ACS Chem Neurosci.2021 Jul 7;12(13):2399-2408.doi: 10.1021/acschemneuro.1c00131.Epub 2021 Jun 13.

Participation of Mind Bomb-2 in Sevoflurane Anesthesia Induces Cognitive Impairment in Aged Mice via Modulating Ferroptosis

Lili Zhao  1 Haixia Gong  1 Haijin Huang  1 Gulisitan Tuerhong  1 Haimei Xia  1 Affiliations

Abstract

Postoperative cognitive dysfunction (POCD) is a complication of the central nervous system (CNS) often occurred after surgery or anesthesia in the elder patients. Mind bomb-2 (MIB2) has been reported to modulate neuronal functions. Here, we aimed to study whether MIB2 exerts roles in the effects of sevoflurane anesthesia on mice hippocampal neurons and function, and how. Aging male C57BL/6 mice were subjected to sevoflurane administration, and primary hippocampal neurons were adopted to study sevoflurane effects in vitro. Western blotting and immunohistochemistry assay were used to study the protein expression of MIB2. CCK-8 assay and propidium iodide (PI) staining were performed to evaluate cell viability and cell death, respectively. Ferroptosis-related indicators malondialdehyde (MDA), glutathione (GSH), and iron levels were checked through indicated ELISA kits. Co-immunoprecipitation was adopted to study the binding effects of MIB2 to GPX4. We found that sevoflurane anesthesia increased MIB2 expression in mice hippocampus tissues and neurons. Knockdown of MIB2 alleviated neuron death and ferroptosis induced by sevoflurane exposure. Downregulated MIB2 enhanced GPX4 stability and reduced its ubiquitination. MIB2 was verified to bind to GPX4. The effects of MIB2 knockdown on the neuron death and ferroptosis can be reversed by further siGPX4 transfection. In vivo results also showed that MIB2 knockdown reduced hippocampal neuron death, ferroptosis, and cognitive impairments in the sevoflurane-exposed mice. Taking all together, downregulation of MIB2 could alleviate the sevoflurane-anesthesia-induced cognitive dysfunction and neuron injury through reducing ferroptosis via GPX4. Our results also provide novel directions for POCD treatment using anti-MIB2-related drugs or strategies.

Keywords: MIB2; POCD; anesthesia; ferroptosis; neuron; sevoflurane.

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