Skip to main content

Advertisement

SpringerLink
Log in

Paeoniflorin Atttenuates Amyloidogenesis and the Inflammatory Responses in a Transgenic Mouse Model of Alzheimer’s Disease

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is associated with the inflammatory response in response to amyloid β-peptide (Aβ). Previous studies have suggested that paeoniflorin (PF) shows anti-inflammatory and neuroprotective effects in inflammation-related diseases. However, the impacts of PF on AD have not been investigated. In the present study, we showed that a 4-week treatment with PF could significantly inhibit Aβ burden, Aβ-induced over activation of astrocytes and microglia, downregulation of proinflammatory cytokines, and upregulation of anti-inflammatory cytokines in the brain. In addition, we demonstrated that chronic treatment with PF inhibited the activation of glycogen synthase kinase 3β (GSK-3β) and reversed neuroinflammtory-induced activation of nuclear factor-kappa B (NF-κB) signaling pathways. Moreover, PF exerted inhibitory effects on NALP3 inflammasome, caspase-1, and IL-1β. Collectively, in the present study, we demonstrated that PF exhibits neuroprotective effects in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice via inhibiting neuroinflammation mediated by the GSK-3β and NF-κB signaling pathways and nucleotide-binding domain-like receptor protein 3 inflammasome. Thus, these results suggest that PF might be useful to intervene in development or progression of neurodegeneration in AD through its anti-inflammatory and anti-amyloidogenic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Cummings JL, Cole G (2002) Alzheimer disease. JAMA 287:2335–2338

    Article  CAS  PubMed  Google Scholar 

  2. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE (2007) Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci 27:3057–3063

    Article  CAS  PubMed  Google Scholar 

  4. Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W (2013) Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Investig 123:224–235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Yuskaitis CJ, Jope RS (2009) Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal 21:264–273

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Beurel E, Jope RS (2009) Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J Neuroinflammation 6:9

    Article  PubMed Central  PubMed  Google Scholar 

  7. Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A (2008) Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med 12:2255–2262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857–865

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55:697–711

    Article  CAS  PubMed  Google Scholar 

  10. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678

    Article  CAS  PubMed  Google Scholar 

  12. Wu SH, Wu DG, Chen YW (2010) Chemical constituents and bioactivities of plants from the genus Paeonia. Chem Biodivers 7:90–104

    Article  CAS  PubMed  Google Scholar 

  13. Nizamutdinova IT, Jin YC, Kim JS, Yean MH, Kang SS, Kim YS, Lee JH, Seo HG, Kim HJ, Chang KC (2008) Paeonol and paeoniflorin, the main active principles of Paeonia albiflora, protect the heart from myocardial ischemia/reperfusion injury in rats. Planta Med 74:14–18

    Article  CAS  PubMed  Google Scholar 

  14. Guo RB, Wang GF, Zhao AP, Gu J, Sun XL, Hu G (2012) Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/NF-kappaB-mediated inflammatory responses. PLoS ONE 7:e49701

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Jiang D, Chen Y, Hou X, Xu J, Mu X, Chen W (2011) Influence of Paeonia lactiflora roots extract on cAMP-phosphodiesterase activity and related anti-inflammatory action. J Ethnopharmacol 137:914–920

    Article  PubMed  Google Scholar 

  16. Wang D, Wong HK, Feng YB, Zhang ZJ (2013) Paeoniflorin, a natural neuroprotective agent, modulates multiple anti-apoptotic and pro-apoptotic pathways in differentiated PC12 cells. Cell Mol Neurobiol 33:521–529

    Article  CAS  PubMed  Google Scholar 

  17. Zhong SZ, Ge QH, Li Q, Qu R, Ma SP (2009) Peoniflorin attentuates Abeta(1–42)-mediated neurotoxicity by regulating calcium homeostasis and ameliorating oxidative stress in hippocampus of rats. J Neurol Sci 280:71–78

    Article  CAS  PubMed  Google Scholar 

  18. Liu HQ, Zhang WY, Luo XT, Ye Y, Zhu XZ (2006) Paeoniflorin attenuates neuroinflammation and dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease by activation of adenosine A1 receptor. Br J Pharmacol 148:314–325

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Liu DZ, Xie KQ, Ji XQ, Ye Y, Jiang CL, Zhu XZ (2005) Neuroprotective effect of paeoniflorin on cerebral ischemic rat by activating adenosine A1 receptor in a manner different from its classical agonists. Br J Pharmacol 146:604–611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858

    Article  PubMed Central  PubMed  Google Scholar 

  21. Zhang M-Y, Zheng C-Y, Zou M-M, Zhu J-W, Zhang Y, Wang J, Liu C-F, Li Q-F, Xiao Z-C, Li S (2014) Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice. Neurobiol Aging 35:2713–2725

    Article  CAS  PubMed  Google Scholar 

  22. Mrak RE, Griffin WS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349–354

    Article  CAS  PubMed  Google Scholar 

  23. Zhang R, Miller RG, Madison C, Jin X, Honrada R, Harris W, Katz J, Forshew DA, McGrath MS (2013) Systemic immune system alterations in early stages of Alzheimer’s disease. J Neuroimmunol 256:38–42

