Geraniin Protects PC12 Cells Against Aβ25–35-Mediated Neuronal Damage: Involvement of NF-κB and MAPK Signaling Pathways

다국어 초록 (Multilingual Abstract)

β-amyloid peptide (Aβ) has been considered a critical factor that is associated with the development of oxidative stress and neuroinflammation in the pathogenesis of Alzheimer's disease. This study was performed to evaluate the effect of geraniin on Aβ25–35-caused oxidative damage and neuroinflammatory response, and its underlying mechanism. Geraniin protected pheochromocytoma12 (PC12) cells from Aβ25–35-mediated cell death by reducing oxidative stress and restoring cell cycle dysregulation. Moreover, geraniin markedly attenuated Aβ-triggered DNA injury that was partially associated with decreases in caspase-3 activity. Moreover, the compound significantly downregulated the release of neuroinflammatory factors. Upregulation of nuclear factor-κB activity was suppressed by geraniin, which was due to suppression of JNK, ERK1/2, and the p38 mitogen-activated protein kinase (MAPK) pathway. This was the first study to support further understanding of geraniin as a promising agent against neurotoxicity in the reduction of oxidative stress and neuroinflammation.

참고문헌 (Reference)

1 Saha B, "trans-4, 40-dihydroxystilbene(DHS)protects PC12 cells from oxidative damage but induces reactive oxygen species-mediated apoptosis in SHSY-5Y cell line" 54 : 719-728, 2016

2 Gouras G, "b-amyloid peptide and amyloid plaques in Alzheimer’s disease" 12 : 3-11, 2015

3 Islam A, "Synergistic effects of geraniin and rutin in the antioxidant properties of major lignins in Phyllanthus amarus" 3 : 1024-1036, 2008

4 Annabi B, "Resveratrol targeting of carcinogen-induced brain endothelial cell inflammation biomarkers MMP-9 and COX-2 is Sirt1-independent" 6 : 1-11, 2012

5 Yang X, "Resveratrol regulates microglia M1/M2 polarization via PGC-1a in conditions of neuroinflammatory injury" 64 : 162-172, 2017

6 Renaud J, "Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis : Effect on p53 and GRP75 localization" 25 : 110-123, 2014

7 Sima˜o F, "Resveratrol preconditioning modulates inflammatory response in the rat hippocampus following global cerebral ischemia" 61 : 659-665, 2012

8 Kim YA, "Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in bamyloid-treated C6 glioma cells" 17 : 1069-1075, 2006

9 Ai Z, "Resveratrol inhibits b-amyloid-induced neuronal apoptosis via regulation of p53 acetylation in PC12 cells" 11 : 2429-2434, 2015

10 O¨ ztu¨rk Y, "Resveratrol enhances apoptotic and oxidant effects of paclitaxel through TRPM2channel activation in DBTRG glioblastoma cells" 2019 : 4619865-, 2019

11 Wei Y, "Resveratrol ameliorates inflammatory damage and protects against osteoarthritis in a rat model of osteoarthritis" 17 : 1493-1498, 2018

12 Kang KA, "Radioprotective effect of geraniin via the inhibition of apoptosis triggered by c-radiationinduced oxidative stress" 27 : 83-94, 2011

13 Aayadi H, "Protective effects of geraniin against carbon tetrachloride induced acute hepatotoxicity in Swiss albino mice" 487 : 62-67, 2017

14 Hu JF, "Protective effect of(–)clausenamide against abeta-induced neurotoxicity in differentiated PC12 cells" 483 : 78-82, 2010

15 Sultana R, "Protective effect of the xanthate, D609, on Alzheimer’s amyloid betapeptide(1–42)-induced oxidative stress in primary neuronal cells" 38 : 449-458, 2004

16 Jang JH, "Protective effect of resveratrol on b-amyloidinduced oxidative PC12 cell death" 34 : 1100-1110, 2003

17 Li G, "Protective effect of erythropoietin on b-amyloid-induced PC12 cell death through antioxidant mechanisms" 442 : 143-147, 2008

18 Song Y, "Protective effect of centipedegrass against Ab oligomerization and Ab-mediated cell death in PC12 cells" 53 : 1260-1266, 2015

19 Zheng X, "Preventive potential of resveratrol in carcinogen-induced rat thyroid tumorigenesis" 10 : E279-, 2018

20 이승호, "Plant Phenolics as Prolyl Endopeptidase Inhibitors" 대한약학회 30 (30): 827-833, 2007

21 Perera A, "Perspectives on geraniin, a multifunctional natural bioactive compound" 44 : 243-257, 2015

22 Turunc Bayrakdar E, "Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Ab(1-42)-induced rat model of Alzheimer’s disease" 48 : 146-158, 2014

23 Okabe S, "New TNF-alpha releasing inhibitors, geraniin and corilagin, in leaves of Acer nikoense, Megusurino-ki" 24 : 1145-1148, 2001

