亨丁頓舞蹈症是一種遺傳性的神經退化疾病，其特徵在於認知和運動功能的障礙。亨丁頓舞蹈症被認為主要是一種神經退行性疾病；然而，心臟衰竭也是亨丁頓舞蹈症患者的主要死亡原因。許多發生在亨丁頓舞蹈症患者神經元當中的病症，如：粒線體功能障礙和代謝損傷，也會發生在亨丁頓舞蹈症患者的心肌細胞當中。然而，用於保護亨丁頓舞蹈症患者心臟功能的臨床藥物卻很少。在國內，有許多中草藥物可以透過刺激血液循環以及補充細胞能量來緩解心血管疾病；為此，這些中草藥應該可以應用於減輕亨丁頓舞蹈症患者的心臟衰竭。在台灣，中藥配方B307是保護心血管功能的知名保健漢方藥品。本論文探討口服中藥配方B307對於R6/2亨丁頓舞蹈症基因轉殖小鼠的心臟保護作用。R6/2小鼠每日口服中藥配方B307或媒介物，飲食治療兩週。然後，透過非侵入性的心臟超聲波影像和moor FLPI雷射都普勒成像儀器，檢視10週齡R6/2小鼠的心臟功能以及皮膚組織的微循環，接著我們利用免疫組織化學和西方轉漬分析，檢查R6/2小鼠心臟組織中特定蛋白質表現，本論文結果顯示，R6/2小鼠的心臟功能以及皮膚組織在服用中藥配方B307後均獲得顯著改善。並且，R6/2小鼠心臟組織的心肌發炎以及亨丁頓蛋白累積，在服用中藥配方B307後也獲得顯著改善。此外，R6/2小鼠服用中藥配方B307後，心臟組織的VEGF、eNOS、SOD2和Bcl-2的蛋白質表現會顯著增加，而TNF-α、3-NT、4-HNE、Bax、Calpain、Caspase 12、Caspase 9、Caspase 3的蛋白質表現則會顯著降低。由本論文研究發現口服中藥配方B307會有效減輕R6/2小鼠心臟組織的氧化壓力、發炎反應以及細胞凋亡的進程。因此，口服中藥配方B307應該可以通過這些保護機制而達到改善亨丁頓舞蹈症患者的心臟功能失調；因此中藥配方B307可能開發成為改善亨丁頓舞蹈症心臟衰竭的保健漢方藥品。

Huntington’s disease (HD) is considered as a irreversibly destructive genetic disease, characterized by cognitive impairment and motor dysfunction. Though HD has been considered as a neurodegenerative disease primarily, cardiac failure is also cause of death in HD patients. Some symptoms such as energetic dysfunction and metabolic injury that occur in HD neurons, and that also can be seen in failing cardiac myocytes of HD. Until now, the clinical drugs with profound cardioprotective effect in HD patients is quite rare. Some Chinese herbs have been claimed to relieve cardiovascular diseases by promoting blood circulation and supplementing vital energy. Thus, some specific Chinese herbs may be used as a potential therapeutic strategy for alleviating cardiac failure in HD patients. The herbal formula B307 is a well-known health supplement for enhancing cardiovascular function in Taiwan. Here we investigated the cardioprotective effects of oral B307 treatment in R6/2 HD mice. R6/2 HD mice were oral treated with B307 or with vehicle diet daily for two weeks. The level of cardiac performance and subcutaneous microcirculation of these R6/2 HD mice were measured at ten-weeks-old by non-invasive echocardiography and moorFLPI Laser Doppler imager respectively. Afterward, R6/2 HD mice and their wild type littermate controls (WT) were sacrificed. The heart tissues were examined by immunohistochemistry and western blotting. Our data showed that cardiac performance and subcutaneous microcirculation were ameliorated in R6/2 HD mice under oral treated with B307. We observed that myocarditis and aggregation of huntingtin protein in heart tissue of R6/2 HD mice were significantly enhanced than that of their WT, but were reduced under oral treated with B307. Proteins expression of VEGF, eNOS, SOD2 and Bcl-2 in heart tissue of R6/2 HD mice were reduced than that of their WT, but were enhanced under oral treated with B307. On the other hand, Proteins expression of 3-NT, 4-HNE, Bax, calpain, caspase-12, caspase-9, caspase-3, and TNF-α in heart tissue of R6/2 HD mice were enhanced than that of their WT, but were reduced under oral treated with B307. Base on our study, inflammation, oxidative stress and apoptosis in heart tissue were alleviated under oral treated with B307. We suggested that oral herbal formula B307 may be beneficial for cardiac protection in HD patients. It is possible that the herbal formula B307 can be developed as a health supplement for ameliorating cardiac failure of HD patients.

Bates G, Harper P, Jones L. (2002) Huntington’s Disease, 3rd ed. Oxford University Press Inc., New York.
Bates GP, Mangiarini L, Davies SW. (1998) Transgenic mice in the study of polyglutamine repeat expansion diseases. Brain Pathol 8(4): 699–714.
