Carbamazepine toxic effects in chick cardiomyocyte micromass culture and embryonic stem cell derived cardiomyocyte systems – Possible protective role of antioxidants

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2014-12, Vol.50, p.49-59
• Main Authors: Shaikh Qureshi, W.M., Memon, S., Latif, M.L., Garle, M.J., Parker, T.L., Pratten, M.K.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - pharmacology; Ascorbic acid; Carbamazepine; Carbamazepine - toxicity; Cardiomyocyte; Chick micromass culture; Chickens; Connexin 43 - analysis; Embryonic stem cells; Embryonic Stem Cells - cytology; Mice; Myocytes, Cardiac - drug effects; Reactive oxygen species; Reactive Oxygen Species - metabolism; Superoxide Dismutase - pharmacology; Teratogenicity
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2014.10.007

•The use of carbamazepine (CBZ) during pregnancy increases cardiovascular anomalies.•CBZ showed pronounced developmental cardiotoxic effects on differentiating cardiomyocyte compared to differentiated ones.•The mechanism mainly involved increased ROS production which was counteracted with ascorbic acid supplements.•CBZ has also affected cardiac connexin 43 expression in differentiating and differentiated cardiomyocytes.•Our results indicated CBZ induced ROS stress as mechanism of developmental cardiotoxicity at early stage of cardiogenesis which can be negated by using antioxidant agent. The use of carbamazepine (CBZ) during pregnancy increases cardiovascular anomalies. In this study CBZ developmental cardiotoxic effects were evaluated using chick cardiomyocyte micromass (MM) culture and mouse embryonic stem cells derived cardiomyocyte (ESDC) systems. In MM culture, CBZ only inhibited the cardiomyocyte contractile activity, while in ESDC it completely ceased the contractile activity at 200μM with decreased cell viability and protein content. The antioxidant superoxide dismutase (SOD) supplement in MM and ascorbic acid (AA) in ESDC showed protective effects on CBZ toxicity, but elevated levels of reactive oxygen species (ROS) production were recorded with CBZ treatment only in ESDC. CBZ has also affected cardiac connexin 43 expression in both in vitro systems. Our results indicated CBZ induced ROS stress as mechanism of developmental cardiotoxicity at early stage of cardiogenesis in ESDC system compared to MM system's differentiated cells. These toxic effects can be negated by using antioxidant agent.