Rutin ameliorates sevoflurane-induced neurotoxicity by inhibiting microglial synaptic phagocytosis through the complement pathway

Repeated neonatal exposure to sevoflurane may impair synapses and lead to developmental neurobehavioral issues. In this study, we assessed the therapeutic effects of rutin on sevoflurane-induced neurotoxicity. The mice were exposed to 3% sevoflurane for 2 h daily on postnatal days (PNDs) 6, 8, and 10. The Morris water maze was used and an open field test was performed to assess the memory and anxiety-like behavior of the mice on PNDs 37-42. The effects of rutin on the complement cascade and microglial synaptic elimination in the hippocampus of mice were validated by Western blotting, real-time RT qPCR, morphological analysis, and immunohistochemistry examinations. The results showed that rutin effectively alleviated cognitive dysfunction and synaptic impairment in sevoflurane-treated mice. By decreasing microglial activation, rutin switched microglia from the ameboid phenotype to the ramified phenotype and decreased the phagocytic properties of microglia. Rutin treatment also rescued sevoflurane-induced synapse loss by preventing microglial synaptic engulfment through complements C1q and C3; this effect could be reversed by an extra C3 supplement. Our findings demonstrated that rutin could alleviate synapse loss and cognitive dysfunction in sevoflurane-treated mice by inhibiting complement-dependent microglial synapse phagocytosis. This provides a promising strategy for the prevention of sevoflurane-induced developmental neurotoxicity.