AMPA/Zn(2+)-induced neurotoxicity in rat primary cortical cultures: involvement of L-type calcium channels.
Zn2+ is believed to be an endogenous modulator of glutamatergic excitation. It has been shown to attenuate NMDA receptor-mediated excitation and to increase AMPA-induced excitatory transmission. The dual activity of Zn2+ on ionotropic excitatory neurotransmission suggests that Zn2+ plays a role in the modulation of excitatory neurodegenerative events. Stimulation of rat primary cortical cultures with the combination of 50 microM AMPA and 300 microM Zn2+ for 30 min induced approximately 50% cell death compared with only approximately 20% cell death induced by AMPA alone. The degree of neurotoxicity 48 h after the incubation was reproducible and was attenuated by CNQX, EDTA, EGTA, diltiazem and DHP-type Ca2+ channel blockers but not by MK-801. These findings suggest that an initial depolarization induced by AMPA and a subsequent influx of Ca2+ and Zn2+ ions through voltage-operated L-type Ca2+ channels are crucial events which finally lead to neuronal death. Racemic nimodipine and its (+)- and (-)-enantiomers had remarkable in vitro neuroprotective efficacies, the IC50 values being 4 nM for the racemate, 11 nM for the (+)- and 1 nM for the (-)-enantiomer. This suggests a possible therapeutic role for Ca2+ channel blockers in neurodegenerative diseases which are characterized by a disturbance of cellular Ca2+ homeostasis.
Freund
W D
WD
Institute for Neurobiology, Troponwerke GmbH & Co. KG, Köln, Germany.
Reddig
S
S
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D002712:Chlorides / Q000633:toxicity*; D004110:Diltiazem / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D005333:Fetus; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D017967:Zinc Compounds / Q000633:toxicity*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity*
D015220:Calcium Channels; D002712:Chlorides; D009498:Neurotoxins; D017967:Zinc Compounds; D004533:Egtazic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C016837:zinc chloride; D004492:Edetic Acid; D004110:Diltiazem