Abstract
The ataxia-telangiectasia mutated (ATM) protein is regarded as the linchpin of cellular defenses to stress. Deletion of ATM results in strong oxidative stress and degenerative diseases in the nervous system. However, the role of ATM in neuronal ischemic preconditioning and lethal ischemic injury is still largely unknown. In this study, mice cortical neurons preconditioned with sublethal exposure to oxygen glucose deprivation (OGD) exhibited ATM/glucose-6-phosphate dehydrogenase pathway activation. Additionally, pharmacological inhibition of ATM prior to the preconditioning reversed neuroprotection provided by preconditioning in vitro and in vivo. Meanwhile, we found that ATM/P53 pro-apoptosis pathway was driven by lethal OGD injury, and pharmacological inhibition of ATM during fatal oxygen–glucose deprivation/reperfusion injury promoted neuronal survival. More importantly, inhibition of ATM activity after cerebral ischemia protected against cerebral ischemic-reperfusion damage in mice. In conclusion, our data show the dual role of ATM in neuronal ischemic preconditioning and lethal ischemic injury, involving in the protection of ischemic preconditioning, but promoting neuronal death in lethal ischemic injury. Thus, the present study provides new opportunity for the treatment of ischemic stroke.
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Abbreviations
- ATM:
-
Ataxia-telangiectasia mutated
- OGD:
-
Oxygen glucose deprivation
- DSBs:
-
Double-strand breaks
- HIF-1:
-
Hypoxia-inducible factor 1
- PC:
-
Preconditioning
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- GSH:
-
Glutathione
- MCAO:
-
Middle cerebral artery occlusion
- HDAC4:
-
Histone deacetylase 4
- CREB:
-
CAMP-response element binding protein
- TTC:
-
2,3,5-Triphenyltetrazolium chloride
- TUNEL:
-
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling
- G6PD:
-
Glucose-6-phosphate dehydrogenase
- γ-H2AX:
-
Phosphorylated Histone H2AX
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Acknowledgements
This research was funded by the National Nature Science Foundation of China (grant no. 81570417 to J.H.W.) and the Foundation of Health and Family Planning Commission of Hubei province (grant no. WJ2017H0026 to J.H.W).
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Experimental design: Jian-hua Wu; stroke model, stereotaxic injection, and writing of the article: Guang-hui Xie; TTC staining, western blotting, magnetic resonance imaging, immunofluorescence, Caspase-3 activity assay, G6PD activity assay, cell viability assay, and TUNEL staining: Han-jun Dai and Fang Liu; cell culture, NADPH/NADP+ and GSH/GSSC assay: Ying-pei Zhang; neurological score and rotarod treadmill test: Li Zhu; data analysis: Jun-jie Nie.
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Xie, Gh., Dai, Hj., Liu, F. et al. A Dual Role of ATM in Ischemic Preconditioning and Ischemic Injury. Cell Mol Neurobiol 40, 785–799 (2020). https://doi.org/10.1007/s10571-019-00773-6
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DOI: https://doi.org/10.1007/s10571-019-00773-6