Benchoua A, Trioulier Y, Zala D, Gaillard MC, Lefort N, Dufour N, Saudou F, Elalouf JM, Hirsch E, Hantraye P, Déglon N, Brouillet E. (2006) Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated Huntington. Mol Biol Cell 17(4): 1652–1663.
Browne SE, Ferrante RJ, Beal MF. (1999) Oxidative stress in Huntington's disease. Brain Pathol 9(1): 147–163.
Buja LM. (2005) Myocardial ischemia and reperfusion injury. Cardiovasc Pathol 14(4): 170–175.
Cai D, Liu T. (2012) Inflammatory cause of metabolic syndrome via brain stress and NF-κB. Aging (Albany NY) 4(2): 98–115.
Calabrese V, Bates TE, Stella AM. (2000) NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role oxidant/antioxidant balance. Neurochem Res 25(9-10): 1315–1341.
Chaiswing L, Cole MP, St Clair DK, Ittarat W, Szweda LI, Oberley TD. (2004) Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. Toxicol Pathol 32(5): 536–547.
Chen XC, Zhu YG, Zhu LA, Huang C, Chen Y, Chen LM, Fang F, Zhou YC, Zhao CH. (2003) Ginsenoside Rg1 attenuates dopamine-induced apoptosis in PC12 cells by suppressing oxidative stress. Eur J Pharmacol 473(1): 1–7.
Chiu E, Alexander L. (1982) Causes of death in Huntington’s disease. Med J Aust 1(4): 153–153.
Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, Cattaneo E, Gage FH, Cleveland DW, Glass CK. (2014) Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci 17(4): 513–521.
Dejeans N, Tajeddine N, Beck R, Verrax J, Taper H, Gailly P, Calderon PB. (2010) Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells. Biochem Pharmacol 79(9): 1221–1230.
Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP. (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90(3): 537–548.
Fang F, Chen X, Huang T, Lue LF, Luddy JS, Yan SS. (2012) Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta 1822(2): 286–292.
Francis GS, McDonald K, Chu C, Cohn JN. (1995) Pathophysiologic aspects of end-stage heart failure. Am J Cardiol 75(3): 11A–16A.
Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK. (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 98(5): 2604-2609.
Gu B, Nakamichi N, Zhang WS, Nakamura Y, Kambe Y, Fukumori R, Takuma K, Yamada K, Takarada T, Taniura H, Yoneda Y. (2009) Possible protection by notoginsenoside R1 against glutamate neurotoxicity mediated by N-methyl-Daspartate receptors composed of an NR1/NR2B subunit assembly. J Neurosci Res 87(9): 2145–2156.
Hamilton JM, Wolfson T, Peavy GM, Jacobson MW, Corey-Bloom J. (2004) Rate and correlates of weight change in Huntington’s disease. J Neurol Neurosurg Psychiatry 75(2): 209–212.
Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6): 971–983.
Lanska DJ, Lavine L, Lanska MJ, Schoenberg BS. (1988) Huntington’s disease mortality in the United States. Neurology 38(5): 769–772.
Lee JS, Song JH, Sohn NW, Shin JW. (2013) Inhibitory effects of ginsenoside Rb1 on neuroinflammation following systemic lipopolysaccharide treatment in mice. Phytother Res 27(9): 1270–1276.
Li J, O W, Li W, Jiang ZG, Ghanbari HA. (2013) Oxidative stress and neurodegenerative disorders. Int J Mol Sci 14(12): 24438–24475.
Li JY, Popovic N, Brundin P. (2005) The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies. NeuroRx 2(3): 447–464.
Liang D, Zhang M. (2000) The thinking on TCM differential treatment of congestive heart failure. J Tradit Chin Med 20(1): 44-47.
Liang W, Ge S, Yang L, Yang M, Ye Z, Yan M, Du J, Luo Z. (2010) Ginsenosides Rb1 and Rg1 promote proliferation and expression of neurotrophic factors in primary Schwann cell cultures. Brain Res 1357: 19–25.
Lin CL, Hsu CH, Wang SE, Sheu SJ, Chuang TY, Lien CY, Chen CM, Chien CT, Wu CH. (2015) Cardiac protection of the oral herbal formula B307 in a R6/2 mouse model of Huntington’s disease via angiogenesis. JOKULL 65(2): 29–47.
Lin WM, Zhang YM, Moldzio R, Rausch WD. (2007) Ginsenoside Rd attenuates neuroinflammation of dopaminergic cells in culture. J Neural Transm Suppl (72): 105–112.
Liu Q, Li J, Wang J, Li J, Janicki JS, Fan D. (2013) Effects and mechanisms of chinese herbal medicine in ameliorating myocardial ischemia-reperfusion injury. Evid Based Complement Alternat Med 2013: 925625.
Liu Q, Li J, Wang J, Li J, Janicki JS, Fan D. (2013) Effects and mechanisms of chinese herbal medicine in ameliorating myocardial ischemia-reperfusion injury. Evid Based Complement Alternat Med 2013: 925625.
