Effect of Remimazolam on Cognitive Impairment in Offspring Models Resulting from Late Gestational Sevoflurane Exposure: Involvement of the HIF-1α/HO-1 Signaling Pathway

This study aims to investigate the effects of Rem (remazolam) on cognitive dysfunction in offspring models exposed to sevoflurane during late pregnancy, and to analyse its potential mechanisms of action. Using a random number table, late-pregnancy rats were divided into the following groups: Con (control), simple Rem, Mod (model), Rem, and Rem+Erastin (ferroptosis inducer), with five rats per group. Following delivery, 15 offspring rats per group underwent water maze and novel object recognition tests; observation of hippocampal histopathological alterations and neuronal morphological changes via HE and Nissl staining; the kit detects ROS (reactive oxygen species), MDA (malondialdehyde), SOD (superoxide dismutase), and Fe²⁺ levels in hippocampal tissue; Prussian blue staining for iron deposition in hippocampal tissue; RT-qPCR for expression of ferroptosis-related genes GPX4 (glutathione peroxidase 4), FTH1 (ferritin heavy chain 1), and ACSL4 (long-chain acyl-CoA synthase 4) in hippocampal tissue; Western blot analysis was employed to detect expression of proteins associated with the HIF-1α (hypoxia-inducible factor-1α)/HO-1 (heme oxygenase-1) pathway in hippocampal tissue. The results showed that compared with the Con group and simple Rem group, the Mod group exhibited disorganised neuronal arrangement in the hippocampal region, with neurons showing signs of atrophy and necrosis, a reduction in Nissl bodies, and a significantly prolonged escape latency (P<0.05). ROS, MDA, Fe²⁺ levels, and ACSL4 mRNA expression were markedly elevated (P<0.05), with increased iron deposition. Platform crossing frequency and novel object recognition index were significantly reduced (P<0.05), while SOD content, GPX4 and FTH1 mRNA expression, and HIF-1α and HO-1 protein levels were markedly decreased (P<0.05). Compared with the Mod group, the Rem and Rem+Erastin groups exhibited varying degrees of recovery in hippocampal neurons, with increased Nissl body counts and significantly shortened escape latency (P<0.05). ROS, MDA, Fe²⁺ levels, and ACSL4 mRNA expression were markedly reduced (P<0.05). Iron deposition decreased to varying degrees, while platform crossing frequency and novel object recognition index significantly increased (P<0.05). SOD content, GPX4 and FTH1 mRNA expression, along with HIF-1α and HO-1 protein levels, were markedly elevated (P<0.05). Compared with Rem group, Rem+Erastin group reversed the above results (P<0.05). In summary, Rem may inhibit iron death by activating HIF-1α/HO-1 signaling pathway, alleviate inflammation and oxidative stress, and alleviate cognitive dysfunction of offspring rats caused by sevoflurane exposure in the third trimester.

CSTR: 32200.14.cjcb.2026.02.0012