Agmatine induces glutamate release and cell death in cultured rat cerebellar granule neurons.
We investigated the effect of agmatine on cell viability of rat cerebellar granule neurons in a high-K+ (27.5 mM) medium. Exposure of cultured rat cerebellar granule neurons to agmatine (200-800 microM) resulted in a significant decrease in cell viability. Agmatine-induced neuronal death began to occur 6-12 h after addition, and gradually progressed. The agmatine neurotoxicity was attenuated by N-methyl-D-aspartate (NMDA) receptor antagonists and by enzymatic degradation of L-glutamate with glutamic pyruvic transaminase. Furthermore, a significant increase in extracellular L-glutamate concentration was detected before cell death occurred. In addition, agmatine-induced glutamate release and cell death were both blocked by pretreatment with botulinum toxin C, which is known to specifically inhibit the exocytosis. The agmatine neurotoxicity was not observed when extracellular K+ concentration was lower (10 mM). These results suggest that agmatine induces glutamate release through the exocytosis and thereby causes NMDA receptor-mediated neuronal death in conditions in which extracellular K+ concentrations are elevated.
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. abe@hoshi.ac.jp
Kazuho
K
Abe
Yuzuru
Y
Abe
Hiroshi
H
Saito
D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles
D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D013778:Tetrazolium Salts; D013844:Thiazoles; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000376:Agmatine; D007770:L-Lactate Dehydrogenase; D001905:Botulinum Toxins; C022616:thiazolyl blue; C096324:botulinum toxin type C; D011188:Potassium