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The Protective Effect of Epoxyeicosatrienoic Acids on Cerebral Ischemia/Reperfusion Injury is Associated with PI3K/Akt Pathway and ATP-Sensitive Potassium Channels

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An Erratum to this article was published on 14 March 2015

Abstract

Epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolite of arachidonic acid, have been demonstrated to have neuroprotective effect. Phosphatidylinositol 3-kinase (PI3K)/Akt and ATP-sensitive potassium (KATP) channels are thought to be important factors that mediate neuroprotection. However, little is known about the role of PI3K/Akt and KATP channels in brain after EETs administration. In vitro experiment, oxygen–glucose deprivation (OGD) was performed in cultured rat cerebral microvascular smooth muscle cells (SMCs) for 4 h. The effect of 14,15-EET on OGD induced cell apoptosis was examined after reoxygenation. Western blot and real-time PCR were used to analyze the expression of Kir6.1, SUR2B (two subunits of KATP channels) and p-Akt on cerebral microvascular SMCs. In vivo experiments, we use 12-(3-adamantan-1-yl-ureido)-dodecanoic acid [AUDA, a specific soluble epoxide hydrolase (sEH) inhibitor] to confirm the effect of EETs indirectly. Rats were injected intraperitoneally with AUDA before being subjected to middle cerebral artery occlusion (MCAO). We detected the apoptosis and the expression of p-Akt, Kir6.1 and SUR2B in ischemic penumbra. The results showed that EETs protect against cerebral ischemia/reperfusion (I/R) injury and upregulated the expression of p-Akt and Kir6.1 in both of ischemic penumbra and OGD induced cerebral microvascular SMCs. The protective effect was inhibited by Wortmannin (a specific PI3K inhibitor) and Glib (a specific KATP inhibitor) respectively in vitro experiment. In conclusion, these results suggested that the protective effect of EETs on cerebral I/R injury is associated with PI3K/Akt pathway and KATP channels. Furthermore, the PI3K pathway may contribute to mediating KATP channels on cerebral microvascular SMCs.

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Abbreviations

EETs:

Epoxyeicosatrienoic acids

PI3K:

Phosphatidylinositol 3-kinase

KATP:

ATP-sensitive potassium

I/R:

Ischemia/reperfusion

OGD:

Oxygen–glucose deprivation

OGD + R:

Oxygen–glucose deprivation + reoxygenation

AA:

Arachidonic acid

MCAO:

Middle cerebral artery occlusion

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81171077). We would like to thank Professor Daling Zhu from College of Pharmacy, Harbin Medical University for technical assistance.

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Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, People’s Republic of China

    You-Yang Qu, Yu Liu, Xing-Jun Xiao & Yu-Lan Zhu

  2. Department of Neurology, Laizhou People’s Hospital, Laizhou, 261400, People’s Republic of China

    Mei-Yan Yuan

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  1. You-Yang Qu
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Correspondence to Xing-Jun Xiao or Yu-Lan Zhu.

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Qu, YY., Yuan, MY., Liu, Y. et al. The Protective Effect of Epoxyeicosatrienoic Acids on Cerebral Ischemia/Reperfusion Injury is Associated with PI3K/Akt Pathway and ATP-Sensitive Potassium Channels. Neurochem Res 40, 1–14 (2015). https://doi.org/10.1007/s11064-014-1456-2

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