S-propargyl-L-cysteine attenuates ketamine induced schizophrenia-like behaviors and neuroinflammation in mice via inhibition of NF-κB/NLRP3 inflammasome-mediated pyroptosis.
Hanxuan Wang, Yu Huang, Qingwen Hu, Fuyuan Zhang, Zhuoyang Wang, Junjia Zeng, Chen Lu, Zhouyang Tian, Chi Kuan Lio, Sin Ieng Vong, Aoran Fang, Zhuoyu Li, Jiayu Zheng, Shi Zhong, Iok Ian Kong, Yi Zhun Zhu, Na Zhou
International Immunopharmacology September 22, 2026 DOI: 10.1016/j.intimp.2026.117446 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice with ketamine-induced schizophrenia-like symptoms |
| Interventions | S-propargyl-L-cysteine (SPRC) ketamine |
| Measures | open-field test, Y-maze test, prepulse inhibition analysis, Nissl staining |
| Topics | Esketamine Ketamine |
| Keywords | Nlrp3 inflammasome Neuroinflammation Phytotherapy Pyroptosis S-propargyl-l-cysteine Schizophrenia |
| Key points | SPRC reversed ketamine-induced hyperactivity and anxiety, improved working memory and sensorimotor gating, and prevented hippocampal neuronal loss in mice. The authors attribute these effects to restoration of the CSE/H2S pathway, maintenance of mBDNF, suppression of NF-κB translocation, and inhibition of NLRP3 inflammasome-mediated pyroptosis. |
Abstract
Schizophrenia (SCZ) is a serious neuropsychiatric disorder with a complex etiology. Neuroinflammation has received much attention as a crucial contributor to the pathogenesis of SCZ. S-propargyl-L-cysteine (SPRC), a synthesized analog of S-allyl-L-cysteine, increases endogenous hydrogen sulfide (H2S) synthesis and exerts potent antioxidative and anti-inflammatory effects. However, its potential role in SCZ-related neuroinflammation remains unclear. The aim of the present study was to investigate whether SPRC protects against ketamine-induced schizophrenia-like symptoms and to explore underlying mechanisms related to cystathionine-γ-lyase (CSE)/H2S signaling and nuclear factor-κB (NF-κB) activation. Behavioral alterations were assessed using the open-field test, Y-maze test, and prepulse inhibition analysis. Neuronal damage in the hippocampus was evaluated using Nissl staining, while changes in the CSE/H2S pathway, mature brain-derived neurotrophic factor (mBDNF), inflammatory pathways, and pyroptosis pathway were also analyzed. SPRC was found to effectively reverse ketamine-induced hyperactivity and anxiety, as well as improve working memory and sensorimotor gating defects. Furthermore, SPRC prevented neuronal loss across the hippocampal CA1, CA3, and dentate gyrus subregions. The mechanism of action involves the reversal of CSE activity and H2S production, maintenance of mBDNF, as well as the suppression of NF-κB translocation. This is also characterized by reduction in tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. Additionally, SPRC inhibited nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation, caspase-1-mediated pyroptosis, and interleukin-1β (IL-1β) secretion. Taken together, these findings demonstrate that SPRC alleviates ketamine-induced behavioral deficits and neuroinflammation in mice, likely via restoration of the CSE/ H2S pathway and suppression of NF-κB/NLRP3-mediated pyroptosis.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |