Evaluating the Acute Toxicity and In vivo Protective Effect of Standardized <i>Andrographis paniculata</i> Extract against Doxorubicin-induced Cardiotoxicity in Sprague-dawley Rats

Authors

  • Wawaimuli Arozal Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia.
  • Septelia I. Wanandi Department of Biochemistry and Molecular Biology, Faculty of Medicine Universitas Indonesia, Jakarta 10430, Indonesia.
  • Melva Louisa Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia.
  • Puspita E. Wuyung Departement of Pathology Anatomy, Universitas Indonesia, Jakarta, 10430, Indonesia.
  • Deni Noviana Faculty of Veterinary Medicine, Bogor Agricultural University, Bogor 16680, Indonesia
  • Oluebube M. Eziefule Master’s Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia.
  • Yulia R. Dewi Master’s Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia.
  • Deya A. Nabillah Master’s Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia.
  • Jude C. Ikewuchi Department of Biochemistry, Faculty of Science, University of Port Harcourt, River State 5323, Nigeria.
  • Anthony S. Purnomo Konimex Pharmaceutical Laboratories, Sukoharjo, Central Java 57552, Indonesia.

DOI:

https://doi.org/10.26538/tjnpr/v8i5.13

Keywords:

Andrographis paniculata, cardiotoxicity, doxorubicin, acute toxicity, biomarkers

Abstract

Doxorubicin fights cancer effectively, but harms heart muscle. The current methods for managing doxorubicin's toxicity are limited. This study determined the acute toxicity and protective effect of a standardized Andrographis paniculata ethanolic leaf extract against doxorubicin- induced cardiotoxicity. The acute toxicity of the extract was first investigated before determining its protective effect. 24 Sprague-Dawley rats were allocated into four groups: normal, DOX, DOX+AP250, and DOX+AP125. Doxorubicin was administered intraperitoneally (4 mg/kg/week) for four weeks. Treatment groups received doxorubicin plus either 250 mg/kg or 125 mg/kg daily dose of Andrographis paniculata ethanolic extract for 4 weeks. The rats were subjected to echocardiography 24 hours prior to sacrifice. After sacrifice, blood and heart tissue were collected to analyze brain natriuretic peptide and troponin level by the enzyme-linked immunosorbent assay. Histopathology assessment of heart tissues was also performed using hematoxylin and eosin staining. Andrographolide content of the extract was determined by HPLC. The bulk capsule extract's lethal dose 50 (LD50) was determined to be above 4166 mg/kg BW and the andrographolide content was 8.98%.  Andrographis paniculata extract (125 or 250 mg) mitigated doxorubicin-induced cardiotoxicity by decreasing serum brain natriuretic peptide and troponin level (p < 0.05), reversing histopathological alterations in heart tissue (p < 0.05), and improving fractional shortening, ejection fraction and heart rate. This study demonstrates that the standardized extract may be a non-toxic herbal and holds promise as a therapeutic agent for mitigating doxorubicin-induced damage in rats. Further studies are needed to elucidate its exact protective molecular mechanism of action.

References

Kang YJ, Chen V, Yu A, Voss-McCowan M, Epstein PN. Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity. J Clin Invest. 1997;100(6):1501–6.

Trapani D, Zagami P, Nicolò E, Pravettoni G, Curigliano G. Management of cardiac toxicity induced by chemotherapy. J Clin Med. 2020;9(9):1–18.

Caruso G, Privitera A, Antunes BM, Lazzarino G, Lunte SM, Aldini G, Caraciet F. The Therapeutic Potential of Carnosine as an Antidote against Drug-Induced Cardiotoxicity and Neurotoxicity: Focus on Nrf2 Pathway. Molecules. 2022;27(14):1–27.

Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021;139 https://doi.org/10.1016/j.biopha.2021.111708

Arcamone F, Cassinelli G, Faktini G, Grein A, Orezzi P, Pol C, Spalla C. Adriamycin, 14-Hydroxydaunomycin, a New Antitumor Antibiotic from S. peucetius var. caesius. Biotechnol Bioeng. 1969; 11:1101–1110.

Găman AM, Egbuna C, Găman MA. Natural bioactive lead compounds effective against haematological malignancies. In: Phytochemicals as Lead Compounds for New Drug Discovery. 2019. 95–115.

