Maduramicin induces apoptosis in chicken myocardial cells via intrinsic and extrinsic pathways. (August 2018)

• Record Type: Journal Article
• Authors: Gao, Xiuge; Zheng, Yani; Peng, Lin; Ruan, Xiangchun; Ji, Hui; Qiu, Yawei; Liu, Xiaoxiao; Teng, Pei; Guo, Dawei; Jiang, Shanxiang
• Is Part Of: Toxicology in vitro. Volume 50(2018)
• Page Start: 190
• Page End: 200
• Publication Date: 2018-08
• Subjects: Apoptosis -- Caspase -- Cytotoxicity -- Maduramicin -- Myocardial cells; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2018.03.008
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Maduramicin is one of the most extensively used anticoccidial drugs for the treatment of Eimeria spp. infections. However, overdosage, misuse and drug interactions have resulted in the development of ionophore toxic syndrome. Heart and skeletal muscles have been identified as the main target organs of toxicity. In the present study, primary chicken myocardial cells were isolated to investigate the toxicity and underlying mechanisms of maduramicin. Our results showed that maduramicin causes morphological changes and a decrease in the viability of chicken myocardial cells. Annexin V-FITC/PI and 4′, 6-diamidino-2-phenylindole (DAPI) staining showed a significant increase in the number of apoptotic cells. Furthermore, caspases-3/8/9 were activated at the gene and protein levels and this was accompanied by the upregulation of apoptosis-related genes, including bcl-2, bax, and cytochrome C . Treatment with the pan-caspase inhibitor N -benzyloxycarbonyl-Val-Ala-Asp (O-Me) fluoromethyl ketone (z-VAD-fmk) ameliorated the apoptosis and cytotoxicity. Furthermore, intracellular Ca 2+ and reactive oxygen species (ROS) were elevated, whereas mitochondrial membrane potential (MMP) and intracellular glutathione (GSH) decreased with exposure to maduramicin. The antioxidant N -acetyl-cysteine (NAC) had no significant effect on maduramicin-induced cytotoxicity and apoptosis. Taken together, our findings demonstrate that maduramicin is cytotoxic to primary chicken myocardial cells via caspase dependent and independent apoptotic pathways. Highlights: Maduramicin induced cell death in primary cultures of chicken myocardial cells. The cell death occurred primarily via apoptosis. Maduramicin increased caspase 3, 8 and 9 gene and protein expression. Maduramicin induced Ca 2+ elevation and ROS formation but decreased the mitochondrial membrane potential and GSH. Maduramicin-induced cell death involved the intrinsic and extrinsic pathways of apoptosis.