Luo FC, Wang SD, Qi L, Song JY, Lv T, Bai J. (2011) Protective effect of panaxatriol saponins extracted from Panax notoginseng against MPTP-induced neurotoxicity in vivo. J Ethnopharmacol 133(2): 448–453.
Machado NG, Alves MG, Carvalho RA, Oliveira PJ. (2009) Mitochondrial involvement in cardiac apoptosis during ischemia and reperfusion: can we close the box? Cardiovasc Toxicol 9(4): 211–227.
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP. (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3): 493–506.
McCoy MK, Tansey MG. (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5: 45.
Mihm MJ, Amann DM, Schanbacher BL, Altschuld RA, Bauer JA, Hoyt KR. (2007) Cardiac dysfunction in the R6/2 mouse model of Huntington's disease. Neurobiol Dis 25(2): 297-308.
Pattison JS, Sanbe A, Maloyan A, Osinska H, Klevitsky R, Robbins J. (2008) Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure. Circulation 117(21): 2743–2751.
Popa C, Netea MG, van Riel PL, van der Meer JW, Stalenhoef AF. (2007) The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res 48(4): 751–762.
Powers SK, Kavazis AN, DeRuisseau KC. (2004) Mechanisms of disuse muscle atrophy: role of oxidative stress. Am J Physiol Regul Integr Comp Physiol 288(2): R337–R344.
Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D'Onofrio F. (1994) Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism 43(2): 174–179.
Rong YZ, Lu BJ, Zhao MH, Zhu XY, Zang YC. (1996) Experimental study and clinical trial of Shengmaisan to protect and treat myocardial injury. Chin J Integr Med 2(4): 242-244.
Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR. (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8(3): 397–407.
Sieveking DP, Woo KS, Fung KP, Lundman P, Nakhla S, Celermajer DS. (2005) Chinese herbs Danshen and Gegen modulate key early atherogenic events in vitro. Int J Cardiol 105(1): 40–45.
Sørensen SA, Fenger K. (1992) Causes of death in patients with Huntington’s disease and in unaffected first degree relatives. J Med Genet 29(12): 911–914.
Squitieri F, Cannella M, Sgarbi G, Maglione V, Falleni A, Lenzi P, Baracca A, Cislaghi G, Saft C, Ragona G, Russo MA, Thompson LM, Solaini G, Fornai F. (2006) Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Mech Ageing Dev 127(2): 217–220.
Strong TV, Tagle DA, Valdes JM, Elmer LW, Boehm K, Swaroop M, Kaatz KW, Collins FS, Albin RL. (1993) Widespread expression of the human and rat Huntington’s disease gene in brain and nonneural tissues. Nat Genet 5(3): 259–265.
Thanan R, Oikawa S, Hiraku Y, Ohnishi S, Ma N, Pinlaor S, Yongvanit P, Kawanishi S, Murata M. (2015) Oxidative stress and its significant roles in neurodegenerative diseases and cancer. Int J Mol Sci 16(1): 193–217.
Tam WY, Chook P, Qiao M, Chan LT, Chan TY, Poon YK, Fung KP, Leung PC, Woo KS. (2009) The efficacy and tolerability of adjunctive alternative herbal medicine (Salvia miltiorrhiza and Pueraria lobata) on vascular function and structure in coronary patients. J Altern Complement Med 15(4): 415–421.
Vogt A, Kűbler W. (1999) Cardiac energy metabolism—A historical perspective. Heart Fail Rev 4(3): 211–219.
Wang SE, Lin CL, Hsu C H, Sheu SJ, Chien CT, Wu CH (2015) Treatment of a herbal formula B401 enhances neuroprotection and angiogenesis in the R6/2 mouse model of Huntington’s Disease. Drug Des Devel Ther 9: 887-900.
Wang Y, Feng Y, Fu Q, Li L. (2013) Panax notoginsenoside Rb1 ameliorates Alzheimer's disease by regulating brain-derived neurtotrophic factor and downregulating Tau protein expression. Exp Ther Med 6(3): 826–830.
Wu J, Jeong HK, Bulin SE, Kwon SW, Park JH, Bezprozvanny I. (2009) Ginsenosides protect striatal neurons in a cellular model of Huntington's disease. J Neurosci Res 87(8): 1904–1912.
Wu L, Qiao H, Li Y, Li L. (2007) Protective roles of puerarin and Danshensu on acute ischemic myocardial injury in rats. Phytomedicine 14(10): 652–658.
Xu YY, Wan RZ, Lin YP, Yang LL, Chen Y, Liu CX. (2007) Recent advance on research and application of Salvia miltiorrhiza. Asian J Pharmacodyn Pharmacokinet 7(2): 99–130.
Yamaguchi O, Higuchi Y, Hirotani S, Kashiwase K, Nakayama H, Hikoso S, Takeda T, Watanabe T, Asahi M, Taniike M, Matsumura Y, Tsujimoto I, Hongo K, Kusakari Y, Kurihara S, Nishida K, Ichijo H, Hori M, Otsu K. (2003) Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc Natl Acad Sci U S A 100(26): 15883–15888.