Cardioprotective Effects of a Phlorotannin Extract Against Doxorubicin-Induced Cardiotoxicity in a Rat Model

다국어 초록 (Multilingual Abstract)

Long-term therapy with doxorubicin (DOX) is associated with high incidence of cumulative and irreversible dilated cardiomyopathy. The goal of this study was to evaluate the cardioprotective effects and safety of a phlorotannin extract from a brown algae Ecklonia cava (Seapolynol™, SPN) against DOX-induced cardiotoxicity in a rat model. A total of 42 rats were divided into six groups: control, low-dose SPN (LDS), high-dose SPN (HDS), DOX, DOX with low-dose SPN (DOX+LDS), and DOX with high-dose SPN (DOX+HDS). Echocardiography was performed at baseline and after 6 weeks. In left ventricular (LV) ejection fraction, DOX and DOX+LDS groups showed significant decreases (P < .001), while LDS, HDS, and DOX+HDS groups showed no significant change compared with control group. In LV mass index, DOX and DOX+LDS groups showed significant increases (P < .001 and P = .013), while LDS, HDS, and DOX+HDS groups showed no significant change compared with control group. In electron microscopy of the LV wall tissue, DOX+HDS group showed markedly less impaired myofibrils and mitochondria compared with both DOX and DOX+LDS groups. On the findings in echocardiography and electron microscopy, 6-week oral administration of SPN was safe and cardioprotective in a DOX-induced rat cardiotoxicity model in a dose-dependent manner.

참고문헌 (Reference)

1 Reffelmann T, "Transthoracic echocardiography in rats. Evalution of commonly used indices of left ventricular dimensions, contractile performance, and hypertrophy in a genetic model of hypertrophic heart failure(SHHF-Mcc-facp-Rats)in comparison with Wistar rats during aging" 98 : 275-284, 2003

2 Curran CF, "Toxicity profile of dexrazoxane(Zinecard, ICRF-187, ADR-529, NSC-169780), a modulator of doxorubicin cardiotoxicity" 18 : 241-252, 1991

3 Chan KYY, "Thrombopoietin protects against doxorubicin-induced cardiomyopathy, improves cardiac function, and reversely alters specific signalling networks" 13 : 366-376, 2011

4 Moulin M, "Sexual dimorphism of doxorubicin-mediated cardiotoxicity : Potential role of energy metabolism remodeling" 8 : 98-108, 2015

5 Lang RM, "Recommendations for chamber quantification : A report from the American society of echocardiography’s guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European association of echocardiography, a branch of the European society of cardiology" 18 : 1440-1463, 2005

6 Tocchetti CG, "Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction" 16 : 358-366, 2014

7 Jung HA, "Protective effect of the edible brown alga Ecklonia stolonifera on doxorubicin-induced hepatotoxicity in primary rat hepatocytes" 66 : 1180-1188, 2014

8 Moon C, "Protective effect of phlorotannin components phloroglucinol and eckol on radiationinduced intestinal injury in mice" 22 : 238-242, 2008

9 Devereux RB, "Prognostic significance of left ventricular mass change during treatment of hypertension" 292 : 2350-2356, 2004

10 Kim MM, "Phlorotannins in Ecklonia cava extract inhibit matrix metalloproteinase activity" 79 : 1436-1443, 2006

11 Wijesekara I, "Phlorotannins from Ecklonia cava(Phaeophyceae) : Biological activities and potential health benefits" 36 : 408-414, 2010

12 Liu XW, "Melatonin as an effective protector against doxorubicin-induced cardiotoxicity" 283 : H254-H263, 2002

13 Kang HS, "Inhibitory phlorotannins from the edible brown alga Ecklonia stolonifera on total reactive oxygen species(ROS)generation" 27 : 194-198, 2004

14 Ahn MJ, "Inhibition of HIV-1 reverse transcriptase and protease by phlorotannins from the brown alga Ecklonia cava" 27 : 544-547, 2004

