Inhibition by lifarizine of intracellular Ca2+ rises and glutamate exocytosis in depolarized rat cerebrocortical synaptosomes and cultured neurones.
1. The effects of lifarizine (RS-87476) on intracellular Ca2+ rises and the release of glutamate from rat cerebrocortical synaptosomes depolarized with 30 mM KCl were investigated by use of entrapped fura 2 and exogenous glutamate dehydrogenase. 2. Prior (1 min) addition of lifarizine decreased 30 mM KCl-induced total glutamate release, with 3 microM and 10 microM causing 39% and 72% averaged decreases from controls. The calcium-dependent component of glutamate release (approx. 40% of total) was similarly decreased by 47% and 74%, whereas the calcium-independent component was decreased by only 32% and 43% respectively. 3. In parallel experiments with fura-2-loaded synaptosomes, lifarizine reduced the depolarization-induced increases in intracellular [Ca2+], suggesting that this is the means by which the decreases in glutamate release are brought about. Lifarizine inhibited both the plateau and the spike phases of the Ca2+ increases suggesting that, in addition to its known sodium channel blocking properties, it may also inhibit more than one class of calcium channel in the synaptosomes. 4. Lifarizine at 1 microM and 3 microM also inhibited the rises in intracellular [Ca2+] in rat cultured cortical neurons depolarized with 60 mM KCl. 5. These effects of lifarizine on intracellular Ca2+ and glutamate exocytosis may contribute to its neuroprotective action.
Budd
D C
DC
Department of Pharmacology, Ninewells Medical School, University of Dundee, Scotland.
May
G R
GR
Nicholls
D G
DG
McCormack
J G
JG
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D007093:Imidazoles; D018696:Neuroprotective Agents; D010879:Piperazines; D015222:Sodium Channels; D018698:Glutamic Acid; D011189:Potassium Chloride; C067927:lifarizine; D002118:Calcium