Neuroprotective Effect and Mechanism of Action of Tetramethylpyrazine Nitrone for Ischemic Stroke Therapy

Zhang, Gaoxiao; Zhang, Tao; Wu, Liangmiao; Zhou, Xinhua; Gu, Jianbo; Li, Cuimei; Liu, Wei; Long, Cheng; Yang, Xifei; Shan, Luchen; Xu, Lipeng; Wang, Yuqiang; Sun, Yewei; Zhang, Zaijun

doi:10.1007/s12017-018-8478-x

Original Paper
Published: 06 February 2018

Neuroprotective Effect and Mechanism of Action of Tetramethylpyrazine Nitrone for Ischemic Stroke Therapy

Gaoxiao Zhang¹,
Tao Zhang¹,
Liangmiao Wu¹,
Xinhua Zhou¹,
Jianbo Gu¹,
Cuimei Li²,
Wei Liu²,
Cheng Long^3,4,
Xifei Yang⁵,
Luchen Shan¹,
Lipeng Xu¹,
Yuqiang Wang¹,
Yewei Sun¹ &
Zaijun Zhang ORCID: orcid.org/0000-0002-0690-1673¹

NeuroMolecular Medicine volume 20, pages 97–111 (2018)Cite this article

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Abstract

Our previous studies demonstrated that the multifunctional agent TBN, a derivative of tetramethylpyrazine armed with a nitrone moiety, displayed high therapeutic efficacy in experimental ischemic stroke models. However, its molecular mechanisms of action underlying the neuroprotective effect need further exploration. In the present study, we found that TBN had significant activities scavenging free radicals such as ^·OH, O ^·−₂ and ONOO⁻, inhibiting Ca²⁺ overload, maintaining mitochondrial function and preventing neuronal damage in primary cortical cultures. Further, TBN was effective in reducing brain infarction and ameliorating impairment of behavioral functions in the permanent middle cerebral artery occlusion (p-MCAo) rat model. TBN down-regulated the expression of pro-apoptotic factors Bax, while up-regulated the expression of anti-apoptotic factor Bcl-2 and increased the expression of pro-survival factors including p-Akt and p-GSK3β in the peri-infarct cortex of p-MCAo rats. In addition, LY-294002 (a PI3K inhibitor) and MK2206 (an Akt inhibitor) significantly blocked the protective effect of TBN against OGD-induced death of cortical neurons. Taken together, the multifunctional mechanisms including scavenging free radicals, blocking calcium overload, maintaining mitochondrial function and activating the PI3K/Akt/p-GSK3β cell survival pathway were possibly involved in the neuroprotective effects of TBN, making it a promising clinical candidate for the treatment of ischemic stroke.

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Acknowledgements

This study was supported in part by the Scientific Projects of Guangdong Province (2013A022100030, 2015A020211019, 2015B020232011, 2016A030313107); the National Science Foundation of China (81502908); the Science and Technology Program of Guangzhou (201704020181); and the Fundamental Research Funds for the Central Universities (21617469).

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Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China
Gaoxiao Zhang, Tao Zhang, Liangmiao Wu, Xinhua Zhou, Jianbo Gu, Luchen Shan, Lipeng Xu, Yuqiang Wang, Yewei Sun & Zaijun Zhang
Guangzhou Magpie Pharmaceuticals Co., Ltd., Guangzhou, 510632, China
Cuimei Li & Wei Liu
School of Life Sciences, South China Normal University, Guangzhou, 510631, China
Cheng Long
Brain Science Institute, South China Normal University, Guangzhou, 510631, China
Cheng Long
Key Laboratory of Modern Toxicology of Shenzhen, Center for Disease Control and Prevention, No. 8, Longyuan Road, Nanshan District, Shenzhen, 518055, China
Xifei Yang

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Gaoxiao Zhang
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Tao Zhang
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Liangmiao Wu
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Xinhua Zhou
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Jianbo Gu
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Cuimei Li
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Wei Liu
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Cheng Long
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Xifei Yang
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Luchen Shan
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Lipeng Xu
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Yuqiang Wang
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Yewei Sun
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Zaijun Zhang
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Zhang, G., Zhang, T., Wu, L. et al. Neuroprotective Effect and Mechanism of Action of Tetramethylpyrazine Nitrone for Ischemic Stroke Therapy. Neuromol Med 20, 97–111 (2018). https://doi.org/10.1007/s12017-018-8478-x

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Received: 19 July 2017
Accepted: 18 January 2018
Published: 06 February 2018
Issue Date: March 2018
DOI: https://doi.org/10.1007/s12017-018-8478-x

Keywords

Ischemic stroke
Free radicals
Calcium overload
Mitochondrial dysfunction
Neuroprotection