International immunopharmacology · 2025
Piezo1 participates in sevoflurane-induced developmental neurotoxicity via neuroinflammation and synaptic damage in the hippocampus.
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Zhang Yang, Liu Xinru, Gao Ying, Fu Chengwen, Xue Yanan, Wang Dongsheng, Hong Jin, Ren Li, Zha Liwen, Ling Yunzhi, Zhang Congli, Li Xiaohong
Аннотация
BACKGROUND: Multiple exposures to sevoflurane in developmental neonatal mice lead to neurocognitive deficits. The present study investigates the role and mechanisms of Piezo1 in sevoflurane-induced developmental neurotoxicity.
METHODS: Neonatal mice received sevoflurane on postnatal days (P) 6, 7, and 8. Piezo1 function was assessed using inhibitor GsMTx4 and agonist Yoda1. Cognitive function was evaluated via behavioral tests. Neuroinflammation was assessed by ELISA, Western blot, and immunofluorescence. Synaptic integrity was analyzed by Golgi staining.
RESULTS: Sevoflurane induced cognitive deficits, neuroinflammation, and synaptic damage, and increased Piezo1 expression. Yoda1 exacerbated cognitive deficits. GsMTx4 rescued cognitive function and synaptic plasticity, reduced microglial phagocytosis, and suppressed complement activation. In vitro, sevoflurane increased Piezo1 expression and intracellular calcium flux in BV2 microglia; GsMTx4 blocked these effects. Yoda1 amplified calcium flux, pro-inflammatory cytokines (TNF-α/IL-6), and C1q expression, which were abolished by calcium chelator BAPTA-AM.
CONCLUSION: Piezo1 mediates sevoflurane-induced developmental neurotoxicity via calcium-dependent microglial complement signaling and synaptic phagocytosis. Piezo1 inhibition is considered a potential therapeutic strategy.
METHODS: Neonatal mice received sevoflurane on postnatal days (P) 6, 7, and 8. Piezo1 function was assessed using inhibitor GsMTx4 and agonist Yoda1. Cognitive function was evaluated via behavioral tests. Neuroinflammation was assessed by ELISA, Western blot, and immunofluorescence. Synaptic integrity was analyzed by Golgi staining.
RESULTS: Sevoflurane induced cognitive deficits, neuroinflammation, and synaptic damage, and increased Piezo1 expression. Yoda1 exacerbated cognitive deficits. GsMTx4 rescued cognitive function and synaptic plasticity, reduced microglial phagocytosis, and suppressed complement activation. In vitro, sevoflurane increased Piezo1 expression and intracellular calcium flux in BV2 microglia; GsMTx4 blocked these effects. Yoda1 amplified calcium flux, pro-inflammatory cytokines (TNF-α/IL-6), and C1q expression, which were abolished by calcium chelator BAPTA-AM.
CONCLUSION: Piezo1 mediates sevoflurane-induced developmental neurotoxicity via calcium-dependent microglial complement signaling and synaptic phagocytosis. Piezo1 inhibition is considered a potential therapeutic strategy.