title: The Cardenolide Glycoside Acovenoside A Affords Protective Activity in Doxorubicin-Induced Cardiotoxicity in Mice.
abstract: The current study aimed to investigate the protective effect of the cardenolide glycoside acovenoside A (AcoA) against doxorubicin-induced cardiotoxicity in mice. AcoA was isolated from the pericarps of Acokanthera oppositifolia to chemical homogeneity and characterized by means of one- and two-dimensional nuclear magnetic resonance spectroscopy. AcoA exhibited relatively low toxicity in mice (LD50 = 223.3 mg/kg bw). Repeated administration of doxorubicin induced cardiotoxicity manifested by reduced activity of myocardial membrane-bound ion pumps and elevated serum biomarkers of myocardial dysfunction, oxidative stress, and inflammation. Pretreatment of doxorubicin-exposed mice with AcoA (11.16 or 22.33 mg/kg bw, i.p.) for 2 weeks after 2 weeks of combined administration of AcoA and doxorubicin protected the animals dose dependently against doxorubicin-induced cardiotoxicity as indicated by normalization of the levels of different myocardial markers of oxidative stress (malondialdehyde, nitric oxide, total antioxidant capacity, and cardiac glutathione), serum myocardial diagnostic marker enzymes (serum cardiac troponin T, creatine kinase isoenzyme MB, aspartate aminotransferase, and lactate dehydrogenase), and inflammatory markers (c-reactive protein, tumor necrosis factor-α, and interleukin-6), as well as myocardial Na(+)/K(+)-ATPase activity. These effects were attributed to the negative impact of AcoA on transcription factors nuclear factor κB and interferon regulatory factor 3/7. Thus acovenoside A might act as a cardioprotective agent to prevent doxorubicin-induced cardiotoxicity.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Shahira M
authors.initials: SM
authors.lastname: Ezzat
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Menna
authors.initials: M
authors.lastname: El Gaafary
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Abeer M
authors.initials: AM
authors.lastname: El Sayed
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Omar M
authors.initials: OM
authors.lastname: Sabry
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Zeinab Y
authors.initials: ZY
authors.lastname: Ali
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Susanne
authors.initials: S
authors.lastname: Hafner
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Michael
authors.initials: M
authors.lastname: Schmiech
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Lu
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.).
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt (S.M.E., M.E.G., A.M.E.S., O.M.S.); Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt (Z.Y.A.); Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany (M.E.G., S.H., M.S., L.J., Ta.S., Th.S.) thomas.simmet@uni-ulm.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
mesh_terms: D000818:Animals; D029062:Apocynaceae / Q000737:chemistry; D055162:Biocatalysis; D015415:Biomarkers / Q000097:blood; D002298:Cardenolides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D066126:Cardiotoxicity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002298:Cardenolides; D002316:Cardiotonic Agents; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; C048124:acovenoside A; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D000254:Sodium-Potassium-Exchanging ATPase