S-ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide-Induced Depression Via Targeting SIRT2.
Cong Lin, Xiaoxuan Zhou, Mingqi Li, Cong Zhang, Haojiang Zhai, Haohong Li, Hongshuang Wang, Xiaohui Wang
Advanced Science April 2, 2025 DOI: 10.1002/advs.202416481 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study with in vitro and in vivo experiments Peer reviewed |
|---|---|
| Population | Lipopolysaccharide (LPS)-induced mouse model |
| Interventions | S-ketamine R-ketamine |
| Topics | Depression Esketamine Ketamine |
| Keywords | R‐ketamine S‐ketamine Depression/mental health/mood disorders Ketamine/s-ketamine/esketamine/r-ketamine Neuroinflammation/brain inflammation/neuroimmunology Molecular biology/sirt2/protein sign |
| Citations | 14 |
| Key findings | S-ketamine, but not R-ketamine, alleviated depressive-like behaviors and reduced neuroinflammation in mice by binding to SIRT2 and suppressing pro-inflammatory gene expression. |
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.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.
Citations in the library
Cited by 3
- Ketamine's Role in Neuroinflammation and Neuroprotection Across Neurological and Psychiatric Disorders: A Narrative Review. Pharmaceuticals August 29, 2025
- Effects of sub-anesthetic doses of esketamine on immune function and postoperative negative emotions in acoustic neuroma patients: a randomized clinical trial. Annals of medicine July 3, 2026
- Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice. Molecular Psychiatry November 18, 2025
Cites 8
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- Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. The Lancet Psychiatry November 1, 2022
- The Antidepressant Actions of Ketamine and its Enantiomers Pharmacology & Therapeutics May 1, 2023
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and 3 more in the library