Browse > Article
http://dx.doi.org/10.4162/nrp.2020.14.6.593

Paeoniflorin ameliorates Aβ-stimulated neuroinflammation via regulation of NF-κB signaling pathway and Aβ degradation in C6 glial cells  

Cho, Eun Ju (Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University)
Kim, Hyun Young (Department of Food Science, Gyeongnam National University of Science and Technology)
Lee, Ah Young (Department of Food Science, Gyeongnam National University of Science and Technology)
Publication Information
Nutrition Research and Practice / v.14, no.6, 2020 , pp. 593-605 More about this Journal
Abstract
BACKGROUND/OBJECTIVES: Alzheimer's disease is common age-related neurodegenerative condition characterized by amyloid beta (Aβ) accumulation that leads cognitive impairment. In the present study, we investigated the protective effect of paeoniflorin (PF) against Aβ-induced neuroinflammation and the underlying mechanism in C6 glial cells. MATERIALS/METHODS: C6 glial cells were treated with PF and Aβ25-35, and cell viability, nitric oxide (NO) production, and pro-inflammatory cytokine release were measured. Furthermore, the mechanism underlying the effect of PF on inflammatory responses and Aβ degradation was determined by Western blot. RESULTS: Aβ25-35 significantly reduced cell viability, but this reduction was prevented by the pretreatment with PF. In addition, PF significantly inhibited Aβ25-35-induced NO production in C6 glial cells. The secretion of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha was also significantly reduced by PF. Further mechanistic studies indicated that PF suppressed the production of these pro-inflammatory cytokines by regulating the nuclear factor-kappa B (NF-κB) pathway. The protein levels of inducible NO synthase and cyclooxygenase-2 were downregulated and phosphorylation of NF-κB was blocked by PF. However, PF elevated the protein expression of inhibitor kappa B-alpha and those of Aβ degrading enzymes, insulin degrading enzyme and neprilysin. CONCLUSIONS: These findings indicate that PF exerts protective effects against Aβ-mediated neuroinflammation by inhibiting NF-κB signaling, and these effects were associated with the enhanced activity of Aβ degradation enzymes.
Keywords
Paeonia; neurodegenerative diseases; amyloid; NF-kappaB; glial cells;
Citations & Related Records
연도 인용수 순위
  • Reference
1 He DY, Dai SM. Anti-inflammatory and immunomodulatory effects of Paeonia lactiflora pall., a traditional Chinese herbal medicine. Front Pharmacol 2011;2:10.   DOI
2 Qiu F, Zhong X, Mao Q, Huang Z. The antidepressant-like effects of paeoniflorin in mouse models. Exp Ther Med 2013;5:1113-6.   DOI
3 Ikeda N, Fukuda T, Jyo H, Shimada Y, Murakami N, Saka M, Yoshikawa M. Quality evaluation on Paeoniae Radix. I. Quantitative analysis of monoterpene glycosides constituents of Paeoniae Radix by means of high performance liquid chromatography. Comparative characterization of the external figures, processing method and the cultivated areas. Yakugaku Zasshi 1996;116:138-47.   DOI
4 Yoo JS, Song MC, Ahn EM, Lee YH, Rho YD, Baek NI. Quantitative analysis of paeoniflorin from Paeonia lactiflora using 1H-NMR. Nat Prod Sci 2006;12:237-40.
5 Zhang MH, Feng L, Zhu MM, Gu JF, Wu C, Jia XB. Antioxidative and anti-inflammatory activities of paeoniflorin and oxypaeoniflora on AGEs-induced mesangial cell damage. Planta Med 2013;79:1319-23.   DOI
6 Wang QS, Gao T, Cui YL, Gao LN, Jiang HL. Comparative studies of paeoniflorin and albiflorin from Paeonia lactiflora on anti-inflammatory activities. Pharm Biol 2014;52:1189-95.   DOI
7 Wang K, Zhu L, Zhu X, Zhang K, Huang B, Zhang J, Zhang Y, Zhu L, Zhou B, Zhou F. Protective effect of paeoniflorin on $A{\beta}_{25-35}$-induced SH-SY5Y cell injury by preventing mitochondrial dysfunction. Cell Mol Neurobiol 2014;34:227-34.   DOI
8 Zhang Y, Li H, Huang M, Huang M, Chu K, Xu W, Zhang S, Que J, Chen L. Paeoniflorin, a monoterpene glycoside, protects the brain from cerebral ischemic injury via inhibition of apoptosis. Am J Chin Med 2015;43:543-57.   DOI
9 Nam MN, Lee AY, Sin SM, Goo YM, Choi JM, Cho EJ. Protective effects of Paeonia lactiflora and its active compound, paeoniflorin, against neuronal oxidative stress in $H_{2}O_{2}$-treated SH-SY5Y cells. Int J Gerontol 2019:S39-44.
