title: Zinc release contributes to hypoglycemia-induced neuronal death.
abstract: Neurons exposed to zinc exhibit activation of poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme that normally participates in DNA repair but promotes cell death when extensively activated. Endogenous, vesicular zinc in brain is released to the extracellular space under conditions causing neuronal depolarization. Here, we used a rat model of insulin-induced hypoglycemia to assess the role of zinc release in PARP-1 activation and neuronal death after severe hypoglycemia. Zinc staining with N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) showed depletion of presynaptic vesicular zinc from hippocampal mossy fiber terminals and accumulation of weakly bound zinc in hippocampal CA1 cell bodies after severe hypoglycemia. Intracerebroventricular injection of the zinc chelator calcium ethylene-diamine tetraacetic acid (CaEDTA) blocked the zinc accumulation and significantly reduced hypoglycemia-induced neuronal death. CaEDTA also attenuated the accumulation of poly(ADP-ribose), the enzymatic product of PARP-1, in hippocampal neurons. These results suggest that zinc translocation is an intermediary step linking hypoglycemia to PARP-1 activation and neuronal death.
authors.affiliation: Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Suh
authors.forename: Philippe
authors.initials: P
authors.lastname: Garnier
authors.forename: Koji
authors.initials: K
authors.lastname: Aoyama
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
mesh_terms: D000818:Animals; D001786:Blood Glucose; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D007003:Hypoglycemia / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D002614:Chelating Agents; D004492:Edetic Acid; D011065:Poly(ADP-ribose) Polymerases; D015032:Zinc