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.
Highlights
The last few years have witnessed the recognition of traumatic brain injury (TBI) as a risk factor for development of chronic traumatic encephalopathy, dementia and various neurodegenerative disorders, accompanied by brain structural and functional alternations (LoBue et al, 2019)
Neurological functions were subsequently evaluated by Modified Neurological Severity Score (mNSS) 3 days later, and it was found there were no significant differences before and after operation in shamoperated rats, whereas Traumatic brain injury (TBI) rats presented with increased mNSS compared to sham-operated rats, yet mNSS decreased after the addition of sevoflurane (Figure 1A)
Additional Krüppel-like factor 4 (KLF4) knockdown in the presence of GSK126 gave an impetus to cell proliferation and caused the inhibition of cell apoptosis (Figures 4F,G). These results indicated that sevoflurane up-regulated enhancer of zeste homolog 2 (EZH2) to inhibit KLF4, by which neuron apoptosis was suppressed in TBI
Summary
The last few years have witnessed the recognition of traumatic brain injury (TBI) as a risk factor for development of chronic traumatic encephalopathy, dementia and various neurodegenerative disorders, accompanied by brain structural and functional alternations (LoBue et al, 2019). Sevoflurane postconditioning was reported to possess the ability to attenuate hypoxic-ischemic brain injury in neonatal rats by curbing excessive autophagy through up-regulation of enhancer of zeste homolog 2 (EZH2) (Xue et al, 2019). Major mitogen-activated protein kinases (MAPKs) such as p38, and extracellular signal-regulated kinase (ERK) are known to play an important role in the mediation of neuronal death or survival (Zhang et al, 2015). Delayed neuroprotection of sevoflurane was suggested to be partly dependent on p38-MAPK phosphorylation in rat models (Ye et al, 2012) In lieu of these findings, the current study set out to investigate the molecule mechanism underlying the neuroprotection of sevoflurane involving EZH2, KLF4, p38-MAPK signaling pathway both in vivo and in vitro
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