title: TPEN, a Specific Zn2+Chelator, Inhibits Sodium Dithionite and Glucose Deprivation (SDGD)-Induced Neuronal Death by Modulating Apoptosis, Glutamate Signaling, and Voltage-Gated K+and Na+Channels.
abstract: Hypoxia-ischemia-induced neuronal death is an important pathophysiological process that accompanies ischemic stroke and represents a major challenge in preventing ischemic stroke. To elucidate factors related to and a potential preventative mechanism of hypoxia-ischemia-induced neuronal death, primary neurons were exposed to sodium dithionite and glucose deprivation (SDGD) to mimic hypoxic-ischemic conditions. The effects of N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a specific Zn2+-chelating agent, on SDGD-induced neuronal death, glutamate signaling (including the free glutamate concentration and expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor (GluR2) and N-methyl-D-aspartate (NMDA) receptor subunits (NR2B), and voltage-dependent K+and Na+channel currents were also investigated. Our results demonstrated that TPEN significantly suppressed increases in cell death, apoptosis, neuronal glutamate release into the culture medium, NR2B protein expression, and IKas well as decreased GluR2 protein expression and Na+channel activity in primary cultured neurons exposed to SDGD. These results suggest that TPEN could inhibit SDGD-induced neuronal death by modulating apoptosis, glutamate signaling (via ligand-gated channels such as AMPA and NMDA receptors), and voltage-gated K+and Na+channels in neurons. Hence, Zn2+chelation might be a promising approach for counteracting the neuronal loss caused by transient global ischemia. Moreover, TPEN could represent a potential cell-targeted therapy.
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Xue-Ling
authors.initials: XL
authors.lastname: Ma
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Yu-Xiang
authors.initials: YX
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Cong-Cong
authors.initials: CC
authors.lastname: He
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Tian
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: An
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Heng
authors.affiliation: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Lai-Hua
authors.initials: LH
authors.lastname: Xie
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China. liuyanq@nankai.edu.cn.
authors.forename: Yan-Qiang
authors.initials: YQ
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology*; D004227:Dithionite / Q000633:toxicity; D005029:Ethylenediamines / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D061566:Voltage-Gated Sodium Channels / Q000502:physiology*; D015032:Zinc / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D005029:Ethylenediamines; D024642:Potassium Channels, Voltage-Gated; D061566:Voltage-Gated Sodium Channels; D004227:Dithionite; D018698:Glutamic Acid; D005947:Glucose; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Glucose deprivation; Glutamate signal path; Neuronal death; Sodium dithionite; TPEN; Voltage-gated channel