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RNA synthesis-dependent potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor-mediated toxicity by antihistamine terfenadine in cultured rat cerebellar neurons

Authors
Journal
Neuroscience Letters
0304-3940
Publisher
Elsevier
Publication Date
Volume
345
Issue
2
Identifiers
DOI: 10.1016/s0304-3940(03)00467-1
Keywords
  • Excitotoxicity
  • Glutamate Receptors
  • Antihistamines
  • Intracellular Calcium
  • Terfenadine
  • Domoate
  • α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate

Abstract

Abstract We have studied the effects of terfenadine on neurotoxicity and elevation of free cytoplasmic Ca 2+ levels upon stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in cultured cerebellar neurons. Pre-exposure to terfenadine (5 μM, 5 h) significantly increased neuronal death following specific stimulation of receptors by 100 μM AMPA or by subtoxic concentrations of domoate (8 μM), 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 [Ca 2+] i by approximately five fold, while AMPA induced no significant increase in [Ca 2+] i in the absence of terfenadine. Terfenadine reduced neuronal steady-state concentrations of [Ca 2+] 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.

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