Abstract
Zn 2+ 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 Zn 2+ on ionotropic excitatory neurotransmission suggests that Zn 2+ plays a role in the modulation of excitatory neurodegenerative events. Stimulation of rat primary cortical cultures with the combination of 50 μM AMPA and 300 μM Zn 2+ for 30 min induced ∼50% cell death compared with only ∼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 Ca 2+ channel blockers but not by MK-801. These findings suggest that an initial depolarization induced by AMPA and a subsequent influx of Ca 2+ and Zn 2+ ions through voltage-operated L-type Ca 2+ channels are crucial events which finally lead to neuronal death. Racemic nimodipine and its (+)- and (−)-enantiomers had remarkable in vitro neuroprotective efficacies, the IC 50 values being 4 nM for the racemate, 11 nM for the (+)- and 1 nM for the (−)-enantiomer. This suggests a possible therapeutic role for Ca 2+ channel blockers in neurodegenerative diseases which are characterized by a disturbance of cellular Ca 2+ homeostasis.
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