Hydrogen Sulfide Alleviates Schizophrenia-Like Behavior Through Regulating Apoptosis by S-Sulfhydrylation Modification

Abstract

Background

We initiated an exploration of the relationship between hydrogen sulfide (H₂S) and Schizophrenia (SZ) as well as its mechanism at the three levels of population study, cellular investigation, and animal model.

Materials and Methods

Clinical data and peripheral blood samples from 78 patients with SZ and 83 healthy controls (HC) were collected for the detection of H₂S levels (ChiCTR (Chinese Clinical Trial Registry) 900026776). MK801 (Dizocilpine) was used to establish SZ models in cells and rats, with sodium hydrosulfide (NaHS) serving as an exogenous H₂S donor. H₂S levels in plasma and hippocampal tissue of rats were measured using Enzyme Linked Immunosorbent Assay (ELISA). Terminal dUTP Nick End Labeling (TUNEL) staining was employed to detect apoptosis, enzyme activity was determined to assess apoptotic protease activity, neuron damage was identified by Nissl staining, and the protein S-sulfhydrylation test was utilized to evaluate alterations in apoptosis-associated protein S-sulfhydrylation.

Results

H₂S content significantly decreased in the plasma of SZ patients and in the plasma and hippocampal tissue of SZ model rats. NaHS pretreatment reduced MK801-induced apoptosis in SH-SY5Y cells. SZ model rats exhibited increased behavioral abnormalities, hippocampal apoptosis, and reduced S-sulfhydrylation of an apoptosis-related protein, both restored after NaHS pretreatment.

Conclusions

H₂S content is significantly reduced in SZ, and supplementation of H₂S can alleviate SZ-like behavior by inducing S-sulfhydration of apoptotic proteins.