflammation, as evidenced by elevated levels of pro‐inflammatory markers such as TNF‐α and IL‐1β observed in patients, which underscores the role of inflammation in its pathophysiology. This study investi...
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| Format: | Article |
| Language: | English |
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202416481 |
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| author | Cong Lin Xiaoxuan Zhou Mingqi Li Cong Zhang Haojiang Zhai Haohong Li Hongshuang Wang Xiaohui Wang |
| author_facet | Cong Lin Xiaoxuan Zhou Mingqi Li Cong Zhang Haojiang Zhai Haohong Li Hongshuang Wang Xiaohui Wang |
| author_sort | Cong Lin |
| collection | DOAJ |
| description | Abstract Depression, a pervasive mental health condition, has increasingly been linked to neuroinflammation, as evidenced by elevated levels of pro‐inflammatory markers such as TNF‐α and IL‐1β observed in patients, which underscores the role of inflammation in its pathophysiology. This study investigates the differential effects of S‐ketamine (S‐KET) and R‐ketamine (R‐KET) on inflammation‐induced depression using a lipopolysaccharide (LPS)‐induced mouse model. Results showed that S‐KET, but not R‐KET, significantly alleviated depressive‐like behaviors and reduced levels of pro‐inflammatory factors in the medial prefrontal cortex (mPFC). Activity‐based protein profiling identified SIRT2 as a key intracellular target of S‐KET, with direct binding observed at the Q167 residue, whereas R‐KET showed no such binding. S‐KET enhanced SIRT2 interaction with NF‐κB subunit p65, reducing its acetylation and suppressing pro‐inflammatory gene expression, effects not seen with R‐KET. In vitro studies with RNA interference and the SIRT2 inhibitor AK‐7, along with in vivo pharmacological blockade, confirmed that SIRT2 is crucial for the anti‐inflammatory and antidepressant actions of S‐KET. These findings suggest that SIRT2 mediates the therapeutic effects of S‐KET, highlighting its potential as a target for treating inflammation‐associated depression. This study provides novel insights into the stereospecific actions of ketamine enantiomers and the promise of targeting SIRT2 for neuroinflammatory depression. |
| format | Article |
| id | doaj-art-87e946a64cf142d5bf5e27ccca54766c |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-87e946a64cf142d5bf5e27ccca54766c2025-08-20T03:22:15ZengWileyAdvanced Science2198-38442025-06-011223n/an/a10.1002/advs.202416481S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2Cong Lin0Xiaoxuan Zhou1Mingqi Li2Cong Zhang3Haojiang Zhai4Haohong Li5Hongshuang Wang6Xiaohui Wang7Laboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaThe MOE Frontier Research Center of Brain and Brain‐Machine Integration Zhejiang University School of Brain Science and Brain Medicine Hangzhou Zhejiang 310058 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaAbstract Depression, a pervasive mental health condition, has increasingly been linked to neuroinflammation, as evidenced by elevated levels of pro‐inflammatory markers such as TNF‐α and IL‐1β observed in patients, which underscores the role of inflammation in its pathophysiology. This study investigates the differential effects of S‐ketamine (S‐KET) and R‐ketamine (R‐KET) on inflammation‐induced depression using a lipopolysaccharide (LPS)‐induced mouse model. Results showed that S‐KET, but not R‐KET, significantly alleviated depressive‐like behaviors and reduced levels of pro‐inflammatory factors in the medial prefrontal cortex (mPFC). Activity‐based protein profiling identified SIRT2 as a key intracellular target of S‐KET, with direct binding observed at the Q167 residue, whereas R‐KET showed no such binding. S‐KET enhanced SIRT2 interaction with NF‐κB subunit p65, reducing its acetylation and suppressing pro‐inflammatory gene expression, effects not seen with R‐KET. In vitro studies with RNA interference and the SIRT2 inhibitor AK‐7, along with in vivo pharmacological blockade, confirmed that SIRT2 is crucial for the anti‐inflammatory and antidepressant actions of S‐KET. These findings suggest that SIRT2 mediates the therapeutic effects of S‐KET, highlighting its potential as a target for treating inflammation‐associated depression. This study provides novel insights into the stereospecific actions of ketamine enantiomers and the promise of targeting SIRT2 for neuroinflammatory depression.https://doi.org/10.1002/advs.202416481DepressionNeuroinflammationR‐ketamineSIRT2S‐ketamine |
| spellingShingle | Cong Lin Xiaoxuan Zhou Mingqi Li Cong Zhang Haojiang Zhai Haohong Li Hongshuang Wang Xiaohui Wang S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2 Advanced Science Depression Neuroinflammation R‐ketamine SIRT2 S‐ketamine |
| title | S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2 |
| title_full | S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2 |
| title_fullStr | S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2 |
| title_full_unstemmed | S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2 |
| title_short | S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2 |
| title_sort | s ketamine alleviates neuroinflammation and attenuates lipopolysaccharide induced depression via targeting sirt2 |
| topic | Depression Neuroinflammation R‐ketamine SIRT2 S‐ketamine |
| url | https://doi.org/10.1002/advs.202416481 |
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