AMPA receptor activation potentiated by the AMPA modulator 1-BCP is toxic to cultured rat hippocampal neurons.
The benzoylpiperidine 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and related compounds, potentiate alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acidergic (AMPAergic) synaptic currents in central neurons, and improve performance of rodents and humans on learning and memory tasks. Their physiological actions are similar but not identical to thiazides, which also enhance AMPAergic synaptic responses and improve performance of rats in water-maze and passive-avoidance tests. Thiazides also dramatically increase AMPA receptor-mediated neuronal death in vitro and in vivo. Here it was evaluated whether 1-BCP potentiated AMPA receptor-mediated excitotoxicity in hippocampal neuron cultures. Glutamate + MK 801 (to block NMDA receptors) + 1 mM 1-BCP produced neuronal death that was reversed by 10 microM 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX), a selective AMPA receptor antagonist. 1-BCP and drugs with similar activities can facilitate AMPA receptor-mediated excitotoxicity.
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. yamadak@neuro.wustl.edu
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D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004149:Dioxoles / Q000633:toxicity*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology; D010880:Piperidines / Q000633:toxicity*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*
D001581:Benzothiadiazines; D004149:Dioxoles; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D010880:Piperidines; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C085415:1-(1,3-benzodioxol-5-ylcarbonyl)piperidine; D018698:Glutamic Acid; C004639:cyclothiazide