002C-3 protects the brain against ischemia-reperfusion injury by inhibiting autophagy and stimulating CaMKK/CaMKIV/HDAC4 pathways in mice

doi:10.5246/jcps.2016.08.067

Journal of Chinese Pharmaceutical Sciences ›› 2016, Vol. 25 ›› Issue (8): 598-604.DOI: 10.5246/jcps.2016.08.067

• Original articles • Previous Articles Next Articles

002C-3 protects the brain against ischemia-reperfusion injury by inhibiting autophagy and stimulating CaMKK/CaMKIV/HDAC4 pathways in mice

Jingliang Zhang^1#,Tao Hu^1#, Xiaoyan Liu¹, Yuanjun Zhu¹, Xiaoling Chen¹, Ye Liu², Yinye Wang^1*

1. Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Beijing Honghui New Medical Technology Co.Ltd., Beijing Daxing Biological Medicine Industry Base, Beijing 102600,China

Received:2016-02-27 Revised:2016-04-15 Online:2016-09-01 Published:2016-05-10
Contact: Tel.: +86-010-82802652/+86-010-62015584, E-mail: wangyinye@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81302763, 81573333) and Beijing Natural Science Foundation (Grant No. 7144218).

Abstract

Abstract:

This study was designed to investigate the effect of 002C-3, a derivative of magnolol, on transient cerebral middle occlusion (tMCAO) in a mice model and to identify the underlying mechanisms. 002C-3 (100 and 150 μg/kg, i.v. after ending occlusion) significantly reduced neurological deficit scores, infarct volumes, and brain water contents after 1.5 h MCAO and 24 h reperfusion. 002C-3 (75-150 µg/kg) decreased the exudation of Evans blue from brain capillaries. 002C-3 (100 μg/kg) significantly inhibited the activity of MMP-9 and MMP-2 in the injured hemisphere. 002C-3 decreased the expression of autophagy-associated proteins, Beclin-1 and LC3B-II, and increased the level of p62 in injured hemisphere. 002C-3 (100 μg/kg) significantly increased the expression of p-CaMKIV and p-HDAC4 in injured hemisphere. In conclusion, 002C-3 shows a neuroprotective effect on tMCAO injury in mice, and its mechanisms may be associated with alleviation of blood-brain barrier damage caused by the activation of MMPs, inhibition of autophagy, and stimulation of calcium signals related to cell survival. These findings suggest that 002C-3 is a neuroprotective agent that acts on multiple pathways.

Key words: 002C-3, Cerebral ischemia-reperfusion, Microvascular permeability, Autophagy, CaMKK/CaMKIV/HDAC4 pathway

CLC Number:

R962

Supporting:

Jingliang Zhang, Tao Hu, Xiaoyan Liu, Yuanjun Zhu, Xiaoling Chen, Ye Liu, Yinye Wang. 002C-3 protects the brain against ischemia-reperfusion injury by inhibiting autophagy and stimulating CaMKK/CaMKIV/HDAC4 pathways in mice[J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(8): 598-604.

