AMPA ZN2+-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 mu M AMPA and 300 mu M Zn2+ for 30 min induced similar to 50% cell death compared with only similar to 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.