Belger C, Abrahams C, Imamdin A, Lecour S. Doxorubicin-induced cardiotoxicity and risk factors. Int J Cardiol Heart Vasc. 2024; 50.

Attar A, Behnagh AK, Hosseini M, Amanollahi F, Shafiekhani P, Kabir A. Beta-Blockers for Primary Prevention of Anthracycline-Induced Cardiac Toxicity: An Updated Meta-Analysis of Randomized Clinical Trials. Cardiovasc Ther. 2022; 2022.

Hullin R, Métrich M, Sarre A, Basquin D, Maillard M, Regamey J, Martin D. Diverging effects of enalapril or eplerenone in primary prevention against doxorubicin-induced cardiotoxicity. Cardiovasc Res. 2018; 114(2):272–81.

Sangweni NF, van Vuuren D, Mabasa L, Gabuza K, Huisamen B, Naidoo S, Barry S, Johnson R. Prevention of Anthracycline-Induced Cardiotoxicity: The Good and Bad of Current and Alternative Therapies. Front Cardiovasc Med. 2022; 9:1–17.

Vuong JT, Stein-Merlob AF, Cheng RK, Yang EH. Novel Therapeutics for Anthracycline Induced Cardiotoxicity. Front Cardiovasc Med. 2022; 9:863314

Langer SW. Dexrazoxane for the treatment of chemotherapy-related side effects. Cancer Manag Res. 2014; 6:357–63.

Koss-Mikołajczyk I, Todorovic V, Sobajic S, Mahajna J, Gerić M, Tur JA, Bartoszek A. Natural products counteracting cardiotoxicity during cancer chemotherapy: The special case of doxorubicin, a comprehensive review. Int J Mol Sci. 2021; 22(18):10037.

Eziefule OM, Arozal W, Wanandi SI, Dewi S, Nafrialdi N, Saraswati M, Louisa M. Andrographis paniculata: A potential supplementary therapy for cardiovascular diseases - A systematic review of its effects and molecular actions. J Pharm Pharmacogn Res. 2024; 12(3):487–513.

Kumar S, Singh B, Bajpai V. Andrographis paniculata (Burm.f.) Nees: Traditional uses, phytochemistry, pharmacological properties and quality control/quality assurance. J Ethnopharmacol 2021; 275

Chao WW, Lin BF. Isolation and identification of bioactive compounds in Andrographis paniculata (Chuanxinlian). Chin Med. 2010; 5:17

Sya’ban PA, Jonathan AP, Respati TS, Siti IR, Fauzia I, Asep B, Masteria YP, Carmen F, Chianese G. Evaluations of Andrographolide-Rich Fractions of Andrographis paniculata with Enhanced Potential Antioxidant, Anticancer, Antihypertensive, and Anti-Inflammatory Activities. Plants. 2023; 1220(12). https://doi.org/ 10.3390/plants12061220

Chen CC, Lii CK, Lin YH, Shie PH, Yang YC, Huang CS, Chen HW. Andrographis paniculata Improves Insulin Resistance in High-Fat Diet-Induced Obese Mice and TNFα-Treated 3T3-L1 Adipocytes. Am J Chin Med. 2020; 48(5):1073–90.

Irawan C, Enriyani R, Ismail, Sukiman M, Putri ID, Utami A, Rahmatia L, Lisandi A. Effects of Solvent Variation on The Antioxidant, Anti-Inflammatory, and Alpha-Glucosidase Inhibitory Activity of Andrographis paniculata (Burm.f.)Wall Leaves Extract. Trop J Nat Prod Res. 2024; 8(1):5968–5972.

Belger C, Abrahams C, Imamdin A, Lecour S. Doxorubicin-induced cardiotoxicity and risk factors. Int J Cardiol Heart Vasc. 2024; 1:50.

Alhazzani K, Alotaibi MR, Alotaibi FN, Aljerian K, Sobeai HMAs, Alhoshani AR, Alanazi AZ, Alswayyed M. Protective effect of valsartan against doxorubicin-induced cardiotoxicity: Histopathology and metabolomics in vivo study. J Biochem Mol Toxicol. 2021; 35(9):e22842.

Patterson CC, Blankenberg S, Ben-Shlomo Y, Heslop L, Bayer A, Lowe G, Zeller T, Gallacher J, Young L, Yarnell 22.JWG. Troponin and BNP are markers for subsequent non-ischaemic congestive heart failure: the Caerphilly Prospective Study (CaPS). Open Heart. 2018; 5(1):e000692.

