H2S Alleviates Propofol-Induced Impaired Learning and Memory by Promoting Nuclear Translocation of Nrf2 and Inhibiting Apoptosis and Pyroptosis in Hippocampal Neurons.

Background: Repeated exposure to propofol can affect their learning and memory functions, but the mechanism remains unclear. The current study aimed to investigate the mechanism underlying the effect of hydrogen sulfide (H₂S) on the alleviation of propofol-induced learning and memory impairment, mediated by promoting nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibiting apoptosis and pyroptosis in hippocampal neurons.

Methods: Rats used in this study were successively exposed to 200 mg/kg propofol for 8 consecutive weeks, followed by inhalation of 10, 40 or 80 ppm H₂S. Subsequently, the effects of different concentrations of H₂S on learning and memory were assessed using the water maze assay. Additionally, the effects of H₂S on cell apoptosis and pyroptosis and nuclear translocation of Nrf2 in hippocampal neurons were also determined. Furthermore, NaHS (200 μmol/L) was used as an in vitro donor for H₂S, and rescue experiments were carried out following Nrf2 knockdown in H19-7 cells. Moreover, Nrf2 function was inhibited following treatment with an intraperitoneal injection of ML385 (30 mg/kg) in the rats. The effects of H₂S on reactive oxygen species (ROS) generation, cell apoptosis, and pyroptosis in propofol-treated and Nrf2-deficient H19-7 cells were also investigated.

Results: Exposure to propofol for 8 weeks affected the ability of the rats to find underwater platforms (p < 0.01). Further, the exposure induced cell apoptosis and NLR family pyrin domain containing 3 (NLRP3)-related pyroptosis (p < 0.01). Although inhalation of 10 ppm H₂S did not attenuate the aforementioned effects (p > 0.05), exposure to 40 and 80 ppm H₂S significantly alleviated propofol-induced injury in the hippocampal neurons (p < 0.01). However, the protective effect of 80 ppm H₂S was more obvious as compared to that of the other two doses (p < 0.01). In addition, Nrf2 knockdown aggravated the propofol-induced cell pyroptosis and apoptosis as well as reversed the protective effect of H₂S against these processes (p < 0.01). In vivo experiments in this study demonstrated that Nrf2 inhibition abrogated the protective effects of H₂S inhalation against learning and memory impairment as well as propofol-induced cell apoptosis and pyroptosis in rats (p < 0.01).

Conclusions: H₂S could attenuate propofol-induced damage in hippocampal neurons by promoting the nuclear translocation of Nrf2 and inhibiting cell apoptosis and pyroptosis.