Effects of remimazolam on postoperative cognitive dysfunction: Hippocampal HIF-1α and neural cell apoptosis

Remimazolam improves postoperative cognitive dysfunction (POCD), although its precise mechanisms remain unclear. Hippocampal hypoxia-inducible factor-1α (HIF-1α) and neural cell apoptosis are recognized to contribute to POCD pathogenesis. This study aimed to investigate whether remimazolam ameliorates cognitive impairment by targeting this specific pathway. Aged, male C57BL/6 J mice were subjected to left liver lobectomy to establish a model of POCD. Remimazolam (20 mg/kg) was administered intraperitoneally 30 min before surgery. To assess the causal involvement of HIF-1α, 5‑[1‑(phenylmethyl)‑1H‑indazol‑3‑yl]‑2‑furanmethanol (YC‑1), a selective HIF-1α inhibitor, was administered intraperitoneally at 2 mg/kg alone or in combination with remimazolam. Cognitive function was tested using the open field test and Morris water maze. Structural changes of hippocampal tissues were analyzed by hematoxylin and eosin staining. The expression of HIF-1α was measured at mRNA and protein levels using real-time PCR and Western blot, respectively. Neural cell apoptosis and its co-localization with HIF-1α were detected by double immunofluorescence staining. Our results demonstrated that remimazolam significantly improved surgery-induced cognitive deficits and alleviated hippocampal neuronal damage. At the molecular level, remimazolam downregulated hippocampal HIF-1α expression and markedly reduced neural cell apoptosis, with a significant decrease in HIF-1α/TUNEL double-positive cells. Notably, YC-1 treatment alone produced similar protective effects as remimazolam, and co-administration of YC-1 with remimazolam did not result in additive effects. Overall, these results suggest that remimazolam ameliorates POCD, which is associated with downregulation of hippocampal HIF-1α and inhibition of neural cell apoptosis.