Design and Synthesis of a Multifunctional Hydrogen Sulfide Donor and Its Application in Depressive-Like Behavior in Mice Induced by Lipopolysaccharide

Depression, characterized by a persistent low mood and apathy, is classified as a mental illness. Lipopolysaccharide (LPS), an inflammatory inducer, reduces plasma concentrations of hydrogen sulfide (H₂S) and gamma-aminobutyric acid (GABA) in mice, resulting in depressive-like behaviors. H₂S, an endogenous gaseous signaling molecule, is crucial for maintaining normal physiological functions of the central nervous system. GABA, an inhibitory neurotransmitter, has been demonstrated to mitigate depression-like behaviors in mice subjected to chronic stress. Sodium hydrosulfide (NaHS), an H₂S donor, alleviates LPS-induced depressive-like behaviors in mice; however, its rapid release of H₂S may lead to accumulation and potential toxicity. This study aimed to mimic the body's natural slow production of H₂S and GABA. To this end, three novel multifunctional donors─BGS, BGF, and BGA─were designed and synthesized. Among them, BGS showed reduced toxicity to HT-22 cells and a sustained release profile <i>in vitro</i>. Furthermore, BGS increased plasma levels of H₂S and GABA in mice, ameliorated LPS-induced depressive-like behaviors, enhanced neuronal count in the hippocampal CA1 subregion, decreased p-NF-κB levels, and upregulated the expression of synaptic proteins SYN and PSD-95. These results suggest that BGS not only elevates plasma H₂S and GABA levels but also inhibits NF-κB activation, enhances synaptic protein expression, and improves synaptic plasticity, thus exerting a multifaceted antidepressant effect.