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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

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.

Keywords

Amantadine Cognitive function Neuroinflammation Sepsis Toll-like receptors 

Notes

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.

References

  1. 1.
    Gofton TE, Young GB (2012) Sepsis-associated encephalopathy. Nat Rev Neurol 8:557–566CrossRefPubMedGoogle Scholar
  2. 2.
    Zampieri FG, Park M, Machado FS, Azevedo LC (2011) Sepsis-associated encephalopathy: not just delirium. Clinics 66:1825–1831CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Sprung CL, Peduzzi PN, Shatney CH, Schein RM, Wilson MF, Sheagren JN, Hinshaw LB (1990) Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med 18:801–806CrossRefPubMedGoogle Scholar
  4. 4.
    Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE (2010) Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med 38:1276–1283CrossRefPubMedGoogle Scholar
  5. 5.
    Zhang J, Tan H, Jiang W, Zuo Z (2014) Amantadine alleviates postoperative cognitive dysfunction possibly by increasing glial cell line-derived neurotrophic factor in rats. Anesthesiology 121:773–785CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Lee J, Sayed N, Hunter A, Au KF, Wong WH, Mocarski ES, Pera RR, Yakubov E, Cooke JP (2012) Activation of innate immunity is required for efficient nuclear reprogramming. Cell 151:547–558CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J et al (2004) Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci U S A 101:3516–3521CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Bi J, Shan W, Luo A, Zuo Z (2017) Critical role of matrix metallopeptidase 9 in postoperative cognitive dysfunction and age-dependent cognitive decline. Oncotarget 8(31):51817–51829CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Zhang J, Jiang W, Zuo Z (2014) Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor kappaB. Neuroscience 261:1–10CrossRefPubMedGoogle Scholar
  10. 10.
    Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11:373–384CrossRefPubMedGoogle Scholar
  11. 11.
    Hoffmann O, Braun JS, Becker D, Halle A, Freyer D, Dagand E, Lehnardt S, Weber JR (2007) TLR2 mediates neuroinflammation and neuronal damage. J Immunol 178:6476–6481CrossRefPubMedGoogle Scholar
  12. 12.
    Lu SM, Yu CJ, Liu YH, Dong HQ, Zhang X, Zhang SS, Hu LQ, Zhang F, Qian YN, Gui B (2015) S100A8 contributes to postoperative cognitive dysfunction in mice undergoing tibial fracture surgery by activating the TLR4/MyD88 pathway. Brain Behav Immun 44:221–234CrossRefPubMedGoogle Scholar
  13. 13.
    Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue LW 3rd, Bland KI, Chaudry IH (2005) Cecal ligation and puncture. Shock 24(Suppl 1):52–57CrossRefPubMedGoogle Scholar
  14. 14.
    Cheng K, Wang X, Zhang S, Yin H (2012) Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. Angew Chem 51:12246–12249CrossRefGoogle Scholar
  15. 15.
    Chaudry IH, Wichterman KA, Baue AE (1979) Effect of sepsis on tissue adenine nucleotide levels. Surgery 85:205–211PubMedGoogle Scholar
  16. 16.
    Kim JH, Lee HW, Hwang J, Kim J, Lee MJ, Han HS, Lee WH, Suk K (2012) Microglia-inhibiting activity of Parkinson's disease drug amantadine. Neurobiol Aging 33:2145–2159CrossRefPubMedGoogle Scholar
  17. 17.
    Bido S, Marti M, Morari M (2011) Amantadine attenuates levodopa-induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels. J Neurochem 118:1043–1055CrossRefPubMedGoogle Scholar
  18. 18.