Silmi H, Wawaimuli A, Vetnizah J. The Effect of Oral Andrographolide on Cardiac Biomarkers in Doxorubicin-induced Rats. J Med Health 2023; 5(2):146–55.

Wahyuni Salam S, Setiyono A, Juniantito V. Protective Effect of Andrographolide on Doxorubicin-Induced Cardiotoxicity in Rat. JSV. 2016; 34(2):259–66.

Wang H, Yu X, Xun Z, Wu Y. Aqueous Extract of Andrographis paniculata Ameliorates Cardiotoxicity Induced by Doxorubicin in vivo. Int J Pharmacol. 2022; 18(3):466–74.

Sprague-Dawley Rats Induced by Uninephrectomy, DOCA Injection, and Sodium Chloride: A Suitable Model for Chronic Hypertension with Cardiac Hypertrophy. Int J Vet Sci. 2024; https://doi.org/10.47278/journal.ijvs/2024.141

Patintingan CG, Louisa M, Juniantito V, Arozal W, Hanifah S, Wanandi SI, Thandavarayan R. Moringa oleifera Leaves Extract Ameliorates Doxorubicin-Induced Cardiotoxicity via Its Mitochondrial Biogenesis Modulatory Activity in Rats. J Exp Pharmacol. 2023; 15:307–319.

Mussard E, Jousselin S, Cesaro A, Legrain B, Lespessailles E, Esteve E, Berteina-Raboin S, Toumi H. Andrographis paniculata and its bioactive diterpenoids against inflammation and oxidative stress in keratinocytes. Antioxidants. 2020; 9(6):1–14.

Liu W, Liang L, Zhang Q, Li Y, Yan S, Tang T, Ren Y, Mo J, Liu F, Chen X, Lan T. Effects of andrographolide on renal tubulointersticial injury and fibrosis. Evidence of its mechanism of action. Phytomedicine. 2021; 91:153650. https://doi.org/10.1016/j.phymed.2021.153650

Qin X, Wang X, Tian M, Dong Z, Wang J, Wang C, Huang Q. The role of Andrographolide in the prevention and treatment of liver diseases. Phytomedicine. 2023; 109(51):154537. https://doi.org/10.1016/j.phymed.2022.154537

A Okhuarobo, JE Falodun, O Erharuyi, V Imieje, A Falodun, P Langer. Harnessing the medicinal properties of Andrographis paniculata for diseases and beyond: a review of its phytochemistry and pharmacology. Asian Pac. J. Trop. 4 (3), 213-222

Antwi-Adjei M, Obese E, Adakudugu EA, Henneh IT, Biney RP, Aboagye B, Amoani B, Anokwah D, Ameyaw EO. Modulating Effects of the Hydroethanolic Leaf Extract of Persicaria lanigera R. Br. Soják (Polygonaceae) against Acute Inflammation. Sci World J. 2023; 2023.

El Kabbaoui M, Chda A, El-Akhal J, Azdad O, Mejrhit N, Aarab L, Bencheikh R, Tazi A. Acute and sub-chronic toxicity studies of the aqueous extract from leaves of Cistus ladaniferus L. in mice and rats. J Ethnopharmacol. 2017; 209:147–56.

Kamsu GT, Djamen Chuisseu DP, Fodouop Chegaing SP, Laure Feudjio HB, Ndel Famen LC, Kodjio N, Sokoudjou JB. Toxicological Profile of the Aqueous Extract of Tectona grandis L.F. (Verbenaceae) Leaves: A Medicinal Plant Used in the Treatment of Typhoid Fever in Traditional Cameroonian Medicine. J Toxicol. 2021; 2021.

OECD. “Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation,” Environmental Health and Safety Monograph Series on Testing and Assessment, OECD Publishing Ltd, Paris, F. 2000

Worasuttayangkurn L, Nakareangrit W, Kwangjai J, Sritangos P, Pholphana N, Watcharasit P, Rangkadilok N, Thiantanawat A, Satayavivad J. Acute oral toxicity evaluation of Andrographis paniculata-standardized first true leaf ethanolic extract. Toxicol Rep. 2019; 6:426–30.

