S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2

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.