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Tert-butylhydroquinone Ameliorates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Mice by Enhancing Nrf2-Independent Autophagy

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Abstract

Evidence has shown that the activation of the autophagy pathway after experimental subarachnoid hemorrhage (SAH) protects against neuronal damage. Tert-butylhydroquinone (tBHQ), a commonly used nuclear factor erythroid 2-related factor 2 (Nrf2) activator, was found to significantly enhance autophagy activation. The aim of this study was to explore the effect of tBHQ treatment on early stage brain injury at 24 h after SAH. The results showed that tBHQ treatment failed to stimulate an effective anti-oxidative effect at 24 h after the SAH operation, but succeeded in ameliorating early brain injury, including alleviated brain edema, BBB disruption, neuronal degeneration and neurological deficits. Further exploration found that tBHQ treatment significantly increased the expression of Beclin-1 and the ratio of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I, suggesting that autophagy was enhanced after tBHQ treatment. Moreover, tBHQ treatment restored Bcl-2 and Bax expression and reduced caspase-3 cleavage, suggesting the protective effect of tBHQ treatment in ameliorating brain injury after SAH. Furthermore, tBHQ enhanced autophagy activation, decreased neuronal degeneration and improved the neurological score after SAH in Nrf2-deficient mice. Taken together, these findings suggest that tBHQ treatment exerts neuro-protective effects against EBI following SAH by enhancing Nrf2-independent autophagy. Therefore, tBHQ is a promising therapeutic agent against EBI following SAH.

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Abbreviations

tBHQ:

Tert-butylhydroquinone

aSAH:

Aneurysmal subarachnoid hemorrhage

SAH:

Subarachnoid hemorrhage

Nrf2:

Nuclear factor erythroid 2-related factor 2

ARE:

Antioxidant response elements

Keap1:

Kelch-like ECH-associated protein 1

RT-PCR:

Reverse transcription-polymerase chain reaction

TBI:

Traumatic brain injury

BBB:

Blood-brain barrier

CSF:

Cerebrospinal fluid

NF-κB:

Nuclear factor-kappa B

PBS:

Phosphate-buffered saline

GPx:

Glutathione peroxidase

SOD:

Superoxide dismutase

LC3-1:

Microtubule-associated protein 1 light chain 3-I

LC3-II:

Microtubule-associated protein 1 light chain 3-II

FJb:

Fluoro-Jade b

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81070974, 81000503, 81371357), the Jiangsu Provincial Key Subject (Nos. BL2013027, xk201129).

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Authors and Affiliations

  1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China

    Tao Li, Kang-jian Sun, Han-Dong Wang, Meng-Liang Zhou, Ke Ding, Xin-Yu Lu, Wu-Ting Wei & Chun-Xi Wang

  2. Department of Neurosurgery, People’s Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu Province, China

    Xin-Yu Lu

  3. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanfang University, Guangzhou, Guangdong Province, China

    Wu-Ting Wei

  4. Department of Neurosurgery, Jinling Hospital, School of Medicine, Second Military Medical University, Shanghai, China

    Xiao-Ming Zhou

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  1. Tao Li
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Correspondence to Han-Dong Wang.

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Li, T., Sun, Kj., Wang, HD. et al. Tert-butylhydroquinone Ameliorates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Mice by Enhancing Nrf2-Independent Autophagy. Neurochem Res 40, 1829–1838 (2015). https://doi.org/10.1007/s11064-015-1672-4

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