Abstract
We have studied the effects of terfenadine on neurotoxicity and elevation of free cytoplasmic Ca2+ levels upon stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in cultured cerebellar neurons. Pre-exposure to terfenadine (5 microM, 5 h) significantly increased neuronal death following specific stimulation of receptors by 100 microM AMPA or by subtoxic concentrations of domoate (8 microM), stimuli that are non-toxic when applied to terfenadine-untreated sister cultures. Terfenadine potentiation was prevented by the transcription inhibitor actinomycin D and was significantly ameliorated by histamine (1 mM). In terfenadine-treated neurons, AMPA increased [Ca2+](i) by approximately five fold, while AMPA induced no significant increase in [Ca2+](i) in the absence of terfenadine. Terfenadine reduced neuronal steady-state concentrations of [Ca2+](i) by approximately 75%. Our results suggest a role for histamine H1 receptors and intracellular calcium in the modulation of the excitotoxic response via AMPA receptors.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Analysis of Variance
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Aniline Compounds / pharmacokinetics
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Animals
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Animals, Newborn
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Calcium / metabolism*
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Cell Survival / drug effects
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Cells, Cultured
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Cerebellum / cytology*
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Dactinomycin / pharmacology
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Dizocilpine Maleate / pharmacology
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Drug Interactions
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Histamine / pharmacology
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Histamine H1 Antagonists / toxicity*
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Kainic Acid / analogs & derivatives*
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Kainic Acid / pharmacology
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Neurons / drug effects*
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Neurons / metabolism
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Protein Synthesis Inhibitors / pharmacology
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RNA / biosynthesis
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RNA / drug effects
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Rats
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Receptors, AMPA / metabolism*
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Terfenadine / toxicity*
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Xanthenes / pharmacokinetics
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Aniline Compounds
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Histamine H1 Antagonists
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Protein Synthesis Inhibitors
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Receptors, AMPA
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Xanthenes
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Dactinomycin
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Fluo-3
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RNA
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Dizocilpine Maleate
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6-Cyano-7-nitroquinoxaline-2,3-dione
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Terfenadine
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Histamine
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domoic acid
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Kainic Acid
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Calcium