10 Chen A, Wang H, Zhang Y, Wang X, Yu L, Xu W, Xu W, Lin Y. Paeoniflorin exerts neuroprotective effects against glutamate-induced PC12 cellular cytotoxicity by inhibiting apoptosis. Int J Mol Med 2017;40:825-33.   DOI
11 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55-63.   DOI
12 Dirsch VM, Stuppner H, Vollmar AM. The Griess assay: suitable for a bio-guided fractionation of anti-inflammatory plant extracts? Planta Med 1998;64:423-6.   DOI
13 McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195-218.   DOI
14 Liu Q, Zhao B. Nicotine attenuates beta-amyloid peptide-induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures. Br J Pharmacol 2004;141:746-54.   DOI
15 Qiu WQ, Ye Z, Kholodenko D, Seubert P, Selkoe DJ. Degradation of amyloid ${\beta}$-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J Biol Chem 1997;272:6641-6.   DOI
16 Peters C, Bascunan D, Opazo C, Aguayo LG. Differential membrane toxicity of amyloid-${\beta}$ fragments by pore forming mechanisms. J Alzheimers Dis 2016;51:689-99.   DOI
17 Hughes E, Burke RM, Doig AJ. Inhibition of toxicity in the beta-amyloid peptide fragment beta -(25-35) using N-methylated derivatives: a general strategy to prevent amyloid formation. J Biol Chem 2000;275:25109-15.   DOI
18 Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR. Alzheimer's disease-associated neurotoxic mechanisms and neuroprotective strategies. Curr Drug Targets CNS Neurol Disord 2005;4:383-403.   DOI
19 Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010;119:7-35.   DOI
20 Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 2003;304:1-7.   DOI
21 Avila-Munoz E, Arias C. When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer's disease. Ageing Res Rev 2014;18:29-40.   DOI
22 Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J. Adult mouse astrocytes degrade amyloid-${\beta}$ in vitro and in situ. Nat Med 2003;9:453-7.   DOI
23 Xiao Q, Yan P, Ma X, Liu H, Perez R, Zhu A, Gonzales E, Burchett JM, Schuler DR, Cirrito JR, Diwan A, Lee JM. Enhancing astrocytic lysosome biogenesis facilitates $A{\beta}$ clearance and attenuates amyloid plaque pathogenesis. J Neurosci 2014;34:9607-20.   DOI
24 Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective ${\beta}$-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 2008;28:8354-60.   DOI
25 Guo RB, Wang GF, Zhao AP, Gu J, Sun XL, Hu G. Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/$NF-{\kappa}B$-mediated inflammatory responses. PLoS One 2012;7:e49701.   DOI
26 Akama KT, Van Eldik LJ. ${\beta}$-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-$1{\beta}$- and tumor necrosis factor-${\alpha}$ (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J Biol Chem 2000;275:7918-24.   DOI
27 Wang HM, Zhang T, Huang JK, Sun XJ. 3-N-butylphthalide (NBP) attenuates the amyloid-${\beta}$-induced inflammatory responses in cultured astrocytes via the nuclear $factor-{\kappa}B$ signaling pathway. Cell Physiol Biochem 2013;32:235-42.   DOI
28 Nam KN, Yae CG, Hong JW, Cho DH, Lee JH, Lee EH. Paeoniflorin, a monoterpene glycoside, attenuates lipopolysaccharide-induced neuronal injury and brain microglial inflammatory response. Biotechnol Lett 2013;35:1183-9.   DOI
29 Reis PA, de Albuquerque CFG, Gutierrez TM, Silva AR, de Castro Faria Neto HC. Role of nitric oxide synthase in the function of the central nervous system under normal and infectious conditions. In: Saravi SSS, editor. Nitric Oxide Synthase - Simple Enzyme-Complex Roles. London: InTech; 2017. p.55-70.