15 Aissiou M, "Imaging of early modification in cardiomyopathy : The doxorubicin-induced model" 29 : 1459-1476, 2013

16 Dong Hyeon Lee, "Effects of Ecklonia cava Polyphenol in Individuals with Hypercholesterolemia: A Pilot Study" 한국식품영양과학회 15 (15): 1038-1044, 2012

17 Kang KA, "Eckol isolated from Ecklonia cava attenuates oxidative stress induced cell damage in lung fibroblast cells" 579 : 6295-6304, 2005

18 Jun YJ, "Eckol enhances heme oxygenase-1 expression through activation of Nrf2/JNK pathway in HepG2 cells" 19 : 15638-15652, 2014

19 Takahashi M, "Ecklonia cava polyphenol protects the liver against ethanol-induced injury in rats" 1820 : 978-988, 2012

20 Takemura G, "Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management" 49 : 330-352, 2007

21 Octavia Y, "Doxorubicin-induced cardiomyopathy : From molecular mechanisms to therapeutic strategies" 52 : 1213-1225, 2012

22 Singal PK, "Doxorubicin-induced cardiomyopathy" 339 : 900-905, 1998

23 Bristow MR, "Doxorubicin cardiomyopathy : Evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization" 88 : 168-175, 1978

24 Zhu SG, "Dietary nitrate supplementation protects against doxorubicininduced cardiomyopathy by improving mitochondrial function" 57 : 2181-2189, 2011

25 Meinardi MT, "Detection of anthracycline-induced cardiotoxicity" 25 : 237-247, 1999

26 Kang KA, "Cytoprotective effect of phloroglucinol on oxidative stress induced cell damage via catalase activation" 97 : 609-620, 2006

27 Kim AD, "Cytoprotective effect of eckol against oxidative stress-induced mitochondrial dysfunction : Involvement of the FoxO3a/AMPK pathway" 115 : 1403-1411, 2014

28 Zhou SY, "Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin" 61 : 771-777, 2001

29 Garibaldi S, "Carvedilol prevents mitochondrial membrane potential loss induced by doxorubicin in cardiomyocytes" 26 : 24-25, 2005

30 Torti FM, "Cardiotoxicity of epirubicin and doxorubicin : Assessment by endomyocardial biopsy" 46 : 3722-3727, 1986

31 Yang YI, "Brown algae phlorotannins enhance the tumoricidal effect of cisplatin and ameliorate cisplatin nephrotoxicity" 136 : 355-364, 2015

32 Kwak JH, "Blood-brain barrier-permeable fluorone-labeled dieckols acting as neuronal ER stress signaling inhibitors" 61 : 52-60, 2015

33 Lipshultz SE, "Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia : Long-term follow-up of a prospective, randomised, multicentre trial" 11 : 950-961, 2010

34 KeejongKang, "Antioxidative Properties of Brown Algae Polyphenolics and Their Perspectives as Chemopreventive Agents Against Vascular Risk Factors" 대한약학회 26 (26): 286-293, 2003

35 Ahn GN, "Antioxidant activities of phlorotannins purified from Ecklonia cava on free radical scavenging using ESR and H2O2-mediated DNA damage" 226 : 71-79, 2007

36 Flecknell PA, "Analgesia in small mammals" 7 : 41-47, 1998

37 신현철, "An Antioxidative and Antiinflammatory Agent for Potential Treatment of Osteoarthritis from Ecklonia cava" 대한약학회 29 (29): 165-171, 2006

38 Fu HY, "A chemical endoplasmic reticulum chaperone alleviates doxorubicin-induced cardiac dysfunction" 118 : 798-809, 2016

39 Yang YI, "8, 80-Bieckol, isolated from edible brown algae, exerts its anti-inflammatory effects through inhibition of NF-kappa B signaling and ROS production in LPSstimulated macrophages" 23 : 460-468, 2014