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01-03-2018 | Original Paper

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

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

Published in: NeuroMolecular Medicine | Issue 1/2018

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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Title: Neuroprotective Effect and Mechanism of Action of Tetramethylpyrazine Nitrone for Ischemic Stroke Therapy
Authors: Gaoxiao Zhang
Tao Zhang
Liangmiao Wu
Xinhua Zhou
Jianbo Gu
Cuimei Li
Wei Liu
Cheng Long
Xifei Yang
Luchen Shan
Lipeng Xu
Yuqiang Wang
Yewei Sun
Zaijun Zhang
Publication date: 01-03-2018
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 1/2018
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-018-8478-x

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

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