30 Jung CH, Kim JH, Park S, Kweon DH, Kim SH, Ko SG. Inhibitory effect of Agrimonia pilosa Ledeb. on inflammation by suppression of iNOS and ROS production. Immunol Invest 2010;39:159-70.   DOI
31 Tsoyi K, Ha YM, Kim YM, Lee YS, Kim HJ, Kim HJ, Seo HG, Lee JH, Chang KC. Activation of PPAR-${\gamma}$ by carbon monoxide from CORM-2 leads to the inhibition of iNOS but not COX-2 expression in LPS-stimulated macrophages. Inflammation 2009;32:364-71.   DOI
32 Hensley K. Neuroinflammation in Alzheimer's disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation. J Alzheimers Dis 2010;21:1-14.   DOI
33 Kim MJ, Seong AR, Yoo JY, Jin CH, Lee YH, Kim YJ, Lee J, Jun WJ, Yoon HG. Gallic acid, a histone acetyltransferase inhibitor, suppresses ${\beta}$-amyloid neurotoxicity by inhibiting microglial-mediated neuroinflammation. Mol Nutr Food Res 2011;55:1798-808.   DOI
34 Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM. Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 2005;26:645-54.   DOI
35 Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ. Enhanced proteolysis of ${\beta}$-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003;40:1087-93.   DOI
36 Wang B, Dai W, Shi L, Teng H, Li X, Wang J, Geng W. Neuroprotection by paeoniflorin against nuclear factor kappa B-induced neuroinflammation on spinal cord injury. BioMed Res Int 2018;2018:9865403.   DOI
37 Deng LJ, Cheng C, Wu J, Wang CH, Zhou HB, Huang J. Oxabicycloheptene sulfonate protects against ${\beta}$-amyloid-induced toxicity by activation of PI3K/Akt and ERK signaling pathways via GPER1 in C6 cells. Neurochem Res 2017;42:2246-56.   DOI
38 Zhao X, Yuan L, Yu H, Xi Y, Ma W, Zhou X, Ding J, Xiao R. Genistein inhibited amyloid-${\beta}$ induced inflammatory damage in C6 glial cells. Arch Med Res 2014;45:152-7.   DOI
39 Lee M, You HJ, Cho SH, Woo CH, Yoo MH, Joe EH, Kim JH. Implication of the small GTPase Rac1 in the generation of reactive oxygen species in response to ${\beta}$-amyloid in C6 astroglioma cells. Biochem J 2002;366:937-43.   DOI
40 Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 2003;100:4162-7.   DOI
41 Liu J, Jin DZ, Xiao L, Zhu XZ. Paeoniflorin attenuates chronic cerebral hypoperfusion-induced learning dysfunction and brain damage in rats. Brain Res 2006;1089:162-70.   DOI
42 Zhang HR, Peng JH, Cheng XB, Shi BZ, Zhang MY, Xu RX. Paeoniflorin atttenuates amyloidogenesis and the inflammatory responses in a transgenic mouse model of Alzheimer's disease. Neurochem Res 2015;40:1583-92.   DOI
43 Kong Y, Peng Q, Lv N, Yuan J, Deng Z, Liang X, Chen S, Wang L. Paeoniflorin exerts neuroprotective effects in a transgenic mouse model of Alzheimer's disease via activation of adenosine A1 receptor. Neurosci Lett 2020;730:135016.   DOI
44 Liu H, Wang J, Wang J, Wang P, Xue Y. Paeoniflorin attenuates $A{\beta}_{1-42}$-induced inflammation and chemotaxis of microglia in vitro and inhibits $NF-{\kappa}B$- and VEGF/Flt-1 signaling pathways. Brain Res 2015;1618:149-58.   DOI
45 He X, Xing D, Ding Y, Li Y, Xiang L, Wang W, Du L. Determination of paeoniflorin in rat hippocampus by high-performance liquid chromatography after intravenous administration of Paeoniae Radix extract. J Chromatogr B Analyt Technol Biomed Life Sci 2004;802:277-81.   DOI
46 Zhong SZ, Ge QH, Li Q, Qu R, Ma SP. Peoniflorin attentuates Abeta((1-42))-mediated neurotoxicity by regulating calcium homeostasis and ameliorating oxidative stress in hippocampus of rats. J Neurol Sci 2009;280:71-8.   DOI
47 Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109-42.
48 Balez R, Ooi L. Getting to NO Alzheimer's disease: neuroprotection versus neurotoxicity mediated by nitric oxide. Oxid Med Cell Longev 2016;2016:3806157.
49 Ayasolla K, Khan M, Singh AK, Singh I. Inflammatory mediator and ${\beta}$-amyloid (25-35)-induced ceramide generation and iNOS expression are inhibited by vitamin E. Free Radic Biol Med 2004;37:325-38.   DOI
50 Lee AY, Lee MH, Lee S, Cho EJ. Neuroprotective effect of alpha-linolenic acid against $A{\beta}$-mediated inflammatory responses in C6 glial cell. J Agric Food Chem 2018;66:4853-61.   DOI
51 Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE. Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 1998;8:65-72.   DOI