Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/92621
標題: 補陽還五湯活性成分對細胞之神經保護作用機制探討
Elucidation of the neuroprotective effects and mechanisms of action by active components from Buyang Huanwu decoction in cellular models
作者: 江政霖
Cheng-Lin Chiang
關鍵字: 細胞凋亡;補陽還五湯;肝醣合成激酶3;雷帕黴素作用標的1;Apoptosis;Buyang Huanwu Decoction;Glycogen synthase kinase-3;mammalian target of rapamycin complex 1
引用: 邱浩彰,在台灣腦中風之現況,醫學繼續教育1996; 6卷二期: 176-181. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001; 2(10):734–744. Autophagic effect of programmed cell death 5 (PDCD5) after focal cerebral ischemic reperfusion injury in rats. Neurosci 2014; 566:298-303. Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol 2000; 190:255-266. Chang CC, Wang YH, Chern CM, Liou KT, Hou YC, Peng YT, et al. Prodigiosin inhibits gp91(phox) and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia. Toxicol Appl Pharmacol 2011; 257:137–147. Chern CM, Liao JF, Wang YH, Shen YC. Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT2 melatonin receptor in ischemic-stroke mice. Free Radic Biol Med 2012; 52:1634–2147. Chern CM, Wang YH, Liou KT, Hou YC, Chen CC, Shen YC. 2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke, Biochemical Pharmacology, 2014; 87:502-514. Chuang DM, Wang Z, Chiu CT. GSK-3 as a target for lithium-induced neuroprotection against excitotoxicity in neuronal cultures and animal models of ischemic stroke. Front Mol Neurosci 2011; 4:15–27. Clarrisa A. Bradley, Stéphane Peineau, Changiz Taghibiglou, Celine S. Nicolas, Daniel J. Whitcom1, Zuner A. Bortolotto, Bong-Kiun Kaang, Kwangwook Cho, Yu Tian Wang and Graham L. Collingridge. A pivotal role of GSK-3 in synaptic plasticity. Front. Mol. Neurosci., 2012; 5:13. Claudie Hooper, Richard Killick, and Simon Lovestone. The GSK3 hypothesis of Alzheimer's disease. J Neurochem. 2008; 104(6):1433–1439. Fernandez-Lopez D, Faustino J, Daneman R, Zhou L, Lee SY, Derugin N, et al. Blood–brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat. J Neurosci 2012; 32:9588–9600. Guo W, Murthy AC, Zhang L, Johnson EB, Schaller EG, Allan AM, et al. Inhibition of GSK3beta improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome. Hum Mol Genet 2012; 21:681–691. Guo Z, Cao G, Yang H, Zhou H, Li L, Cao Z, Yu B, Kou J. Han L, Li J, Lin X, Ma YF, Huang YF. Protective effect of astragaloside IV on oxidative damages of chang liver cell induced by ethanol and H2O2. Zhongguo Zhong Yao Za Zhi. 2014; 39(22):4430-4435. Huang H, Zhao J, Jiang L, Xie Y, Xia Y, Lv R, Dong L. Paeoniflorin improves menopause depression in ovariectomized rats under chronic unpredictable mild stress.Int J Clin Exp Med. 2015; 8(4):5103-5011. Hur EM, Zhou FQ. GSK3 signalling in neural development. Int Immunopharmacol. 2015; 28(1):115-120. Jiang Z, Chen CH, Chen YY, Han JY, Riley J, Zhou CM A combination of four active compounds alleviates cerebral ischemia-reperfusion injury in correlation with inhibition of autophagy and modulation of AMPK/mTOR and JNK pathways. J Neurosci Res. 2014; 92(10):1295-1306. Jianrong Li, Olivier Baud, Timothy Vartanian, Joseph J. Volpe , Paul A. Rosenberg. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA. 2005; 102, 9936-9941. Li J, Han L, Ma YF, Huang YF. Inhibiting effects of three components of Astragalus membranaceus on oxidative stress in Chang Liver cells. Zhongguo Zhong Yao Za Zhi. 2015; 40(2):318-323. Li P, Li Z.Neuroprotective effect of paeoniflorin on H2O2-induced apoptosis in PC12 cells by modulation of reactive oxygen species and the inflammatory response.Exp Ther Med. 2015; 9(5):1768-1772. Liu H, Wang J, Wang J, Wang P, Xue Y. Paeoniflorin attenuates Aβ1-42-induced inflammation and chemotaxis of microglia in vitro and inhibits NF-κB- and VEGF/Flt-1 signaling pathways. Brain Res. 2015; 1618:149-158. