microRNA-140-3p protects hippocampal neuron against pyroptosis to attenuate sevoflurane inhalation-induced post-operative cognitive dysfunction in rats via activation of HTR2A/ERK/Nrf2 axis by targeting DNMT1

Abstract

The incidence of post-operative cognitive dysfunction (POCD) remains a relatively prevalent complication in the elderly after surgery, especially in those receiving sevoflurane (Sevo) anesthesia. microRNA (miR)−140-3p has been demonstrated to orchestrate neuroinflammation and neuron apoptosis. However, the role of miR-140-3p in POCD remains largely unknown. In this context, this research was designed to explore whether miR-140-3p mediated Sevo inhalation-induced POCD in rats. A POCD rat model was established by Sevo inhalation, and a Sevo cell model was constructed in primary hippocampal neurons isolated from rats, followed by detection of miR-140-30 and HTR2A expression. Then, gain- and loss-of-function assays were implemented in rats and neurons. In rats, the cognitive function was evaluated by Water maze test and step-through test, and neuron apoptosis by TUNEL staining. In neurons, cell viability, apoptosis, and pyroptosis-related factors were tested by MTT, flow cytometry, and Western blot analysis respectively. Interaction between HTR2A and DNMT1 was assessed by MSP, and ChIP assay, and interaction between miR-140-3p and DNMT1 by dual-luciferase reporter assay, RIP and RNA pull-down. HTR2A and miR-140-3p were downregulated in POCD rats and Sevo-treated hippocampal neurons. Mechanistically, miR-140-3p negatively targeted DNMT1 to decrease HTR2A promoter methylation, thus upregulation HTR2A to activate ERK/Nrf2 pathway. miR-140-3p or HTR2A overexpression or activation of ERK/Nrf2 pathway elevated neuron viability and diminished their apoptosis and pyroptosis while alleviating Sevo-induced POCD in rats. Collectively, miR-140-3p might repress neuron pyroptosis to alleviate Sevo inhalation-induced POCD in rats via DNMT1/HTR2A/ERK/Nrf2 axis.