title: Zn2+ entry produces oxidative neuronal necrosis in cortical cell cultures.
abstract: Evidence has accumulated that Zn2+ plays a central role in neurodegenerative processes following brain injuries including ischaemia or epilepsy. In the present study, we examined patterns and possible mechanisms of Zn2+ neurotoxicity. Inclusion of 30-300 microM Zn2+ for 30 min caused neuronal necrosis apparent by cell body and mitochondrial swelling in cortical cell cultures. This Zn2+ neurotoxicity was not attenuated by antiapoptosis agents, inhibitors of protein synthesis or caspase. Blockade of glutamate receptors or nitric oxide synthase showed no beneficial effect against Zn2+ neurotoxicity. Interestingly, antioxidants, trolox or SKF38393, attenuated Zn(2+)-induced neuronal necrosis. Pretreatment with insulin or brain-derived neurotrophic factor increased the Zn(2+)-induced free radical injury. Kainate or AMPA facilitated Zn2+ entry and potentiated Zn2+ neurotoxicity in a way sensitive to trolox. Reactive oxygen species and lipid peroxidation were generated in the early phase of Zn2+ neurotoxicity. These findings indicate that entry and accumulation of Zn2+ result in generation of toxic free radicals and then cause necrotic neuronal degeneration under certain pathological conditions in the brain.
authors.affiliation: Department of Pharmacology, School of Medicine, Ajou University, Suwon, Kyungkido, Korea.
authors.forename: E Y
authors.initials: EY
authors.lastname: Kim
authors.forename: J Y
authors.initials: JY
authors.lastname: Koh
authors.forename: Y H
authors.initials: YH
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Sohn
authors.forename: E
authors.initials: E
authors.lastname: Joe
authors.forename: B J
authors.initials: BJ
authors.lastname: Gwag
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002839:Chromans / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008854:Microscopy, Electron; D008933:Mitochondrial Swelling; D009336:Necrosis; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009498:Neurotoxins / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D015032:Zinc / Q000493:pharmacokinetics* / Q000633:toxicity*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology