S-Propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: Involvement of TNF signaling and NF-κB pathway in rats

Neuroinflammation exacerbates hyperphosphorylated tau and amyloid-β (Aβ) generation by generating a plethora of inflammatory mediators and neurotoxic compounds in a transgenic model of Alzheimer’s disease (AD), and it was reported that hydrogen sulfide (H2S) attenuates lipopolysaccharide (LPS)-induced neuroinflammation both in vitro and in vivo. In the present study, the protective effects of S-propargyl-cysteine (SPRC) on spatial learning and memory impairment induced by LPS were examined in vivo, and the possible mechanisms were explored. The data showed that SPRC administration by intraperitoneal (i.p.) injection may attenuate cognitive impairment induced by bilateral intracerebroventricular (b.i.c.v.) injection of 5 μg of LPS in rats. Subsequently, SPRC prevented a decrease of H2S levels in rat hippocampus subjected to LPS. Furthermore, SPRC afforded beneficial actions in inhibitions tumor necrosis factor (TNF)-α, TNF-α receptor 1 (TNFR1) and Aβ generation, as well as IκB-α degradation and phospho-transcription factors of the nuclear factor κB p65 (p-NF-κB p65) activation induced by LPS. These findings suggested that SPRC, a novel H2S-modulated agent, might be a potential agent for the treatment of neuroinflammation-related diseases, such as AD.

Research highlights
► Hydrogen sulfide (H2S), recently hypothesized as the third ‘gasotransmitter’ alongside nitric oxide and carbon monoxide, has been attracting extensive attention because of its multiple physiological and pathophysiological roles in various body systems.
► Levels of H2S are decreased in AD patients, and H2S alteration in level may be associated with the severity of AD.
► The present study evaluated the activity of SPRC, a novel H2S-moduated agent, to inhibit LPS-induced cognitive impairment and neuronal ultrastructure damage in rats for the first time.
► After that, we also investigated the mechanism of SPRC inhibitions of TNF-α, TNFR1 and AβPP generations, and the related degradation of IκB-α and thereafter activation of NF-κB.
► These findings suggested that SPRC might be a potential agent for treatment of neuroinflammation-related diseases, such as AD.