Hydrogen Sulfide Attenuates Lipopolysaccharide-Induced Inflammation via the P-glycoprotein and NF-κB Pathway in Astrocytes

Astrocyte activation is key in neurodegenerative diseases. Hydrogen sulfide (H₂S) exhibits neuroprotective effects on astrocytes, although the underlying molecular mechanism remains unclear. Here, we explored the effects of H₂S on lipopolysaccharide (LPS)-induced astrocyte activation and astrocyte-mediated neuroinflammation. After inducing primary astrocytes via LPS exposure, H₂S levels were altered. The generation and secretion of inflammatory mediators by astrocytes and their interrelation with P-glycoprotein (P-gp), an important transporter belonging to the ABC transporter family, were assessed. Activated astrocytes showed upregulated glial fibrillary acidic protein (GFAP) mRNA expression, and significantly increased proinflammatory factor mRNA/protein expression and release. The secretory capacity of astrocytes was reduced, with significantly decreased proinflammatory factor levels in culture supernatant after P-gp inhibitor verapamil pretreatment. The increase in the intracellular H₂S level inhibited LPS-induced GFAP expression and P65 nuclear entry in astrocytes. mRNA expression and release of proinflammatory factors were reduced significantly, with no significant changes in cytoplasmic protein expression. S-sulfhydration levels increased significantly with the increased concentration of sodium hydrosulfide or S-adenosyl-L-methionine addition, with only moderate changes in astrocyte P-gp expression. H₂S regulates NF-κB activation, leads to S-sulfhydration of P-gp, and inhibits the biosynthesis and secretion of proinflammatory factors by astrocytes. The regulatory effects of H₂S on astrocytes may have clinical value for exploring new therapeutic strategies against neurodegenerative diseases.

Astrocyte; Hydrogen sulfide; NF-κB; Neuroinflammation; P-glycoprotein.