title: Cyclosporin A protects against Lead neurotoxicity through inhibiting mitochondrial permeability transition pore opening in nerve cells.
abstract: Mitochondria play a key role in the process of lead (Pb)-induced impairment in nervous system. To further clarify the underlying mechanism of Pb neurotoxicity, this study was designed to investigate the role of mitochondrial permeability transition (MPT) and cyclophilin D (CyPD), a component of MPT pore (MPTP), in Pb-induced mitochondrial apoptosis in nerve cells. In SH-SY5Y and PC12 cells, Cyclosporin A (CSA), a special inhibitor of CyPD, could alleviate cell death, lactate dehydrogenase (LDH) leakage and adenosine 5 triphosphate (ATP) decrease caused by PbAc. In the following experiments, we found PbAc increased the protein level of CyPD and induced MPT pore (MPTP) opening. When cells were pretreated with CSA to inhibit MPTP opening, the Pb-induced impairment of mitochondrial morphology (swelling and rupture) and the loss of mitochondria were attenuated. In addition, CSA obviously ameliorated the Pb-induced damage of mitochondrial function, such as reactive oxygen species (ROS) boost and mitochondrial membrane potential (MMP) collapse, as well as the release of cytochrome C (Cyto C) and apoptosis-inducing factor (AIF) from mitochondria. These beneficial effects could finally result in cell survival under Pb-exposure conditions. Furthermore, scavenging ROS also significantly abrogated MPTP opening and attenuated Pb neurotoxicity. Therefore, we found that MPT played an important role in Pb-induced mitochondrial damage and, ultimately, cell death. Our results provided a potential strategy for inhibiting PbAc neurotoxicity. However, due to the high Pb concentrations used in this study further investigations at Pb concentrations closer to human exposure are needed to verify the results.
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; Disease Control and Prevention Center of Xiqing, Tianjin, PR China.
authors.forename: Fen
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Xiaonan Maternity and Child Health Hospital, Xiaogan, PR China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. Electronic address: chen-jun@hust.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002461:Cell Line, Transformed; D003524:Cyclosporins / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D003524:Cyclosporins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D007854:Lead; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007770:L-Lactate Dehydrogenase
keywords: CSA; CyPD; MPTP; Neurotoxicity; Pb; ROS