    Ji YR, Kim HJ, Bae KB, Lee S, Kim MO, Ryoo ZY (2015) Hepatic serum amyloid A1 aggravates T cell-mediated hepatitis by inducing chemokines via toll-like receptor 2 in mice. J Biol Chem 290:12804–12811CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Li L, Wang Z, Zuo Z (2013) Chronic intermittent fasting improves cognitive functions and brain structures in mice. PLoS One 8:e66069CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Wang Z, Park SH, Zhao H, Peng S, Zuo Z (2014) A critical role of glutamate transporter type 3 in the learning and memory of mice. Neurobiol Learn Mem 114:70–80CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Wang Z, Huang W, Zuo Z (2014) Perioperative aspirin improves neurological outcome after focal brain ischemia possibly via inhibition of notch 1 in rat. J Neuroinflammation 11:56CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Li H, Yin J, Li L, Deng J, Feng C, Zuo Z (2013) Isoflurane postconditioning reduces ischemia-induced nuclear factor-κB activation and interleukin 1β production to provide neuroprotection in rats and mice. Neurobiol Dis 54:216–224CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Della Giustina A, Goldim MP, Danielski LG, Florentino D, Mathias K, Garbossa L, Oliveira Junior AN, Fileti ME, Zarbato GF, da Rosa N, Martins Laurentino AO, Fortunato JJ, Mina F, Bellettini-Santos T, Budni J, Barichello T, Dal-Pizzol F, Petronilho F (2017) Alpha-lipoic acid attenuates acute neuroinflammation and long-term cognitive impairment after polymicrobial sepsis. Neurochem Int 108:436–447CrossRefPubMedGoogle Scholar
  24. 24.
    Cao L, Li L, Lin D, Zuo Z (2012) Isoflurane induces learning impairment that is mediated by interleukin 1beta in rodents. PLoS One 7:e51431CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Ziegler G, Harhausen D, Schepers C, Hoffmann O, Rohr C, Prinz V, Konig J, Lehrach H, Nietfeld W, Trendelenburg G (2007) TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 359:574–579CrossRefPubMedGoogle Scholar
  26. 26.
    Lehnardt S, Lehmann S, Kaul D, Tschimmel K, Hoffmann O, Cho S, Krueger C, Nitsch R, Meisel A, Weber JR (2007) Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmun 190:28–33CrossRefGoogle Scholar
  27. 27.
    Kilic U, Kilic E, Matter CM, Bassetti CL, Hermann DM (2008) TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiol Dis 31:33–40CrossRefPubMedGoogle Scholar
  28. 28.
    Du X, Poltorak A, Wei Y, Beutler B (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw 11:362–371PubMedGoogle Scholar
  29. 29.
    Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar a{beta}-stimulated microglial activation. J Neurosci 29:11982–11992CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34:269–281CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Lien E, Ingalls RR (2002) Toll-like receptors. Crit Care Med 30:S1–S11CrossRefGoogle Scholar
  32. 32.
    Mishra BB, Mishra PK, Teale JM (2006) Expression and distribution of toll-like receptors in the brain during murine neurocysticercosis. J Neuroimmun 181:46–56CrossRefGoogle Scholar
  33. 33.
    Wang Y, He H, Li D, Zhu W, Duan K, Le Y, Liao Y, Ou Y (2013) The role of the TLR4 signaling pathway in cognitive deficits following surgery in aged rats. Mol Med Rep 7:1137–1142CrossRefPubMedGoogle Scholar
  34. 34.
    Yu L, Sun L, Chen S (2014) Protective effect of senegenin on splenectomy-induced postoperative cognitive dysfunction in elderly rats. Exp Ther Med 7:821–826CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Singleton KD, Wischmeyer PE (2003) Distance of cecum ligated influences mortality, tumor necrosis factor-alpha and interleukin-6 expression following cecal ligation and puncture in the rat. Euro Surg Res 35:486–491CrossRefGoogle Scholar
  36. 36.
    Maier S, Traeger T, Entleutner M, Westerholt A, Kleist B, Huser N, Holzmann B, Stier A, Pfeffer K, Heidecke CD (2004) Cecal ligation and puncture versus colon ascendens stent peritonitis: two distinct animal models for polymicrobial sepsis. Shock 21:505–511CrossRefPubMedGoogle Scholar
  37. 37.
    Tian J, Dai H, Deng Y, Zhang J, Li Y, Zhou J, Zhao M, Zhao M, Zhang C, Zhang Y, Wang P, Bing G, Zhao L (2015) The effect of HMGB1 on sub-toxic chlorpyrifos exposure-induced neuroinflammation in amygdala of neonatal rats. Toxicology 338:95–103CrossRefPubMedGoogle Scholar
  38. 38.
    Fan D, Li J, Zheng B, Hua L, Zuo Z (2016) Enriched environment attenuates surgery-induced impairment of learning, memory, and neurogenesis possibly by preserving BDNF expression. Mol Neurobiol 53:344–354CrossRefPubMedGoogle Scholar

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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