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Emulsified Isoflurane Protects Against Transient Focal Cerebral Ischemia Injury in Rats via the PI3K/Akt Signaling Pathway

Zhang, Hongfei MD, PhD; Xiong, Xiaoxing MD, PhD; Liu, Jin MD; Gu, Lijuan MD; Li, Fengxian MD; Wan, Yi MD; Xu, Shiyuan MD

doi: 10.1213/ANE.0000000000001172
Anesthetic Pharmacology: Research Report

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® (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.

Published ahead of print February 8, 2016

From the *Department of Anesthesiology and Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; §Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; Department of Basic Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; and Department of Health Statistics, Forth Military Medical University, Xi’an, Shaanxi, People’s Republic of China.

Accepted for publication December 10, 2015.

Published ahead of print February 8, 2016

Funding: This work was supported by grant 2015A030313258 (to Dr. Zhang) from the Natural Science Foundation of Guangdong Province, Guangdong, People’s Republic of China, and by grant 81070117 (to Dr. Liu) from the National Natural Science Foundation of China, Beijing, People’s Republic of China.

The authors declare no conflicts of interest.

Drs. Zhang and Xiong were the co-first authors.

Reprints will not be available from the authors.

Address correspondence to Shiyuan Xu, MD, Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, No. 253 Gong Ye Da Dao Zhong, Guangzhou, Guangdong 510280, People’s Republic of China; and Jin Liu, MD, Department of Anesthesiology, and Translational Neuroscience Center, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan 610041, People’s Republic of China. Address e-mail to shiyuanxu355@163.com; and scujinliu@gmail.com.

© 2016 International Anesthesia Research Society