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Amantadine attenuates sepsis-induced cognitive dysfunction possibly not through inhibiting toll-like receptor 2

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Abstract

Amantadine has been shown to reduce anesthesia and surgery-induced neuroinflammation and cognitive dysfunction. It is known that sepsis can impair brain function. We determined whether amantadine-attenuated sepsis-induced neuroinflammation and dysfunction of learning and memory and whether toll-like receptors (TLRs) play a role in the effects. Six- to eight-week-old mice were subjected to cecal ligation and puncture (CLP). Amantadine at 30 mg/kg/day was injected intraperitoneally for 3 days. CU-CPT22, a TLR1/TLR2 inhibitor, at 3 mg/kg/day was injected intraperitoneally for 2 days. Mice were subjected to Barnes maze and fear conditioning tests from 1 week after CLP. CLP induced neuroinflammation and cognitive dysfunction. CLP also increased the expression of toll-like receptor 2 (TLR2), TLR4, and TLR9, three major TLRs in the brain, in CD-1 male mice. Amantadine attenuated CLP-induced neuroinflammation and dysfunction of learning and memory but did not have significant effects on the expression of TLRs. CU-CPT22 also attenuated sepsis-induced neuroinflammation and cognitive dysfunction. Similarly, sepsis induced neuroinflammation and cognitive dysfunction in the C57BL/6J mice. Interestingly, sepsis also induced neuroinflammation and cognitive dysfunction in the TLR2 knockout mice. The effects of amantadine on the neuroinflammation and cognitive dysfunction were still apparent in these knockout mice. TLR2 contributes to sepsis-induced neuroinflammation and cognitive dysfunction. However, inhibiting TLR2 may not be a major mechanism for amantadine to inhibit sepsis-induced neuroinflammation and cognitive dysfunction.

Key messages

  • Sepsis induces neuroinflammation and cognitive impairment, which were attenuated by amantadine. Toll-like receptors 2 mediates these sepsis effects but may not be the major target for amantadine to reduce these effects.

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Author information

Authors and Affiliations

  1. Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, PO Box 800710, Charlottesville, VA, 22908-0710, USA

    Wei Xing, Pinjie Huang, Yang Lu & Zhiyi Zuo

  2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Wei Xing & Weian Zeng

  3. Department of Anesthesiology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China

    Pinjie Huang

  4. Department of Anesthesiology, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China

    Yang Lu

  5. Department of Anesthesiology and Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China

    Zhiyi Zuo

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  1. Wei Xing
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  2. Pinjie Huang
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  3. Yang Lu
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  4. Weian Zeng
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Contributions

ZZ conceived the project. WX, PH, WZ, and ZZ designed the study, WX, PH, and YL performed the experiments. WX and PH did the initial data analysis and drafted “Materials and methods” section. ZZ performed the final data analysis and wrote the manuscript.

Corresponding author

Correspondence to Zhiyi Zuo.

Ethics declarations

The animal protocol was approved by the institutional Animal Care and Use Committee of the University of Virginia (Charlottesville, VA). All animal experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publications number 80-23) revised in 2011.

Conflict of interest

The authors declare that they have no conflict of interest.

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Xing, W., Huang, P., Lu, Y. et al. Amantadine attenuates sepsis-induced cognitive dysfunction possibly not through inhibiting toll-like receptor 2. J Mol Med 96, 391–402 (2018). https://doi.org/10.1007/s00109-018-1631-z

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  • DOI: https://doi.org/10.1007/s00109-018-1631-z

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