title: The Zinc Ion Chelating Agent TPEN Attenuates Neuronal Death/apoptosis Caused by Hypoxia/ischemia Via Mediating the Pathophysiological Cascade Including Excitotoxicity, Oxidative Stress, and Inflammation.
abstract: OBJECTIVE
  We aim to determine the significant effect of TPEN, a Zn(2+) chelator, in mediating the pathophysiological cascade in neuron death/apoptosis induced by hypoxia/ischemia.
  
  
  METHODS
  We conducted both in vivo and in vitro experiments in this study. PC12 cells were used to establish hypoxia/ischemia model by applying oxygen-glucose deprivation (OGD). SHR-SP rats were used to establish an acute ischemic model by electrocoagulating middle cerebral artery occlusion. The effect of TPEN on neuron death/apoptosis was evaluated. In addition, the relative biomarks of excitotoxicity, oxidative stress, and inflammation reactions in hypoxia/ischemia PC12 cell model as well as in SHR-SP rat hypoxia/ischemia model were also assessed.
  
  
  RESULTS
  TPEN significantly attenuates the neurological deficit, reduced the cerebral infarction area and the ratio of apoptotic neurons, and increased the expression of GluR2 in the rat hypoxia/ischemia brain. TPEN also increased blood SOD activity, decreased blood NOS activity and blood MDA and IL-6 contents in rats under hypoxia/ischemia. In addition, TPEN significantly inhibited the death and apoptosis of cells and attenuated the alteration of GluR2 and NR2 expression caused by OGD or OGD plus high Zn(2+) treatments.
  
  
  CONCLUSIONS
  Zn(2+) is involved in neural cell apoptosis and/or death caused by hypoxia/ischemia via mediating excitotoxicity, oxidative stress, and inflammation.
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.|Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Liu
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Yu-Xiang
authors.initials: YX
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Di
authors.initials: D
authors.lastname: An
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 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: Department of Gerontology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Duan
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Yan-Qiang
authors.initials: YQ
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D005029:Ethylenediamines / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000172:deficiency; D020244:Infarction, Middle Cerebral Artery; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D011918:Rats, Inbred SHR; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D005029:Ethylenediamines; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D005947:Glucose; D015032:Zinc; C104722:glutamate receptor ionotropic, AMPA 2; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Excitotoxicity; Free Zn2+; Hypoxia/ischemia; Inflammation; Oxidative stress; TPEN