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 in vitro. 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.