Repeated Neonatal Sevoflurane Induced Neurocognitive Impairment Through NF-κB-Mediated Pyroptosis

Abstract Background: Exposure to general anesthesia (GA) during the postnatal period is associated with neuroinflammation and long-term neurocognitive impairment in preclinical and clinical settings. Pyroptosis, a novel type of programmed cell death that along with inflammation, plays an important role in the mechanism of diverse neurological diseases. Nevertheless, its role in GA-induced neuroinflammation and neurocognitive impairment in developing brain has not been investigated. Methods: Rats at postnatal day 6 or primary hippocampal neurons at 9 days in vitro, received 3% sevoflurane for 2 hours daily for three consecutive days. A pharmacological inhibitor of nuclear factor (NF)‑κB (BAY 11-7082) was administered to suppress NF-κB activation. Histological and biochemical analysis were performed to assess the pyroptosis and neuronal and synaptic damages both in vivo and in vitro. In addition, behavioral tests were performed to evaluate the neurocognitive ability in rats.Results: Repeated sevoflurane exposures activated NF-κB-mediated pyroptosis and neuroinflammation in the hippocampus of developing rats, caused damages in neuronal morphology and synaptic integrity, and induced neurocognitive impairment in rats. BAY 11-7082, the inhibitor of NF-κB, suppressed the activation of pyroptosis, attenuated the neuronal and synaptic damages, and ameliorated the neurocognitive impairment induced by repeated sevoflurane in the developing rats.Conclusions: These results demonstrated that repeated sevoflurane GA might induce neuroinflammation and cognitive impairment in developing rats via activation of NF-κB-mediated pyroptosis. Our findings characterize a novel role for pyroptosis as a potential therapeutic target in neuroinflammation to repeated neonatal GA.