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D’Hooge R, Rodrigues CM (2012) TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol Neurobiol 45:440–454

    Article  CAS  PubMed  Google Scholar 

  25. Ding Y, Qiao A, Wang Z, Goodwin JS, Lee ES, Block ML, Allsbrook M, McDonald MP, Fan GH (2008) Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer’s disease transgenic mouse model. J Neurosci 28:11622–11634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y (2007) Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 178:829–841

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Shi JQ, Zhang CC, Sun XL, Cheng XX, Wang JB, Zhang YD, Xu J, Zou HQ (2013) Antimalarial drug artemisinin extenuates amyloidogenesis and neuroinflammation in APPswe/PS1dE9 transgenic mice via inhibition of nuclear factor-kappaB and NLRP3 inflammasome activation. CNS Neurosci Ther 19:262–268

    Article  CAS  PubMed  Google Scholar 

  28. Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harbor Perspect Med 2:a006346

    Article  Google Scholar 

  29. Lin GH, Lee YJ, Choi DY, Han SB, Jung JK, Hwang BY, Moon DC, Kim Y, Lee MK, Oh KW, Jeong HS, Leem JY, Shin HK, Lee JH, Hong JT (2012) Anti-amyloidogenic effect of thiacremonone through anti-inflamation in vitro and in vivo models. JAD 29:659–676

    CAS  PubMed  Google Scholar 

  30. Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM, Lee K, Cho WG, Jung JK, Han SB, Han JY, Nam SY, Yun YW, Jeong JH, Oh KW, Hong JT (2012) Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J Neuroinflam. 9:35

    Article  CAS  Google Scholar 

  31. Choi DY, Lee JW, Peng J, Lee YJ, Han JY, Lee YH, Choi IS, Han SB, Jung JK, Lee WS, Lee SH, Kwon BM, Oh KW, Hong JT (2012) Obovatol improves cognitive functions in animal models for Alzheimer’s disease. J Neurochem 120:1048–1059

    Article  CAS  PubMed  Google Scholar 

  32. Puli L, Pomeshchik Y, Olas K, Malm T, Koistinaho J, Tanila H (2012) Effects of human intravenous immunoglobulin on amyloid pathology and neuroinflammation in a mouse model of Alzheimer’s disease. J Neuroinflam. 9:105

    Article  CAS  Google Scholar 

  33. Ruan L, Kang Z, Pei G, Le Y (2009) Amyloid deposition and inflammation in APPswe/PS1dE9 mouse model of Alzheimer’s disease. Curr Alzheimer Res 6:531–540

    Article  CAS  PubMed  Google Scholar 

  34. Takada Y, Fang X, Jamaluddin MS, Boyd DD, Aggarwal BB (2004) Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. J Biol Chem 279:39541–39554

    Article  CAS  PubMed  Google Scholar 

  35. Steinbrecher KA, Wilson W 3rd, Cogswell PC, Baldwin AS (2005) Glycogen synthase kinase 3beta functions to specify gene-specific NF-kappaB-dependent transcription. Mole Cell Biol 25:8444–8455

    Article  CAS  Google Scholar 

  36. Paris D, Patel N, Quadros A, Linan M, Bakshi P, Ait-Ghezala G, Mullan M (2007) Inhibition of Abeta production by NF-kappaB inhibitors. Neurosci Lett 415:11–16

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by funding from the “National Natural Science Foundation of guangdong’’ (Grant No. 32215050) and “Scientific research and innovation project of Jinan University” (Grant No. 21615336). This work was also supported by the “Scientific research and innovation project of Luoyang”(Grant No. 150415), the “Natural Scientific Research funds of China” (No. 81301116) and “China Postdoctoral Science Foundation”(Grant No. 2012M521922).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, 471003, Henan, China

    Hong-Ri Zhang, Xiao-Bing Cheng & Bao-Zhong Shi

  2. Department of Neurosurgery, The First Affiliated Hospital, Jinan University, No. 613, Huangpudadaoxi, Tianhe District, Guangzhou, 510630, Guangdong, China

    Hong-Ri Zhang, Xiao-Bing Cheng, Bao-Zhong Shi & Mao-Ying Zhang

  3. Department of Neurology, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, 471003, Henan, China

    Jing-Hua Peng

  4. Affiliated Bayi Brain Hospital, The Military General Hospital of Beijing PLA, No. 5, Nanmencang, Dongcheng District, Beijing, 100700, China

    Ru-Xiang Xu

Authors
  1. Hong-Ri Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing-Hua Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Bing Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bao-Zhong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mao-Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ru-Xiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mao-Ying Zhang or Ru-Xiang Xu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, HR., Peng, JH., Cheng, XB. et al. Paeoniflorin Atttenuates Amyloidogenesis and the Inflammatory Responses in a Transgenic Mouse Model of Alzheimer’s Disease. Neurochem Res 40, 1583–1592 (2015). https://doi.org/10.1007/s11064-015-1632-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1632-z

Keywords

Search

Navigation