Journal of Molecular Medicine

, Volume 96, Issue 5, pp 391–402 | Cite as

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

  • Wei Xing
  • Pinjie Huang
  • Yang Lu
  • Weian Zeng
  • Zhiyi Zuo
Original Article


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.


Amantadine Cognitive function Neuroinflammation Sepsis Toll-like receptors 


Authors’ 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.

Compliance with ethical standards

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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of AnesthesiologyUniversity of Virginia Health SystemCharlottesvilleUSA
  2. 2.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of AnesthesiologySun Yat-Sen University Cancer CenterGuangzhouPeople’s Republic of China
  3. 3.Department of AnesthesiologyThird Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouPeople’s Republic of China
  4. 4.Department of Anesthesiology, Second Affiliated HospitalXi’an Jiaotong UniversityXi’anChina
  5. 5.Department of Anesthesiology and Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina

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