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Neuroprotective Effects Against Cerebral Ischemic Injury Exerted by Dexmedetomidine via the HDAC5/NPAS4/MDM2/PSD-95 Axis

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Abstract

Numerous evidences have highlighted the efficient role of dexmedetomidine (DEX) in multi-organ protection. In the present study, the neuroprotective role of DEX on cerebral ischemic injury and the underlining signaling mechanisms were explored. In order to simulate cerebral ischemic injury, we performed middle cerebral artery occlusion in mice and oxygen-glucose deprivation in neurons. Immunohistochemistry, Western blot analysis, and RT-qPCR were used to examine expression of HDAC5, NPAS4, MDM2, and PSD-95 in hippocampus tissues of MCAO mice and OGD-treated neurons. MCAO mice received treatment with DEX and sh-PSD-95, followed by neurological function evaluation, behavioral test, infarct volume detection by TTC staining, and apoptosis by TUNEL staining. Additionally, gain- and loss-of-function approaches were conducted in OGD-treated neuron after DEX treatment. Cell viability and apoptosis were assessed with the application of CCK-8 and flow cytometry. The interaction between MDM2 and PSD-95 was evaluated using Co-IP assay, followed by ubiquitination of PSD-95 detection. As per the results, HDAC5 and MDM2 were abundantly expressed, while NPAS4 and PSD-95 were poorly expressed in hippocampus tissues of MCAO mice and OGD-treated neurons. DEX elevated viability, and reduced LDH leakage rate and apoptosis rate of OGD-treated neurons, which was reversed following the overexpression of HDAC5. Moreover, HDAC5 augmented MDM2 expression via NPAS4 inhibition. MDM2 induced PSD-95 ubiquitination and degradation. In MCAO mice, DEX improved neurological function and behaviors and decreased infarct volume and apoptosis, which was negated as a result of PSD-95 silencing. DEX plays a neuroprotective role against cerebral ischemic injury by disrupting MDM2-induced PSD-95 ubiquitination and degradation via HDAC5 and NPAS4.

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Acknowledgments

We would like show sincere appreciation to the reviewers for critical comments on this article.

Funding

This project was supported by the Natural Science Foundation of Shanghai (No. 14ZR1407500).

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Authors and Affiliations

  1. Department of Anesthesiology, Fudan University Shanghai Cancer Center, No. 270, Dong’an Road, Shanghai, 200032, People’s Republic of China

    Hu Lv, Ying Li, Qian Cheng, Jiawei Chen & Wei Chen

  2. Department of Oncology, Shanghai Medical College, Fudan University, No. 270, Dong’an Road, Shanghai, 200032, People’s Republic of China

    Hu Lv, Ying Li, Qian Cheng, Jiawei Chen & Wei Chen

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  1. Hu Lv
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  2. Ying Li
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  3. Qian Cheng
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  5. Wei Chen
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Contributions

Hu Lv, Ying Li, and Qian Cheng designed the study, collated the data, and carried out data analyses. Wei Chen and Jiawei Chen contributed to drafting and polishing the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Jiawei Chen or Wei Chen.

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This study was conducted with the approval of the ethics committee of Shanghai Medical College of Fudan University and in strict accordance with the Guide for the Care and Use of Laboratory animals published by the US National Institutes of Health, with extensive efforts made to minimize animal suffering.

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Hu Lv, Ying Li, and Qian Cheng are regarded as co-first authors.

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Lv, H., Li, Y., Cheng, Q. et al. Neuroprotective Effects Against Cerebral Ischemic Injury Exerted by Dexmedetomidine via the HDAC5/NPAS4/MDM2/PSD-95 Axis. Mol Neurobiol 58, 1990–2004 (2021). https://doi.org/10.1007/s12035-020-02223-7

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  • DOI: https://doi.org/10.1007/s12035-020-02223-7

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