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003; 4:399-415. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 2001; 20:27–39. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2011; 21:103–115. Oksana Kaidanovich-Beilin, Jean-Martin Beaulieu,Richard Scott Jope, and James Robert Woodgett. Neurological Functions of the Masterswitch Protein Kinase – Gsk-3.Front Mol Neurosci. 2012; 5: 48. Pap M1, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem. 1998; 273(32):19929-19932. Qin H, Liu P, Lin S.Effects of Astragaloside IV on the SDF-1/CXCR4 Expression in Atherosclerosis of apoE(-/-) Mice Induced by Hyperlipaemia. Evid Based Complement Alternat Med. 2015; 2015:385154. Shi GB, Fan R, Zhang W, Yang C, Wang Q, Song J, Gao Y, Hou MX, Chen YF, Wang TC, Cai GJ. Antinociceptive activity of astragaloside IV in the animal model of chronic constriction injury. Behav Pharmacol 2015; 26(5):436-446. Shi L, Teng H, Zhu M, Li C, Huang K, Chen BI, Dai Y, Wang J. Paeoniflorin inhibits nucleus pulposus cell apoptosis by regulating the expression of Bcl-2 family proteins and caspase-9 in a rabbit model of intervertebral disc degeneration.Exp Ther Med. 2015; 10(1):257-262. Sirerol-Piquer M, Gomez-Ramos P, Hernandez F, Perez M, Moran MA, Fuster-Matanzo A, et al. GSK3beta overexpression induces neuronal death and a depletion of the neurogenic niches in the dentate gyrus. Hippocampus 2011; 21:910–922. Wang H, Zhang D, Ge M, Li Z, Jiang J, Li Y. Formononetin inhibits enterovirus 71 replication by regulating COX- 2/PGE₂ expression. Virol J. 2015; 12:35. Wang ZS, Xiong F, Xie XH, Chen D, Pan JH, Cheng L. Astragaloside IV attenuates proteinuria in streptozotocin-induced diabetic nephropathy via the inhibition of endoplasmic reticulum stress. BMC Nephrol. 2015; 16:44. Yi Yang, Yi Zhao, Xinghao Ai, Baijun Cheng, Shun Lu. Formononetin suppresses the proliferation of human non-small cell lung cancer through induction of cell cycle arrest and apoptosis. Int J Clin Exp Pathol. 2014; 7(12): 8453–8461. Yu J, Chen Y, Li M, Gao Q, Peng Y, Gong Q, Zhang Z, Wu X. Paeoniflorin down-regulates ATP-induced inflammatory cytokine production and P2X7R expression on peripheral blood mononuclear cells from patients with primary Sjögren's syndrome. Nat Rev Neurosci 2010; 11:539-551. Yue R, Li X, Chen B, Zhao J, He W, Yuan H, Yuan X, Gao N, Wu G, Jin H, Shan L, Zhang W. Astragaloside IV Attenuates Glutamate-Induced Neurotoxicity in PC12 Cells through Raf-MEK-ERK Pathway. PLoS One. 2015; 10(5):e0126603. 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; 1583-1592. Zhang WJ, Frei B. Astragaloside IV inhibits NF- κ B activation and inflammatory gene expression in LPS-treated mice. Mediators Inflamm. 2015; 2015:274314. Zhao Y, Li Q, Zhao W, Li J, Sun Y, Liu K, Liu B, Zhang N. Astragaloside IV and cycloastragenol are equally effective in inhibition of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in the endothelium.J Ethnopharmacol. 2015; 169:210-218. Zheng YB, Xiao GC, Tong SL, Ding Y, Wang QS, Li SB, Hao ZN.Paeoniflorin inhibits human gastric carcinoma cell proliferation through up-regulation of microRNA-124 and suppression of PI3K/Akt and STAT3 signaling. World J Gastroenterol. 2015; 21(23):7 197-207. Zhu YL, Zhang JJ, Wang JX, Yang ZH, Huang YF, Qu SS, Zhou TT. Comparative study on effects of blood enriching on mouse model of blood deficiency syndrome induced by cyclophosphamide of albiflorin, paeoniflorin on levels of GM-CSF, IL-3 and TNF-α. Zhongguo Zhong Yao Za Zhi. 2015; 40(2):330-333.
