S-propargyl-L-cysteine attenuates ketamine induced schizophrenia-like behaviors and neuroinflammation in mice via inhibition of NF-κB/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.