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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
-
6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
-
Amino Acid Chloromethyl Ketones / pharmacology
-
Animals
-
Antioxidants / pharmacology
-
Apoptosis / drug effects
-
Brain-Derived Neurotrophic Factor / pharmacology
-
Cells, Cultured
-
Cerebral Cortex / cytology
-
Chromans / pharmacology
-
Cysteine Proteinase Inhibitors / pharmacology
-
Dizocilpine Maleate / pharmacology
-
Dopamine Agonists / pharmacology
-
Drug Synergism
-
Excitatory Amino Acid Agonists / pharmacology
-
Excitatory Amino Acid Antagonists / pharmacology
-
Female
-
Free Radicals / metabolism
-
Hypoglycemic Agents / pharmacology
-
Insulin / pharmacology
-
Kainic Acid / pharmacology
-
Lipid Peroxidation / drug effects
-
Mice
-
Microscopy, Electron
-
Mitochondrial Swelling
-
Necrosis
-
Nerve Degeneration / chemically induced*
-
Nerve Degeneration / metabolism
-
Neurons / metabolism*
-
Neurons / pathology*
-
Neurons / ultrastructure
-
Neurotoxins / pharmacology
-
Oligopeptides / pharmacology
-
Oxidative Stress / drug effects
-
Pregnancy
-
Zinc / pharmacokinetics*
-
Zinc / toxicity*
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
-
Amino Acid Chloromethyl Ketones
-
Antioxidants
-
Brain-Derived Neurotrophic Factor
-
Chromans
-
Cysteine Proteinase Inhibitors
-
Dopamine Agonists
-
Excitatory Amino Acid Agonists
-
Excitatory Amino Acid Antagonists
-
Free Radicals
-
Hypoglycemic Agents
-
Insulin
-
Neurotoxins
-
Oligopeptides
-
benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
-
benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
-
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
-
Dizocilpine Maleate
-
6-Cyano-7-nitroquinoxaline-2,3-dione
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
-
Zinc
-
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
-
Kainic Acid