Attenuation of cerebral ischemia-reperfusion injury by exogenous hydrogen sulphide: involvement of the Nrf2/HO-1 pathway in NLRP3 inflammasome inhibition.

Abstract

Objectives: Cerebral ischemia-reperfusion injury (CIRI) presents a major therapeutic challenge in stroke management, where oxidative stress and neuroinflammation synergistically exacerbate neuronal damage. This study examined whether exogenous hydrogen sulphide (H₂S) protects against CIRI by simultaneously modulating the nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) antioxidant response and inhibiting nuclear factor kappa-B (NF-κB) and Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome engagement in mice.

Methods: Animal models were subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) in mice, and neurological deficits were subsequently assessed using a rating scale and 2,3,5-triphenyltetrazolium chloride (TTC) staining to evaluate MCAO/R damage. The expression level of reactive oxygen species (ROS) was detected using an assay kit. The levels of Nrf2/HO-1 pathway and NLRP3 inflammasome were examined by Western blot and immunohistochemical staining.

Key findings: The experimental data showed that exogenous administration of H₂S was effective in improving behavioral disorders and reducing infarct volume. Treatment with exogenous H₂S regulated the expression of the Nrf2/HO-1 signalling pathway, while H₂S effectively inhibited the expression of NF-κB and the formation of the NLRP3 inflammasome, as evidenced by reduced levels of phosphorylated NF-κB subunit p65 (p-p65), NLRP3, apoptosis-associated speck-like protein (ASC), and activated Caspase-1, and led to decreased maturation of the proinflammatory cytokines interleukin (IL)-1β and IL-18.

Conclusion: This study demonstrated that exogenous administration of H₂S exerted neuroprotective effects by regulating the Nrf2/HO-1 antioxidant pathway and inhibiting NLRP3 inflammasome activation.