Prolonged exposure to inhaled anesthetics may lead to postoperative cognitive dysfunction (POCD). Nevertheless, the underlying mechanisms are not known. Hypoxia-inducible factor-1α (HIF-1α) and its target gene vascular endothelial growth factor (VEGF) were shown to be activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1α in isoflurane-induced blood-brain barrier (BBB) disruption and resultant cognitive impairment. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in vascular permeability, and disrupted BBB ultrastructure were accompanied by the degradation of tight junction proteins occludin and collagen type IV in brain blood vessels. Increases in HIF-1α and VEGF proteins and activation of MMP-2 in the hippocampus were also observed in the hippocamp of isoflurane-exposed rats compared with control rats. Pharmacological inhibition of HIF-1α activation by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) markedly suppressed the expression of HIF-1α, VEGF and MMP-2, and mitigated the severity of BBB disruption.YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits in the Morris water maze task. Overall, our results demonstrate that hippocampal HIF-1α/VEGF signaling seems to be the upstream mechanism of isoflurane-induced cognitive impairment, and provides apotential preventive and therapeutic target for POCD.

译文

长期接触吸入麻醉药可能导致术后认知功能障碍 (POCD)。然而,潜在的机制尚不清楚。低氧诱导因子-1α (HIF-1α) 及其靶基因血管内皮生长因子 (VEGF) 被吸入麻醉药激活。本研究的目的是确定HIF-1α 在异氟醚诱导的血脑屏障 (BBB) 破坏和导致的认知障碍中的作用。在20个月大的大鼠中暴露于1.5% 异氟烷4小时后,血管通透性增加和BBB超微结构破坏伴随着脑血管中紧密连接蛋白occludin和IV型胶原的降解。与对照组相比,在异氟醚暴露的大鼠海马中还观察到HIF-1α 和VEGF蛋白的增加以及海马中MMP-2的激活。3-(5 '-hydroxymethyl-2'-呋喃基)-1-苄基利达唑 (YC-1) 对HIF-1α 激活的药理抑制作用可显着抑制HIF-1α,VEGF和MMP-2的表达,并减轻BBB破坏的严重程度。YC-1预处理还可显着减轻异氟烷诱导的莫里斯水迷宫任务中的认知缺陷。总体而言,我们的结果表明,海马HIF-1α/VEGF信号似乎是异氟醚诱导的认知障碍的上游机制,并为POCD提供了潜在的预防和治疗靶点。

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