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Chikusetsu Saponin IVa Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice via Adiponectin-Mediated AMPK/GSK-3β Pathway In Vivo and In Vitro

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Abstract

Diabetes mellitus substantially increases the risk of stroke and enhances brain’s vulnerability to ischemia insult. In a previous study, Chikusetsu saponin IVa (CHS) pretreatment was proved to protect the brain from cerebral ischemic in normal stroke models. Whether CHS could attenuate cerebral ischemia/reperfusion (I/R) injury in diabetic mice and the possible underlying mechanism are still unrevealed. Male C57BL/6 mice were injected streptozotocin to induce diabetes. After that, the mice were pretreated with CHS for 1 month, and then, focal cerebral ischemia was induced following 24-h reperfusion. The neurobehavioral scores, infarction volumes, and some cytokines in the brain were measured. Apoptosis was analyzed by caspase-3, Bax, and Bcl-2 expression. Downstream molecules of adiponectin (APN) were investigated by Western blotting. The results showed that CHS reduced infarct size, improved neurological outcomes, and inhibited cell injury after I/R. In addition, CHS pretreatment increased APN level and enhanced neuronal AdipoR1, adenosine monophosphate-activated protein kinase (AMPK), and glycogen synthase kinase 3 beta (GSK-3β) expression in a concentration-dependent manner in diabetic mice, and these effects were abolished by APN knockout (KO). In vitro test, CHS treatment also alleviated PC12 cell injury and apoptosis, evidenced by reduced tumor necrosis factor alpha (TNF-α), malondialdehyde (MDA) and caspase-3 expression, and Bax/Bcl-2 ratio in I/R injured cells. Moreover, CHS enhanced AdipoR1, AMPK, and GSK-3β expression in a concentration-dependent manner. Likewise, short interfering RNA (sinRNA) knockdown of liver kinase B1 (LKB1), an upstream kinase of AMPK, reduced the ability of CHS in protecting cells from I/R injury. Furthermore, this LKB1-dependent cellular protection resulted from AdipoR1 and APN activation, as supported by the experiment using sinRNA knockdown of AdipoR1 and APN. Thus, CHS protected brain I/R in diabetes through AMPK-mediated phosphorylation of GSK-3β downstream of APN-LKB1 pathway.

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Acknowledgments

This work was supported by the National Science Foundation of China (Nos. 81173514, 81303264, 81403134, 81403135, 81403182, and 81470174) and Excellent Civil Service Training Fund of Forth Military Medical University (No. 4138C4IDK6).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Road 127, Xi’an, Shaanxi, China

    Jialin Duan, Ying Yin, Jia Cui, Jiajia Yan, Yanrong Zhu, Yue Guan, Guo Wei, Yan Weng, Xiaoxiao Wu, Chao Guo, Yanhua Wang, Miaomiao Xi & Aidong Wen

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  1. Jialin Duan
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  2. Ying Yin
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  3. Jia Cui
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Correspondence to Miaomiao Xi or Aidong Wen.

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Jialin Duan, Ying Yin, Jia Cui, Jiajia Yan, and Yanrong Zhu have equally contributed to this work.

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Duan, J., Yin, Y., Cui, J. et al. Chikusetsu Saponin IVa Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice via Adiponectin-Mediated AMPK/GSK-3β Pathway In Vivo and In Vitro. Mol Neurobiol 53, 728–743 (2016). https://doi.org/10.1007/s12035-014-9033-x

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