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Role of autophagy in early brain injury after subarachnoid hemorrhage in rats

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Abstract

Early brain injury (EBI) occurred after aneurismal subarachnoid hemorrhage (SAH) strongly determined the patients’ prognosis. Autophagy was activated in neurons in the acute phase after SAH, while its role in EBI has not been examined. This study was designed to explore the effects of autophagy on EBI post-SAH in rats. A modified endovascular perforating SAH model was established under monitoring of intracranial pressure. Extent of autophagy was regulated by injecting autophagy-regulating drugs (3-methyladenine, wortmannin and rapamycin) 30 min pre-SAH intraventricularly. Simvastatin (20 mg/kg) was prophylactically orally given 14 days before SAH induction. Mortality, neurological scores, brain water content and blood–brain barrier (BBB) permeability were evaluated at 24 h post-SAH. Microtubule-associated protein light chain-3 (LC3 II/I) and beclin-1 were detected for monitoring of autophagy flux. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, expression of cleaved caspase-3 and cytoplasmic histone-associated DNA fragments were used to detect apoptosis. The results showed that mortality was reduced in rapamycin and simvastatin treated animals. When autophagy was inhibited by 3-methyladenine and wortmannin, the neurological scores were decreased, brain water content and BBB permeability were further aggravated and neuronal apoptosis was increased when compared with the SAH animals. Autophagy was further activated by rapamycin and simvastatin, and apoptosis was inhibited and EBI was ameliorated. The present results indicated that activation of autophagy decreased neuronal apoptosis and ameliorated EBI after SAH. Aiming at autophagy may be a potential effective target for preventing EBI after SAH.

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Abbreviations

SAH:

Subarachnoid hemorrhage

3-MA:

3-Methyladenine

Sim:

Simvastatin

Rap:

Rapamycini

Wort:

Wortmannin

TUNEL:

Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling

EBI:

Early brain injury

BBB:

Blood brain barrier

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Acknowledgments

This study was supported by Grant from Natural Science Fund of China (No. 81070944), Youth Special Fund of Heilongjiang Province (No. Q07C100), and Fund of The First Affiliated Hospital of Harbin Medical University (No. Q08-003).

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China

    Hongbo Zhao, Zhiyong Ji, Cong Yan, Wenyang Zhao & Cheng Gao

  2. Department of Neurosurgery, The Third Hospital of Heilongjiang Province, Beian, 164000, Heilongjiang, China

    Deji Tang

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  1. Hongbo Zhao
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  2. Zhiyong Ji
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  3. Deji Tang
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  4. Cong Yan
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  5. Wenyang Zhao
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  6. Cheng Gao
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Corresponding author

Correspondence to Cheng Gao.

Additional information

Zhao Hongbo and Ji Zhiyong have contributed equally to the work.

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Zhao, H., Ji, Z., Tang, D. et al. Role of autophagy in early brain injury after subarachnoid hemorrhage in rats. Mol Biol Rep 40, 819–827 (2013). https://doi.org/10.1007/s11033-012-2120-z

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  • DOI: https://doi.org/10.1007/s11033-012-2120-z

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