title: Intracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia.
abstract: Despite considerable evidence for contributions of both Zn(2+) and Ca(2+) in ischemic brain damage, the relative importance of each cation to very early events in injury cascades is not well known. We examined Ca(2+) and Zn(2+) dynamics in hippocampal slices subjected to oxygen-glucose deprivation (OGD). When single CA1 pyramidal neurons were loaded via a patch pipette with a Ca(2+)-sensitive indicator (fura-6F) and an ion-insensitive indicator (AlexaFluor-488), small dendritic fura-6F signals were noted after several (approximately 6-8) minutes of OGD, followed shortly by sharp somatic signals, which were attributed to Ca(2+) ("Ca(2+) deregulation"). At close to the time of Ca(2+) deregulation, neurons underwent a terminal increase in plasma membrane permeability, indicated by loss of AlexaFluor-488 fluorescence. In neurons coloaded with fura-6F and a Zn(2+)-selective indicator (FluoZin-3), progressive rises in cytosolic Zn(2+) levels were detected before Ca(2+) deregulation. Addition of the Zn(2+) chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) significantly delayed both Ca(2+) deregulation and the plasma membrane permeability increases, indicating that Zn(2+) contributes to the degenerative signaling. Present observations further indicate that Zn(2+) is rapidly taken up into mitochondria, contributing to their early depolarization. Also, TPEN facilitated recovery of the mitochondrial membrane potential and of field EPSPs after transient OGD, and combined removal of Ca(2+) and Zn(2+) markedly extended the duration of OGD tolerated. These data provide new clues that Zn(2+) accumulates rapidly in neurons during slice OGD, is taken up by mitochondria, and contributes to consequent mitochondrial dysfunction, cessation of synaptic transmission, Ca(2+) deregulation, and cell death.
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, California 92697, USA.
authors.forename: Yuliya V
authors.initials: YV
authors.lastname: Medvedeva
authors.forename: Bin
authors.initials: B
authors.lastname: Lin
authors.forename: C William
authors.initials: CW
authors.lastname: Shuttleworth
authors.forename: John H
authors.initials: JH
authors.lastname: Weiss
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D005029:Ethylenediamines / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism*; D005456:Fluorescent Dyes; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000473:pathology; D000860:Hypoxia / Q000150:complications; D066298:In Vitro Techniques; D007511:Ischemia / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011083:Polycyclic Compounds / Q000378:metabolism; D017966:Pyramidal Cells / Q000473:pathology*; D013569:Synapses / Q000502:physiology*; D015032:Zinc / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D005029:Ethylenediamines; C451182:FluoZin-3; D005456:Fluorescent Dyes; D011083:Polycyclic Compounds; D005947:Glucose; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D002118:Calcium