Sampaio DPS, Silva JBM, do Carmo Rassi D, Freitas AF, Rassi S. Echocardiographic strategy for early detection of cardiotoxicity of doxorubicin: a prospective observational study. Cardiooncology. 2022; 8(1):1–9. https://doi.org/10.1186/s40959-022-00143-0

Zhang J, Li X, Liu J, Shang Y, Tan L, Guo Y. Early and dynamic detection of doxorubicin induced cardiotoxicity by myocardial contrast echocardiography combined with two-dimensional speckle tracking echocardiography in rats. Front Cardiovasc Med. 2023; 9:1–10.

Wang F, Chandra J, Kleinerman ES. Exercise intervention decreases acute and late doxorubicin-induced cardiotoxicity. Cancer Med. 2021; 10(21):7572–7584.

Nabiev SR, Kochurova AM, Nikitina L V., Beldiia EA, Matyushenko AM, Yampolskaya DS, Bershitsky XY, Kopylova GV, Shchepkin DV. N-Terminal Fragment of Cardiac Myosin Binding Protein-C Increases the Duration of Actin—Myosin Interaction. Bull Exp Biol Med. 2024; 176(3):324–7.

Schmidt WM, Lehman W, Moore JR. Direct observation of tropomyosin binding to actin filaments. Cytoskeleton. 2015; 72(6):292–303.

Lehman William, Galińska-Rakoczy A, Hatch V, S TL, Craig R. Structural Basis for the Activation of Muscle Contraction by Troponin and Tropomyosin. J Mol Biol. 2009; 388(4):673–681.

Giordano S, Estes R, Li W, George R, Gilford T, Glasgow K, Hallman H, Josephat F, Oliveira A, Xavier N, Chiasera JM. Troponin Structure and Function in Health and Disease. ASCLS. 2018; 31(4):192–199.

Pan DS, Li B, Wan SL. Evaluation of biomarkers for doxorubicininduced cardiac injury in rats. Exp Ther Med. 2022; 24(6):1–13.

Hekmat AS, Navabi Z, Alipanah H, Javanmardi K. Alamandine significantly reduces doxorubicin-induced cardiotoxicity in rats. Hum Exp Toxicol. 2021; 40(10):1781–95.

Nakagawa Y, Nishikimi T, Kuwahara K. Atrial and brain natriuretic peptides: Hormones secreted from the heart. Peptides (NY). 2019; 111:18–25: https://doi.org/10.1016/j.peptides.2018.05.012

Cao Z, Jia Y, Zhu B. BNP and NT-proBNP as diagnostic biomarkers for cardiac dysfunction in both clinical and forensic medicine. Int J Mol Sci. 2019; 20(8):18–20.

Sarzani R, Allevi M, Di Pentima C, Schiavi P, Spannella F, Giulietti F. Role of Cardiac Natriuretic Peptides in Heart Structure and Function. Int J of Mol Sci. 2022; 23.

Hayakawa H, Komada Y, Hirayama M, Hori H, Ito M, Sakurai M. Plasma levels of natriuretic peptides in relation to doxorubicin-induced cardiotoxicity and cardiac function in children with cancer. Med Pediatr Oncol. 2001; 37(1):4–9.

Koh E, Nakamura T, Takahashi H. Troponin-T and Brain Natriuretic Peptide as Predictors for Adriamycin-Induced Cardiomyopathy in Rats. Circ J. 2004; 68(2):163–7.

Atas E, Kismet E, Kesik V, Karaoglu B, Aydemir G, Korkmazer N, Demirkaya E, Karslioglu Y, Yurttutan N, Unay B, Koseoglu V, Gokcay E. Cardiac troponin-I, brain natriuretic peptide and endothelin-1 levels in a rat model of doxorubicin-induced cardiac injury. J Cancer Res Ther. 2015; 11(4):882–6.

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Published

2024-05-30

How to Cite

Arozal, W., Wanandi, S. I., Louisa, M., Wuyung, P. E., Noviana, D., Eziefule, O. M., … Purnomo, A. S. (2024). Evaluating the Acute Toxicity and In vivo Protective Effect of Standardized <i>Andrographis paniculata</i> Extract against Doxorubicin-induced Cardiotoxicity in Sprague-dawley Rats. Tropical Journal of Natural Product Research (TJNPR), 8(5), 7134–7141. https://doi.org/10.26538/tjnpr/v8i5.13

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