Sevoflurane Inhibits Traumatic Brain Injury-Induced Neuron Apoptosis via EZH2-Downregulated KLF4/p38 Axis

Abstract

Traumatic brain injury (TBI) is characterized by physical damage to the brain tissues, ensuing transitory or permanent neurological dysfunction featured with neuronal loss and subsequent brain damage. Sevoflurane, a widely used halogenated anesthetic in clinical settings, has been reported to alleviate neuron apoptosis in TBI. Nevertheless, the underlying mechanism behind this alleviation remains unknown, and thus was the focus of the current study. First, Feeney models were established to induce TBI in rats. Subsequently, evaluation of the modified neurological severity scores, measurement of brain water content, Nissl staining, and TUNEL assay were employed to investigate the neuroprotective effects of sevoflurane. Immunofluorescence and Western blot analysis were further applied to detect the expression patterns of apoptosis-related proteins as well as the activation of the p38-mitogen-activated protein kinase (MAPK) signaling pathway within the lesioned cortex. Additionally, a stretch injury model comprising cultured neurons was established, followed by neuron-specific enolase staining and Sholl analysis. Mechanistic analyses were performed using dual-luciferase reporter gene and chromatin immunoprecipitation assays. The results demonstrated sevoflurane treatment brought about a decrease blood-brain barrier (BBB) permeability, brain water content, brain injury and neuron apoptosis, to improve neurological function. The neuroprotective action of sevoflurane could be attenuated by inactivation of the p38-MAPK signaling pathway. Mechanistically, sevoflurane exerted an inhibitory effect on neuron apoptosis by up-regulating enhancer of zeste homolog 2 (EZH2), which targeted Krüppel-like factor 4 (KLF4) and inhibited KLF4 transcription. Collectively, our findings indicate that sevoflurane suppresses neuron apoptosis induced by TBI through activation of the p38-MAPK signaling pathway via the EZH2/KLF4 axis, providing a novel mechanistic explanation for neuroprotection of sevoflurane in TBI.

Knockdown of UAF1 alleviates sevoflurane-induced cognitive impairment and neurotoxicity in rats by inhibiting pro-inflammatory signaling and oxidative stress

“…In addition, anesthetics have been reported to trigger apoptosis (Shi et al, 2020;Wang et al, 2021). In agreement with this, we found that the number of apoptotic cells in the hippocampal tissues was significantly increased after SEV treatment and this was rescued by UAF1 downregulation.…”

Comparisons of quantitative approaches for assessing microglial morphology reveal inconsistencies, ecological fallacy, and a need for standardization

“…Our study should provide researchers with the necessary information to make study design and analytical decisions that result in more appropriate characterization of microglial morphology. We also note that the findings of our study might be applicable to other areas of neuroscience, because the morphology of neurons 15 , 32 – 34 and astrocytes 12 , 35 are commonly assessed using the same or similar immunohistochemistry techniques and metrics. Quantitative methods to describe microglial morphology should be selected based on several criteria including the research question, immunohistochemical experience of the researchers, and time required to isolate individual cells versus analyze full photomicrographs.…”

Sevoflurane Preconditioning Alleviates Posttraumatic Stress Disorder—Induced Apoptosis in the Hippocampus via the EZH2-Regulated Akt/mTOR Axis and Improves Synaptic Plasticity

“…The primary aim was to investigate the potential benefits of sevoflurane intervention on PTSD and to determine its underlying mechanisms. In addition, previous studies have confirmed that sevoflurane has no significant effects on control samples (Wang et al 2021). Pretreatment with sevoflurane has been shown to effectively reduce the incidence of PTSD.…”