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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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-06-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202416481 |
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| Summary: | 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. |
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| ISSN: | 2198-3844 |