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Edaravone at high concentrations attenuates cognitive dysfunctions induced by abdominal surgery under general anesthesia in aged mice

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Abstract

Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3β (pSer9-GSK3β) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD.

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Abbreviations

AChE:

Acetylcholinesterase

ANOVA:

Analysis of variance

DAPI:

4′,6-diamidino-2-phenylindole

ELISA:

Enzyme linked immunosorbent assay

GFAP:

Glial fibrillary acidic protein

GSK3β:

Glycogen synthase kinase-3β

Iba-1:

Ionized calcium binding adaptor molecule-1

IHC:

Immunohistochemical

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

LPS:

Lipopolysaccharide

OD:

Optical density

PBS:

Phosphate buffer solution

POCD:

Post-operative cognitive dysfunction

SD:

Standard deviation

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

This research was funded by the National Natural Science Foundation of China (81870853), Zhejiang Provincial Natural Science Foundation of China (LY19H250001), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2019325190), Ningbo Sci & Tech Project for Common Wealth (2017C50042), Zhejiang Key Laboratory of Pathophysiology (201804), Ningbo municipal innovation team of life science and health (2015C110026), LiDakSum Marine Biopharmaceutical Development Fund, and the K. C. Wong Magna Fund in Ningbo University.

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Authors and Affiliations

  1. The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315211, China

    Yiying Zhou, Xiang Wu, Binbin Zhu & Wei Cui

  2. Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China

    Luying Ye, Yujing Bai, Hui Zhang, Zhenquan Xuan, Yi Feng, Panpan Zhang, Yi Chen, Yushan Yan & Wei Cui

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  1. Yiying Zhou
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Correspondence to Wei Cui.

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Yiying Zhou and Xiang Wu contribute equally as co-first authors.

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Zhou, Y., Wu, X., Ye, L. et al. Edaravone at high concentrations attenuates cognitive dysfunctions induced by abdominal surgery under general anesthesia in aged mice. Metab Brain Dis 35, 373–383 (2020). https://doi.org/10.1007/s11011-019-00532-y

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