PirB介导海马突触可塑性改变参与七氟醚早期暴露诱导远期认知损害发生

Adulthood learning and cognition impairment resulted from early-life exposure to general anesthesia has been becoming a focus of multiple medical disciplines, and also a critical iatrogenic public health issue. Sevoflurane is the choice of anesthesia for children. Previous reports demonstrated that the impairment of adulthood cognition and memorization would be worse if the rodent animals were exposed to sevoflurane with much younger age, more repeated times, and much longer duration; and there were studies presented that PirB mediated memory impairment in Alzheimer’s disease (AD). Based on these, our exploratory experiments showed that: 1) Infancy sevoflurane anesthesia upregulated hippocampal PirB expression, but PirB inhibition improved spatial cognition markedly; 2) sevoflurane induced increase in hippocampal protein phosphatases (PPs), and decrease in p-Cofilin; 3) sevoflurane downregulated hippocampal post-synaptic density-95 (PSD-95), and actin monomer increased with actin polymer reduced, but PirB inhibition could attenuate all these alterations. Moreover, reports showed that PirB is involved in the regulation of p-Cofilin-associated synaptic plasticity. As thus we proposed that early exposure of sevoflurane induced adulthood cognition impairment through activating hippocampal PirB–p-Cofilin–Actin pathway which is involved in the regulation of synaptic plasticity. Our research proposal will test the interrelationship among hippocampal PirB–p-Cofilin–Actin pathway, synaptic plasticity, and memorization and cognition in infancy rats after sevoflurane anesthesia to disclose novel mechanisms of adulthood cognition impairment from the early exposure of sevoflurane, and to provide new clues for corresponding potential preventive interventions.

早期全麻药物暴露损害远期认知已引起多学科关注，是一医源性公共健康问题。七氟醚是儿童全麻首选。报道七氟醚暴露年龄越小、重复次数越多、持续时间越长远期认知损害更严重；且有PirB介导AD记忆损害机制。继而预实验发现：1）婴儿期七氟醚麻醉上调海马PirB表达，PirB抑制可显著改善空间认知；2）七氟醚诱导海马PPs增加，p-Cofilin下降；3）七氟醚下调海马PSD-95表达，Actin单体增加、多聚体减少，PirB抑制显著减缓此变化。结合PirB介导p-Cofilin相关突触可塑性调控报道，提出早期七氟醚暴露通过海马PirB–p-Cofilin–Actin通路参与突触可塑性调控介导远期认知损害。研究拟以婴幼儿期大鼠为对象，深入探讨七氟醚暴露与海马PirB–p-Cofilin–Actin通路、突触可塑性与记忆认知之间关系，揭示七氟醚麻醉早期暴露损害远期认知新机制，为其早期干预和预防提供新线索。