RNA synthesis-dependent potentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor-mediated toxicity by antihistamine terfenadine in cultured rat cerebellar neurons.
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.
Díaz-Trelles
Ramón
R
Department of Biochemistry and Molecular Biology, University of Oviedo, Campus el Cristo, 33071 Oviedo, Spain.
Novelli
Antonello
A
Fernández-Sánchez
M Teresa
MT
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000493:pharmacokinetics; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D003609:Dactinomycin / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D016593:Terfenadine / Q000633:toxicity*; D014966:Xanthenes / Q000493:pharmacokinetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000814:Aniline Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D006634:Histamine H1 Antagonists; D011500:Protein Synthesis Inhibitors; D018091:Receptors, AMPA; D014966:Xanthenes; D003609:Dactinomycin; C059715:Fluo-3; D012313:RNA; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016593:Terfenadine; D006632:Histamine; C012301:domoic acid; D007608:Kainic Acid; D002118:Calcium