Nerve growth factor increases the sensitivity to zinc toxicity and induces cell cycle arrest in PC12 cells |
| |
| Authors: | Francisco J. Sánchez-Martín Elvira Valera Ilda Casimiro Jaime M. Merino |
| |
| Affiliation: | 1. Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071 Badajoz, Spain;2. Departamento de Anatomía, Biología Celular y Zoología, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain;1. Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing 400042, China;2. Chongqing Institute of Cardiology, Chongqing, China;1. School of Natural Sciences, Technology and Environmental studies, Södertörn University, SE-141 89 Huddinge, Sweden;2. Department of Pharmacology, Faculty of Medicine, Dalhousie University, 1459 Oxford Street, Halifax, NS B3H 4R2, Canada;3. School of Health and Medical Sciences, Örebro University, SE-701 82 Örebro, Sweden;1. Department of Neurology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan;2. Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;3. The National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20892, USA;4. Nippon-Zoki Pharmaceutical Co., Ltd., Osaka 564-0052, Japan;3. From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101;4. the State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking University, Beijing 100871;5. the Laboratory of Disease Genomics and Individual Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China;1. Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London NW3 2PF, UK;2. Department of Pharmacology and Therapeutics, The University of Melbourne, Australia |
| |
| Abstract: | Zinc is a basic trace element that plays important roles in brain and, consequently, its homeostasis needs to be critically controlled. High zinc concentrations in the interneuron synaptic space may induce neuronal death through mechanisms still partially solved. Undifferentiated pheochromocytoma (PC12) cells have been used to study zinc toxicity. As these cells can be differentiated into neuronal-like cells, the results obtained from differentiated cultures are more useful to understand zinc toxicity in neurons. In this paper, we show by flow cytometry that nerve growth factor (NGF) induces PC12 cells differentiation characterized by cell cycle arrest in the G1/G0 phase, similarly to that observed in serum-deprived cultures. Zinc induces cell death in NGF-differentiated PC12 cultures with an EC50 value of 143 ± 14 μM, which reveals a higher sensitivity with respect to undifferentiated PC12 cultures (EC50, 308 ± 32 μM) and a similar response to that obtained in hippocampal neurons (134 ± 12 μM). Thus, the differentiation process appeared responsible for such increase in sensitivity. To further support this tenet, when the NGF differentiation was impaired in presence of 10 μM MK-801, a selective blocker of the N-methyl-d-aspartate (NMDA) receptor that plays a role in the differentiation process, the higher sensitivity to zinc was reverted to an EC50 value of 241 ± 26 μM. Flow cytometry experiments showed that NGF-differentiated PC12 cells in presence of zinc were positive for propidium iodide but not for annexin-V labeling. These results, together with data from fluorescent labeling of nuclear fragmentation, caspase-3 activation, and reactive oxygen species generation, support the view that zinc toxicity in NGF-differentiated PC12 cells takes place mainly through a necrotic process. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