References

[1] Turner, R.C.; Dodson, S.C.; Rosen, C.L.; Huber, J.D. J. Neurosurg. 2013, 118, 1072-1085.
[2] Fisher, M.; Feuerstein, G.; Howells, D.W.; Hurn, P.D.; Kent, T.A.; Savitz, S.I.; Lo, E.H. Stroke. 2009, 40, 2244-2250.
[3] Lo, E.H.; Dalkara, T.; Moskowitz, M.A. Nat. Rev. Neurosci. 2003, 4, 399-415.
[4] Lee, W.T.; Lin, M.H.; Lee, E.J.; Hung, Y.C.; Tai, S.H.; Chen, H.Y.; Chen, T.Y.; Wu, T.S. PloS One. 2012, 7, e39952.
[5] Chen, Y.H.; Huang, P.H.; Lin, F.Y.; Chen, W.C.; Chen, Y.L.; Yin, W.H.; Man, K.M.; Liu, P.L. Eur. J. Integ. Med. 2011, 3, e317-e324.
[6] Liang, C.J.; Lee, C.W.; Sung, H.C.; Chen, Y.H.; Wang, S.H.; Wu, P.J.; Chiang, Y.C.; Tsai, J.S.; Wu, C.C.; Li, C.Y.; Chen, Y.L. Am. J. Chin. Med. 2014, 42, 619-637.
[7] Huang, X.; Wang, C.; Chen, K.; Xiang, T.; Han, Z. Chin. J. Neuroimmunol. Neurol. 2007, 14, 118-119.
[8] Lin, Y.R.; Chen, H.H.; Ko, C.H.; Chan, M.H. Eur. J. Pharmacol. 2006, 537, 64-69.
[9] Pyo, M.K.; Lee, Y.; Yun-Choi, H.S. Arch. Pharmacol. Res. 2002, 25, 325-328.
[10] Yan, Y.; Lin, Q.; Xu, Y.; Huang, X. Chin. J. Exp. Tradit. Med. Formul. 2011, 17, 223-225.
[11] Li, H.; Liu, X.; Zhu, Y.; Liu, Y.; Wang, Y. Neurosci. Lett. 2015, 588, 178-183.
[12] Chiang, T.; Messing, R.O.; Chou, W.H. J. Visual. Exp. 2011. JoVE (48).
[13] Liu, F.; McCullough, L.D. Methods Mol. Biol. 2014, 1135, 81-93.
[14] Rousselet, E.; Kriz, J.; Seidah, N.G. J. Visual. Exp. 2012, JoVE(69).
[15] Chao, X.; Zhou, J.; Chen, T.; Liu, W.; Dong, W.; Qu, Y.; Jiang, X.; Ji, X.; Zhen, H.; Fei, Z. Brain Res. 2010, 1363, 206-211.
[16] Cevik, N.G.; Orhan, N.; Yilmaz, C.U.; Arican, N.; Ahishali, B.; Kucuk, M.; Kaya, M.; Toklu, A.S. Brain Res. 2013, 1531, 113-121.
[17] Toth, M.; Sohail, A.; Fridman, R. In Metastasis Research Protocols, 2012, Springer. 121-135.
[18] McCullough, L.D.; Tarabishy, S.; Liu, L.; Benashski, S.; Xu, Y.; Ribar, T.; Means, A.; Li, J. Stroke. 2013. 44, 2559-2566.
[19] Bolger, T.A.; Yao, T.P. J. Neurosci: the official journal of the Society for Neuroscience. 2005, 25, 9544-9553.
[20] Liu, Y.; Liu, K.; Liu, J.; Li, J. Chin. J. Gerontol. 2014, 1, 135.
[21] Xu, F.; Gu, J.; Qin, Z. Neurosci. Bullet. 2012, 28, 658-666.
[22] Carloni, S.; Buonocore, G.; Balduini, W. Neurobiol Dis. 2008, 32, 329-339.
[23] Zheng, Y.; Liu, J.; Li, X.; Xu, L.; Xu, Y. Acta Pharmacol. Sin. 2009, 30, 919-927.
[24] Wang, J.; Xia, Q.; Chu, K.; Pan, J.; Sun, L.; Zeng, B.; Zhu, Y.; Wang, Q.; Wang, K.; Luo, B. J. Neuropathol. Exp. Neurol. 2011, 70, 314-322.
[25] Zhang, X.; Yan, H.; Yuan, Y.; Gao, J.; Shen, Z.; Cheng, Y.; Shen, Y.; Wang, R.R.; Wang, X.; Hu, W.W.; Wang, G.; Chen, Z. Autophagy. 2013, 9,1321-1333.
[26] Yano, S.; Tokumitsu, H.; Soderling, T.R. Nature. 1998, 396, 584-587.
[27] Means, A.R. Mol. Endocrinol. 2008, 22, 2759-2765.
[28] Wayman, G.A.; Lee, Y.S.; Tokumitsu, H.; Silva, A.J.; Soderling, T.R. Neuron. 2008, 59, 914-931.

002C-3 protects the brain against ischemia-reperfusion injury by inhibiting autophagy and stimulating CaMKK/CaMKIV/HDAC4 pathways in mice

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 7

Recommended Articles

Metrics

Comments

[1]	Wuyinxiao Zheng, Haiping Li, Laichun Luo, Chunling Hu, Pengtao You. PI3K/AKT/mTOR pathway inhibition and miR-210-mediated suppression of Atg7 promote autophagy in TOPC-induced apoptosis of H1975 cells [J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(11): 881-892.
[2]	Shengxin Wang, Xiangli Yan, Haozhen Zheng, Jianye Yu, Aiming Yu, Xiao Shen, Lisheng Wang. Pharmacokinetics of different dosage of astragalus membranaceus of buyang huanwu decoction in rats with cerebral ischemic injury by microdialysis combined with LC/MS [J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(2): 90-101.
[3]	Yunong Pang, Yinwen Liang, Yugang Wang, Fan Lei, Zhiyi Yuan, Dongming Xing, Jun Li, Lijun Du. Effect of berberine against cerebral ischemia and reperfusion involving in the methylation of PPARγ promoter [J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(3): 170-182.
[4]	Yao Zhao, Jingying Zhang, Yingjie Hu, Jiashuan Wu, Yingzi Bu, Wanliang Lu. Augmented efficacy and the mechanism of a combined use of daunorubicin with rofecoxib in treatment of triple-negative breast cancer [J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(6): 438-447.
[5]	Xiaoyan Liu, Zhenyu Hu, Shizhong Chen, Jiancheng Wang, Yinye Wang. Protective effects of orally administered honokiol on cerebral ischemia reperfusion in rats and on stroke in SHRsp [J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(12): 882-891.
[6]	Zhe Wang, Xia Yuan, Zemei Ge, Fuxiang Ran, Jun Wu, Runtao Li, Jingrong Cui. A new proteasome inhibitor YSY-01A induced autophagy in PC-3M cells [J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(8): 565-571.
[7]	Xiao-Xia Chen, Bing He. Effects of Breviscapine on the Changes in Antioxidant Enzyme Activity Induced by Cerebral Ischemia-reperfusion in Rats [J]. , 1998, 7(2): 91-93.