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Tetramethylpyrazine Nitrone Improves Neurobehavioral Functions and Confers Neuroprotection on Rats with Traumatic Brain Injury

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Abstract

Oxidative stress is one of the major secondary injury mechanisms after traumatic brain injury (TBI). 2-[[(1,1-Dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a derivative of the clinically used anti-stroke drug tetramethylpyrazine armed with a powerful free radical-scavenging nitrone moiety, has been demonstrated promising therapeutic efficacy in ischemic stroke and Parkinson’s models. The present study aims to investigate the effects of TBN on behavioral function and neuroprotection in rats subjected to TBI. TBN (90 mg/kg) was administered twice daily for 7 days by intravenous injection following TBI. TBN improved neuronal behavior functions after brain injury, including rotarod test and adhesive paper removal test. Compared with the TBI model group, TBN treatment significantly protected NeuN-positive neurons, while decreased glial fibrillary acidic protein (GFAP)-positive cells. The number of 4-hydroxynonenal (4-HNE)-positive and 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive cells around the damaged area after TBI were significantly decreased in the TBN treatment group. In addition, TBN effectively reversed the altered expression of Bcl-2, Bax and caspase 3, and the down-regulation of nuclear factor erythroid-derived 2-like 2 (Nrf-2) and hemeoxygenase-1 (HO-1) proteins expression stimulated by TBI. In conclusion, TBN improves neurobehavioral functions and protects neurons against TBI. This protective effect may be achieved by anti-neuronal apoptosis, alleviating oxidative stress damage and up-regulating Nrf-2 and HO-1 expression.

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Abbreviations

ARE:

Anti-oxidative response element

Bcl-2:

B cell lymphoma-2

Bax:

Bcl-2-associated X protein

CCI:

Controlled cortical impact

HO-1:

Hemeoxygenase-1

Nrf-2:

Nuclear factor erythroid-derived 2-like 2

ROS:

Reactive oxygen species

TBI:

Traumatic brain injury

4-HNE:

4-Hydroxynonenal

8-OHdG:

8-Hydroxy-2′-deoxyguanosine

PFA:

Paraformaldehyde

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Acknowledgments

This work is supported by grants from the Science and Technology Project of Guangdong (2015B020232011 to YW, 2013A022100030 and 2016A020217013 to PY, 2015A030313317 to ZZ), and the Key Laboratory Project of Guangzhou (151800010 to YW).

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Authors and Affiliations

  1. Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China

    Gaoxiao Zhang, Fen Zhang, Tao Zhang, Jianbo Gu, Cuimei Li, Yewei Sun, Pei Yu, Zaijun Zhang & Yuqiang Wang

  2. Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China

    Gaoxiao Zhang, Fen Zhang, Tao Zhang, Jianbo Gu, Cuimei Li, Yewei Sun, Pei Yu, Zaijun Zhang & Yuqiang Wang

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  1. Gaoxiao Zhang
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Correspondence to Zaijun Zhang.

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Zhang, G., Zhang, F., Zhang, T. et al. Tetramethylpyrazine Nitrone Improves Neurobehavioral Functions and Confers Neuroprotection on Rats with Traumatic Brain Injury. Neurochem Res 41, 2948–2957 (2016). https://doi.org/10.1007/s11064-016-2013-y

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  • DOI: https://doi.org/10.1007/s11064-016-2013-y

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