1. Academic Validation
  2. 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

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

  • Cell Death Discov. 2022 Jun 16;8(1):290. doi: 10.1038/s41420-022-01068-4.
Zhiguo Wu 1 Jian Tan 2 Lichang Lin 3 Wenting Zhang 2 Wanqiu Yuan 2
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Pingxiang People's Hospital of Southern Medical University, Pingxiang, 337055, PR China. 13707993072@gmu.edu.cn.
  • 2 Department of Anesthesiology, Pingxiang People's Hospital of Southern Medical University, Pingxiang, 337055, PR China.
  • 3 Department of Vascular Interventional Surgery, Pingxiang People's Hospital of Southern Medical University, Pingxiang, 337055, PR China.
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.

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