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Tetramethylpyrazine Nitrone Reduces Oxidative Stress to Alleviate Cerebral Vasospasm in Experimental Subarachnoid Hemorrhage Models

NeuroMolecular Medicine volume 21, pages 262–274 (2019)Cite this article

Abstract

Cerebral vasospasm is one of the deleterious complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and permanent neurological deficits or even death. Free radicals and oxidative stress are considered as crucial causes contributing to cerebral vasospasm and brain damage after SAH. Tetramethylpyrazine nitrone (TBN), a derivative of the clinically used anti-stroke drug tetramethylpyrazine armed with a powerful free radical scavenging nitrone moiety, has been reported to prevent brain damage from ischemic stroke. The present study aimed to investigate the effects of TBN on vasospasm and brain damage after SAH. Two experimental SAH models were used, a rat model by endovascular perforation and a rabbit model by intracisternal injection of autologous blood. The effects of TBN on SAH were evaluated assessing basilar artery spasm, neuronal apoptosis, and neurological deficits. TBN treatment significantly attenuated vasospasm, improved neurological behavior functions and reduced the number of apoptotic neurons in both the SAH rats and rabbits. Mechanistically, TBN suppressed the increase in 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immuno-positive cells in the cortex of SAH rat brain. Western blot analyses indicated that TBN effectively reversed the altered expression of Bcl-2, Bax and cytochrome C, and up-regulated nuclear factor erythroid-derived 2-like 2 (Nrf2) and hemeoxygenase-1 (HO-1) protein expressions. In the in vitro studies, TBN inhibited H2O2-induced bEnd.3 cell apoptosis and reduced ROS generation. Additionally, TBN alleviated the contraction of rat basilar artery rings induced by H2O2 ex vivo. In conclusion, TBN ameliorated SAH-induced cerebral vasospasm and neuronal damage. These effects of TBN may be attributed to its anti-oxidative stress effect and up-regulation of Nrf2/HO-1.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (NSFC 81872842, 81502908), the Scientific Projects of Guangdong Province (2015B020232011, 2016A020217013), the Scientific Projects of Guangzhou (201704020181), and the Scientific Projects of Foshan (2017IT100153).

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Affiliations

  1. Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, China

    Liangmiao Wu, Zhiyang Su, Ling Zha, Zeyu Zhu, Yewei Sun, Pei Yu, Yuqiang Wang, Gaoxiao Zhang & Zaijun Zhang

  2. Foshan Magpie Pharmaceuticals Co., LTD, Foshan, Guangdong Province, China

    Wei Liu

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  1. Liangmiao Wu
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  2. Zhiyang Su
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  3. Ling Zha
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  4. Zeyu Zhu
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  5. Wei Liu
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  6. Yewei Sun
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  7. Pei Yu
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  8. Yuqiang Wang
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  9. Gaoxiao Zhang
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Contributions

YW, GZ, and ZZ designed and supervised the project. GZ, YS, and LZ participated in making experimental rat model. LW and LZ contributed to establish experimental SAH rabbit model. LW and ZS performed the H&E and immunofluorescence staining. ZS performed the vitro experiments. WL, PY, and ZZ analyzed the samples and data. YW, and ZZ wrote the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Gaoxiao Zhang or Zaijun Zhang.

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Wu, L., Su, Z., Zha, L. et al. Tetramethylpyrazine Nitrone Reduces Oxidative Stress to Alleviate Cerebral Vasospasm in Experimental Subarachnoid Hemorrhage Models. Neuromol Med 21, 262–274 (2019). https://doi.org/10.1007/s12017-019-08543-9

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  • DOI: https://doi.org/10.1007/s12017-019-08543-9

Keywords

  • Subarachnoid hemorrhage
  • Cerebral vasospasm
  • Tetramethylpyrazine nitrone
  • Anti-oxidative stress
  • Nrf2
  • HO-1