Abstract
Sevoflurane (SEVO) is a highly fluorinated methyl isopropyl ether used as an inhalational anesthetic for general anesthesia. Previous studies have shown that SEVO may induce impaired memory and recognition ability and may be associated with neurodegenerative disease, e.g., Alzheimer’s disease (AD). However, the underlying mechanism remains unknown. Here, we used a mouse AD model, APP/PS1, to study the effects of SEVO on neurodegeneration occurring in AD. We found that SEVO exposure significantly impaired the spatial reference memory, sensorimotor, and cognitive function of the mice. Mechanistically, we found that SEVO induced formation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and its downstream caspase 1-mediated production of IL-1β and IL-18, which subsequently deactivated brain-derived neurotrophic factor (BDNF) to promote neurodegeneration. Together, these data suggest that NLRP3 inflammasome is essential for SEVO-induced AD.
Highlights
Isoflurane and sevoflurane (SEVO) are the most widely used inhaled anesthetics, given their rapid induction and prompt recovery coupled with stimulation
The detrimental effects of SEVO on neuronal cell integrity have been proposed in some previous studies
Wild-type mice are not used in the current study since they are not susceptible to SEVO compared to APP/PS1 mice, a widely used mouse model generated for studying neurodegeneration in Alzheimer’s disease (AD) (Jankowsky et al, 2004)
Summary
Isoflurane and sevoflurane (SEVO) are the most widely used inhaled anesthetics, given their rapid induction and prompt recovery coupled with stimulation. These commonly used volatile anesthetics have been recently shown to exert neurotoxic effects, like brain injury (Zhang et al, 2015; Wang et al, 2018) and behavioral impairments (Zhao et al, 2018). SEVO exposure in 7-day-old rats was found to impair neurogenesis, induce neurodegeneration, and affect neurocognitive function (Fang et al, 2012). SEVO was shown to activate gamma-aminobutyric acid (GABA) to induce overexcitability of GABA receptors and subsequent inflow of extracellular calcium ions, which caused neurotoxicity and longterm cognitive impairment (Morris et al, 1982; Burgess et al, 2002; Fang et al, 2012). To date, the exact molecular mechanisms that underlie the neurotoxic effects of SEVO are still elusive, which prevents effective interference to prevent neurotoxicity
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