摘要: 
台灣腦中風在近幾年的流行病學統計中皆為十大死因第二名及第三名。除rt-PA外補陽還五湯 (Buyang Huanwu Decoction, BHD)是華人地區用於輔助治療中風病人後遺症最常用的傳統中藥方劑之一,但其有效成分 (如:4A、X系列 (分離自芍藥)、Y系列 (分離自黃耆)等12種成分)的作用機制並不清楚。為探討BHD不同藥效成分的藥理作用,本研究利用Oxygen / Glucose Deprivation (OGD)及BV-2細胞發炎模式以探討BHD的保護作用機轉。由研究結果可以得知,這12種活性成分並沒有直接清除DPPH及抑制NADPH oxidase (NOX)的作用,但對由LPS活化微膠細胞BV-2產生NO研究顯示X、X8、Y、Y2可顯著抑制BV-2的發炎作用,效果與PDTC (NF-κB抑制劑)相當,將進一步探討是否對iNOS及p65 (NF-κB)有抑制作用。OGD可以活化PI3K/Akt、GSK-3造成Neuro-2a神經細胞凋亡,12種活性成分皆可以有效抑制細胞凋亡及抑制PI3K/Akt、GSK-3活化。OGD亦可造成mTORC1抑制,而4A、X7、Y2、Y3可以逆轉此情形。綜合上述研究顯示BHD保護中風的機制可能透過這些有效成分能分別有效抗發炎 (例:X、X8、F、Y2),或逆轉OGD造成的PI3K/Akt、GSK-3活化及抑制mTORC1,達到抗細胞凋亡作用。

Acute ischemic stroke (AIS) ranks as the third position among the top ten leading causes of death in Taiwan in recent years. In addition to rt-PA, Buyang Huanwu Decoction (BHD), a famous traditional Chinese medicine (TCM), is one of the most popular used AIS-supporting treatment in Taiwan. Many active compounds such as 4A, as well as compounds X series and Y series have been isolated from Paeonia lactiflora and Astragalus membrane, recently in my laboratory. The aim of this thesis to elucidate how and which component is specifically responsible for neuroprotection and/ or anti-inflammation by these 12 components from BHD using two cellular models i.e., oxygen & glucose deprivation (OGD)-induced N2a apoptosis and lipopolysaccharide (LPS)-induced BV2 microglial cell activation. Our results showed that all these 12 active components did not directly scavenge DPPH radicals and nor did they inhibit NADPH oxidase (NOX) activity. However they inhibited NO production by LPS-activated microglia with X, X8, Y, and Y2 being as potent as PDTC (a NF-κB inhibitor). Whether these effective compounds also interfered the activity of iNOS and p65NFkB is still under elucidation. Furthermore, OGD induced a dramatic caspases (3, 8, 9, and 12)-, free radical- and calcium-dependent apoptosis of Neuro-2a cells by activation of PI3K/Akt, GSK-3, and suppression of mTORC1 signaling. All these 12 compounds can significantly prevent OGD-induced N2a apoptosis most possibly by inhibiting the activation of PI3K/Akt, GSK-3 and suppression of mTORC1 signaling. We conclude that the AIS protective effect by BHD may rely majorly on the anti-apoptosis and anti-inflammatory activities mediated by these 12 compounds through modulation of PI3K/Akt, GSK-3, and mTORC1 pathways to achieve its neuroprotective effect by BHD. More studies are needed to provide precise mechanisms of action by these compounds.
URI: http://hdl.handle.net/11455/92621
其他識別: U0005-1608201514202700
Rights: 同意授權瀏覽/列印電子全文服務,2018-08-20起公開。
Appears in Collections:生命科學院碩士在職專班

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