Emulsified Isoflurane Protects Against Transient Focal Cerebral Ischemia Injury in Rats via the PI3K/Akt Signaling Pathway
Emulsified Isoflurane Protects Against Transient Focal Cerebral Ischemia Injury in Rats via the PI3K/Akt Signaling Pathway
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DOI：
10.1213/ane.0000000000001172
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发表时间：
2016-05-01
影响因子：
5.7
通讯作者：
Xu, Shiyuan
中科院分区：
文献类型：
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作者：
Zhang, Hongfei;Xiong, Xiaoxing;Xu, Shiyuan
背景：磷酸肌醇 3 激酶 (PI3K)/蛋白激酶 B (Akt) 通路激活可能通过脑缺血后炎症期间的神经保护来促进神经元存活。在本研究中，我们研究了乳化异氟烷 (EI) 的 IV 预处理是否可以减少与 PI3K/Akt 通路相关的缺血性脑损伤。 方法：雄性 Sprague-Dawley 大鼠接受不同剂量的 IV EI（1、2、4 或 8 mL/kg/h）或 Intralipid r（8 mL/kg/h）30 分钟（每组 n = 6-12），然后大脑中动脉注射闭塞 (MCAO) 100 分钟以诱导短暂性局灶性缺血。 MCAO后48小时测量神经系统评分和梗塞体积。使用免疫染色、蛋白质印迹分析和酶联免疫吸附测定来评估EI对细胞炎症反应、高迁移率组box-1释放和磷酸化Akt（表达）的影响。在EI之前将PI3K抑制剂LY294002注入心室空间以确定EI的效果。结果：每小时每公斤4毫升的EI减少了梗死面积（21.08+/- 11.24 vs 37.09 +/- 10.46，P = 0.006），MCAO后神经系统评分改善（1.13 +/- 0.48 vs 1.95 +/- 0.65，P = 0.015），显着增强神经元存活（982.7 +/- 364.4 vs 439.8 +/- 278.4，P =与载体组相比，EI预处理组血清高迁移率组box-1浓度（3.62+/-0.72 vs 5.73+/-0.65，P=0.036），并抑制缺血核心区的CD68+巨噬细胞/巨胶质细胞浸润（188.2+/-49.1 vs 282+/-49.4，P = 0.018）。 < 0.001）降低，48小时时脑磷酸化Akt水平（50.33 +/- 4.73 vs 37.5 +/- 3.11，P = 0.007）增加，与媒介物组相比，LY294002抑制了这一水平（5.31 +/- 0.72 vs 5.73 +/- 0.65，P = 0.216； 43.00 +/- 4.84 vs 37.5 +/- 3.11，P = 0.091）。结论：这些研究结果表明，EI 预处理可通过抑制脑部炎症来预防缺血性脑损伤，并且与 MCAO 大鼠的 PI3K-Akt 通路相关。该药物可能是中风后患者的新型治疗剂。
BACKGROUND: Phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathway activation may promote neuronal survival via neuroprotection during inflammation after cerebral ischemia. In this study, we investigated whether IV pretreatment with emulsified isoflurane (EI) could decrease ischemic brain injury related to the PI3K/Akt pathway.METHODS: Male Sprague-Dawley rats received different doses of IV EI (1, 2, 4, or 8 mL/kg/h) or Intralipid r (8 mL/kg/h) for 30 minutes (n = 6-12 per group), followed by middle cerebral artery occlusion (MCAO) for 100 minutes to induce transient focal ischemia. The neurologic score and infarct volume were measured 48 hours after MCAO. Immunostaining, Western blot analysis, and an enzyme-linked immunosorbent assay were used to assess EI effects on the cell inflammatory response, high-mobility group box-1 release, and phosphorylated Akt (expression. LY294002, a PI3K inhibitor, was also infused into the ventricular space before EI to determine the effect of EI.RESULTS: Four milliliters per kilogram per hour of EI reduced the infarct size (21.08 +/- 11.24 vs 37.09 +/- 10.46, P = 0.006), improved neurologic scores after MCAO (1.13 +/- 0.48 vs 1.95 +/- 0.65, P = 0.015), significantly reinforced neuronal survival (982.7 +/- 364.4 vs 439.8 +/- 278.4, P = 0.036), and inhibited CD68+ macrophage/macroglial infiltration in the ischemic core (188.2 +/- 49.1 vs 282 +/- 49.4, P = 0.018) compared with the vehicle group. In the EI pretreatment group, the serum high-mobility group box-1 concentration (3.62 +/- 0.72 vs 5.73 +/- 0.65, P < 0.001) was decreased, and the cerebral phosphorylated Akt level (50.33 +/- 4.73 vs 37.5 +/- 3.11, P = 0.007) was increased at 48 hours, which was inhibited by LY294002 compared with the vehicle group (5.31 +/- 0.72 vs 5.73 +/- 0.65, P = 0.216; 43.00 +/- 4.84 vs 37.5 +/- 3.11, P = 0.091).CONCLUSIONS: These findings suggest that EI pretreatment protects against ischemic brain injury via the inhibition of cerebral inflammation and is associated with the PI3K-Akt pathway in rats with MCAO. This drug may be a novel therapeutic agent for patients after stroke.