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Sevoflurane Promotes Neurodegeneration Through Inflammasome Formation in APP/PS1 Mice
Guohua Li1, Yu Wang1, Fang Cao2
1Department of Anesthesiology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, China.
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.
Insights
Sevoflurane anesthesia impairs memory and cognitive function in an Alzheimer's disease mouse model. This effect is mediated by NLRP3 inflammasome activation, leading to neuroinflammation and reduced BDNF levels.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Sevoflurane (SEVO), an inhalational anesthetic, is linked to memory deficits and neurodegenerative diseases like Alzheimer's disease (AD).
- The precise mechanisms underlying SEVO-induced neurotoxicity remain largely unknown.
- Alzheimer's disease is characterized by progressive cognitive decline and neurodegeneration.
Purpose of the Study:
- To investigate the impact of sevoflurane exposure on neurodegeneration in a mouse model of Alzheimer's disease (APP/PS1 mice).
- To elucidate the molecular mechanisms by which sevoflurane may exacerbate AD pathology.
Main Methods:
- Utilized the APP/PS1 mouse model to assess the effects of sevoflurane on cognitive and sensorimotor functions.
- Analyzed the activation of the NLRP3 inflammasome pathway, including caspase-1, IL-1β, and IL-18.
- Measured brain-derived neurotrophic factor (BDNF) levels to assess its role in sevoflurane-induced neurodegeneration.
Main Results:
- Sevoflurane exposure significantly impaired spatial reference memory, sensorimotor function, and overall cognitive abilities in APP/PS1 mice.
- Sevoflurane induced the formation of the NLRP3 inflammasome and subsequent caspase-1-mediated production of IL-1β and IL-18.
- These inflammatory mediators led to the deactivation of brain-derived neurotrophic factor (BDNF), promoting neurodegeneration.
Conclusions:
- The NLRP3 inflammasome plays a critical role in sevoflurane-induced neurodegeneration in the context of Alzheimer's disease.
- Targeting the NLRP3 inflammasome pathway may offer a therapeutic strategy to mitigate sevoflurane's adverse effects on cognitive function in AD patients.