24 Picone P, "Mitochondrial dysfunction : Different routes to Alzheimer’s disease therapy" 2014 : 780179-, 2014

25 Ito H, "Metabolites of the ellagitannin geraniin and their antioxidant activities" 77 : 1110-1115, 2011

26 Kwon SH, "Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK, p38, and ERK 1/2 MAPKs in SH-SY5Y cells" 58 : 533-541, 2011

27 Gonza´lez-Reyes RE, "Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective" 10 : 427-446, 2017

28 Wang P, "Inhibitory effects of geraniin on LPS-induced inflammation via regulating NF-jB and Nrf2pathways in RAW 264. 7 cells" 253 : 134-142, 2016

29 Tsang SW, "Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol : Implication for treatment of acute pancreatitis" 6 : 22859-, 2016

30 Youn K, "In vitro BACE1 inhibitory activity of geraniin and corilagin from Geranium thunbergii" 79 : 1038-1042, 2013

31 Wang X, "Geraniin suppresses ovarian cancer growth through inhibition of NF-jB activation and downregulation of Mcl-1 expression" 31 : e21929-, 2017

32 Guo X, "Geraniin selectively promotes cytostasis and apoptosis in human colorectal cancer cells by including catastrophic chromosomal instability" 33 : 271-281, 2018

33 Chung APYS, "Geraniin protects high-fat diet-induced oxidative stress in Sprague Dawley rats" 5 : 17-30, 2018

34 Huang D, "Geraniin protects bone marrowderived mesenchymal stem cells against hydrogen peroxideinduced cellular oxidative stress in vitro" 41 : 739-748, 2018

35 Wang P, "Geraniin exerts cytoprotective effect against cellular oxidative stress by upregulation of Nrf2-mediated antioxidant enzyme expression via PI3K/AKT and ERK1/2 pathway" 1850 : 1751-1761, 2015

36 Londhe JS, "Geraniin and amariin, ellagitannins from Phyllanthus amarus, protect liver cells against ethanol induced cytotoxicity" 83 : 1562-1568, 2012

37 Jiang L, "Geraniin ameliorates cisplatininduced nephrotoxicity in mice" 50 : 813-819, 2016

38 남현화, "Geraniin ameliorate experimental acute reflux esophagitis via NF‑κB regulated anti‑inflammatory activities in rats" 한국응용생명화학회 62 : 1-11, 2019

39 Cerda B, "Evaluation of the bioavailability and metabolism in the rats of punicalagin, an antioxidant polyphenol from pomegranate juice" 42 : 18-28, 2003

40 Chung APYS, "Ellagitannin geraniin supplementation ameliorates metabolic risks in high-fat-dietinduced obese Sprague Dawley rats" 9 : 173-182, 2014

41 Geske FJ, "Early stages of p53-induced apoptosis are reversible" 8 : 182-191, 2001

42 Youn K, "Discovery of nobiletin from citrus peel as a potent inhibitor of b-amyloid peptide toxicity" E2648-, 2019

43 Thummayot S, "Cyanidin attenuates Ab25–35-induced neuroinflammation by suppressing NF-jB activity downstream of TLR4/NOX4 in human neuroblastoma cells" 39 : 1439-1452, 2018

44 Parrish AB, "Cellular mechanisms controlling caspase activation and function" 5 : a008672-, 2013

45 Nath S, "Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway" 18 : 445-455, 2012

46 Busciglio J, "Beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding" 14 : 879-888, 1995

47 Lin SY, "Antioxidant, antisemicarbazide-sensitive amine oxidase, and anti-hypertensive activities of geraniin isolated from Phyllanthus urinaria" 46 : 2485-2492, 2008

48 Lee S, "Anti-neuroinflammatory property of phlorotannins from Ecklonia cava on Ab25–35-induced damage in PC12 cells" 17 : 7-22, 2019

49 양승주, "Anti-inflammatory and anti-oxidative effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on β-amyloid-induced microglial activation" 생화학분자생물학회 50 (50): 634-639, 2017

50 Sadigh-Eteghad S, "Amyloidbeta : A crucial factor in Alzheimer’s disease" 24 : 1-10, 2015

51 Subramaniam S, "Acute and sub chronic oral toxicity assessment of the ethanolic extract from the rind of Nephelium lappaceum in rats" 7 : 345-385, 2012

52 Moon JH, "Activation of nicotinic acetylcholine receptor prevents the production of reactive oxygen species in fibrillar beta amyloid peptide(1–42)-stimulated microglia" 40 : 11-18, 2008

53 Park S, "5-LOX inhibitor modulates the inflammatory responses provoked by Helicobacter pylori infection" 12 : 49-58, 2007

54 Ma L, "3, 5, 4’-Tri-O-acetylresveratrol attenuates Lipopolysaccharide-induced acute respiratory distress syndrome via MAPK/SIRT1 Pathway" 2015 : 143074-, 2015