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Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

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Abstract

DNA damage is associated with aging and neurological disorders, including Alzheimer’s disease. Isoflurane is a commonly used anesthetic. It remains largely unknown whether isoflurane induces DNA damage. Phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X) is a marker of DNA damage. We therefore set out to assess the effects of isoflurane on γH2A.X level in H4 human neuroglioma cells and in brain tissues of mice. Oxidative stress, caspase-activated DNase (CAD), and the p53 signaling pathway are involved in DNA damage. Thus, we determined the interaction of isoflurane with reactive oxygen species (ROS), CAD, and p53 to illustrate the underlying mechanisms. The cells were treated with 2 % isoflurane for 3 or 6 h. The mice were anesthetized with 1.4 % isoflurane for 2 h. Western blot, immunostaining and live cell fluorescence staining were used in the experiments. We showed that isoflurane increased levels of γH2A.X, cleaved caspase-3, and nucleus translocation of CAD and decreased levels of inhibitor of CAD (ICAD) and p53. Isoflurane enhanced the nucleus level of γH2A.X. Moreover, caspase inhibitor Z-VAD and ROS generation inhibitor N-acetyl-L-cysteine (NAC) attenuated the isoflurane-induced increase in γH2A.X level. However, NAC did not significantly alter the isoflurane-induced reduction in p53 level. Finally, p53 activator (actinomycin D) and inhibitor (pifithrin-α) attenuated and potentiated the isoflurane-induced increase in γH2A.X level, respectively. These findings suggest that isoflurane might induce DNA damage, as represented by increased γH2A.X level, via induction of oxidative stress and inhibition of the repair of DNA damage through the p53 signaling pathway.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

β-amyloid protein

DSBs:

DNA double-strand breaks

ATM:

Ataxia telangiectasia mutated

γH2A.X:

Phosphorylation of histone protein H2A variant X at Ser139

ROS:

Reactive oxygen species

CAD:

Caspase-activated DNase

ICAD:

Inhibitor of caspase-activated DNase

NAC:

N-acetyl-L-cysteine

DCFH-DA:

2′,7′-Dichlorfluorescein-diacetate

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Acknowledgments

This research was supported by R21 AG038994, R01 GM088801, and R01 AG041274 from National Institutes of Health, Bethesda, Maryland, and Investigator-initiated Research grant from Alzheimer’s Association, Chicago, Illinois to Zhongcong Xie. Anesthetic isoflurane was generously provided by the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. The experiments were performed in Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

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Authors and Affiliations

  1. Department of Anesthesiology, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, 100191, China

    Cheng Ni & Xiangyang Guo

  2. Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA, 02129, USA

    Cheng Ni, Cheng Li, Yuanlin Dong, Yiying Zhang & Zhongcong Xie

  3. Department of Anesthesiology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200072, China

    Cheng Li

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Correspondence to Zhongcong Xie.

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The animal protocol was approved by the Massachusetts General Hospital (Boston, Massachusetts) Standing Committee on the Use of Animals in Research and Teaching. All experiments followed the National Institutes of Health guidelines, and efforts were made to minimize the number of animals used.

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The authors declare that they have no competing interests.

Author Contributions

C.N., C.L., and Y.D. performed experiments, generated and analyzed the data, contributed to project design and manuscript writing. Y.Z. and X.G. contributed to the design of experiments and data analysis. Z.X. designed and directed the project, participated in experiments, and wrote the manuscript. All authors read and approved the manuscript.

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Ni, C., Li, C., Dong, Y. et al. Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway. Mol Neurobiol 54, 3591–3605 (2017). https://doi.org/10.1007/s12035-016-9937-8

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