Sun Qingmei, Yan Hongdan, Chen Falong, Jiang Fen, Chen Wenjuan, Li Dongliang, Guo Yongmin
Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, China.
Front Pharmacol. 2021 Jul 23;12:720249. doi: 10.3389/fphar.2021.720249. eCollection 2021.
Sevoflurane (SEV), a commonly used volatile anesthetic, has been shown to cause cognitive decline in diabetic rats by aggregating neuroinflammation in the hippocampus, but the underlying mechanisms are unknown. Recent evidence suggests that neuroinflammation could be a consequence of failure to resolve inflammation by specialized pro-resolving lipid mediators including resolvin D1 (RvD1). Here we first examined whether type 2 diabetes mellitus (DM) alters RvD1 proresolution pathway. Diabetic Goto-Kakizaki (GK) rats and non-diabetic Wistar rats received control or 2.6% SEV exposure for 4 h. Seven days after exposure, GK control rats, compared with Wistar control rats, had significantly lower RvD1 levels in plasma and CSF and decreased RvD1 receptor FPR2 expression in the hippocampus. SEV increased RvD1 levels in plasma and CSF and FPR2 expression in the hippocampus in Wistar rats but not in GK rats. We next examined whether RvD1 treatment of GK rats can prevent SEV-induced neuroinflammation and cognitive decline. GK rats received control, SEV or SEV and once-daily treatment with exogenous RvD1 (0.2 ug/kg, ip) for 7 days. RvD1 administration markedly increased RvD1 levels in plasma and CSF and FPR2 expression in the hippocampus in GK rats received SEV. Compared with GK control rats, GK rats received SEV exhibited shorter freezing times in trace fear conditioning task, which was accompanied by increased microglia activity and pro-inflammatory cytokine expression in the hippocampus. RvD1 administration attenuated SEV-induced increases in microglia activity and pro-inflammatory cytokine expression in the hippocampus, preventing cognitive decline in GK rats. Notably, neither SEV nor RvD1 altered metabolic parameters in GK rats. The results suggest that RvD1 proresolution pathway is impaired in the brain of diabetic GK rats. which may enhance the susceptibility to SEV, contributing to neuroinflammation and cognitive decline. Restoration of RvD1 proresolution pathway in diabetic GK rats with exogenous RvD1 can prevent SEV-induced cognitive decline by attenuating neuroinflammation in the hippocampus.
七氟醚（SEV）是一种常用的挥发性麻醉剂，已被证明可通过聚集海马体中的神经炎症导致糖尿病大鼠认知功能下降，但其潜在机制尚不清楚。最近的证据表明，神经炎症可能是包括消退素D1（RvD1）在内的特殊促消退脂质介质未能解决炎症的结果。在这里，我们首先研究了2型糖尿病（DM）是否会改变RvD1促消退途径。将糖尿病Goto-Kakizaki（GK）大鼠和非糖尿病Wistar大鼠分为对照组或暴露于2.6%的SEV中4小时。暴露7天后，与Wistar对照大鼠相比，GK对照大鼠血浆和脑脊液中的RvD1水平显著降低，海马体中RvD1受体FPR2的表达减少。SEV增加了Wistar大鼠血浆和脑脊液中的RvD1水平以及海马体中FPR2的表达，但在GK大鼠中未增加。接下来，我们研究了用RvD1治疗GK大鼠是否可以预防SEV诱导的神经炎症和认知功能下降。GK大鼠接受对照、SEV或SEV治疗，并每天一次给予外源性RvD1（0.2μg/kg，腹腔注射），持续7天。在接受SEV的GK大鼠中，给予RvD1显著增加了血浆和脑脊液中的RvD1水平以及海马体中FPR2的表达。与GK对照大鼠相比，接受SEV的GK大鼠在痕迹恐惧条件任务中的冻结时间更短，这伴随着海马体中微胶质细胞活性和促炎细胞因子表达的增加。给予RvD1减弱了SEV诱导的海马体中微胶质细胞活性和促炎细胞因子表达的增加，预防了GK大鼠的认知功能下降。值得注意的是，SEV和RvD1均未改变GK大鼠的代谢参数。结果表明，糖尿病GK大鼠大脑中的RvD1促消退途径受损，这可能会增加对SEV的易感性，导致神经炎症和认知功能下降。用外源性RvD1恢复糖尿病GK大鼠的RvD1促消退途径可以通过减轻海马体中的神经炎症来预防SEV诱导的认知功能下降。
