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Dexmedetomidine Ameliorates Postoperative Cognitive Dysfunction via the MicroRNA-381-Mediated EGR1/p53 Axis

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Abstract

Postoperative cognitive dysfunction (POCD; cognitive change associated with anesthesia and surgery) is one of the most serious long-term postoperative complications that occur in elderly patients. Dexmedetomidine (DEX) has been shown to be beneficial for improving outcomes of postoperative cognitive function. However, the exact mechanism underlying this role requires is yet to be found. The present study aims to determine the pathways involved in the protective effects of DEX against POCD in C57BL/6 J aged mice. DEX was administered after POCD modeling in C57BL/6 J aged mice. The cognitive function was evaluated after DEX treatment using novel object recognition, open field, and Y-maze tests. We also assessed its effects on neuron apoptosis and production of TNF-α and IL-1β in mouse brain tissues as well as expression levels of DNA damage-related proteins p53, p21, and γH2AX. Interactions between early growth response 1 (EGR1) and p53, microRNA (miR)-381, and EGR1 were identified by ChIP and luciferase reporter assays, and gain- and loss-of-function experiments were performed to confirm the involvement of their interaction in POCD. DEX administration attenuated hippocampal neuron apoptosis, neuroinflammation, DNA damage, and cognitive impairment in aged mice. miR-381 targeted EGR1 and disrupted its interaction with p53, leading to a decline in hippocampal neuron apoptosis, DNA damage, neuroinflammation, and cognitive impairment. Furthermore, DEX administration resulted in the enhancement of miR-381 expression and the subsequent inhibition of EGR1/p53 to protect against cognitive impairment in aged mice. Overall, these results indicate that DEX may have a potential neuroprotective effect against POCD via the miR-381/EGR1/p53 signaling, shedding light on the mechanisms involved in neuroprotection in POCD.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Anesthesiology, The First Hospital of China Medical University, No. 155, North Nanjing Road, Heping DistrictLiaoning Province, Shenyang, 110001, People’s Republic of China

    Yi-Liang Wang & Da-Sheng Cai

  2. Department of Thyroid and Breast Surgery, The People’s Hospital of Liaoning Province, Shenyang, 110001, People’s Republic of China

    Ying Zhang

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  1. Yi-Liang Wang
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Contributions

Yi-Liang Wang designed the study. Da-Sheng Cai was involved in data collection. Ying Zhang and Da-Sheng Cai performed the statistical analysis and preparation of figures. Yi-Liang Wang and Ying Zhang drafted the paper. All authors read and approved the final manuscript.

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Correspondence to Da-Sheng Cai.

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This study was carried out after being approved by the ethics committee of the First Hospital of China Medical University and was performed according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. Extensive efforts were made to ensure minimal suffering of the animals used in the study.

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Wang, YL., Zhang, Y. & Cai, DS. Dexmedetomidine Ameliorates Postoperative Cognitive Dysfunction via the MicroRNA-381-Mediated EGR1/p53 Axis. Mol Neurobiol 58, 5052–5066 (2021). https://doi.org/10.1007/s12035-021-02417-7

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