Single and combined effects of carbamazepine and vinpocetine on depolarization-induced changes in Na+, Ca2+ and glutamate release in hippocampal isolated nerve endings

The single and combined effects of carbamazepine and vinpocetine on the release of the excitatory amino acid neurotransmitter glutamate, on the rise in internal Na+ (Na-i, as determined with SBFI), and on the rise in internal Ca2+ (Ca-i, as determined with fura-2) induced by an increased permeability of presynaptic Na+ channels, with veratridine, or by an increased permeability of presynaptic Ca2+ channels with high K+, were investigated in isolated hippocampal nerve endings. The present study shows that carbamazepine and vinpocetine, both inhibit dose dependently the release of preloaded [H-3]Glu induced by veratridine. However, carbamazepine is two orders of magnitude less potent than vinpocetine. The calculated IC50's for carbamazepine and vinpocetine to inhibit veratridine-induced [H-3]Glu release are 200 and 2 mu M, respectively. Consistently 150 mu M carbamazepine and 1.5 mu M vinpocetine reduce the veratridine-induced rise in Na-i in a similar extent. The single effects of carbamazepine and of vinpocetine on the presynaptic Na+ channel mediated responses, namely the rise in Nai and the release of Glu induced by veratridine, are additive. Responses that depend on the entrance of external Ca2+ via presynaptic Ca2+ channels, such as the release of [H-3]Glu and the rise in Ca-i induced by high K+, are insensitive to 300 mu M carbamazepine and slightly reduced by 5 mu M vinpocetine. It is concluded that the additive effects of carbamazepine, which is one of the most common antiepileptic drugs, and vinpocetine that besides its known neuroprotective action and antiepileptic potential is a memory enhancer, may perhaps be advantageous in the treatment of epileptic patients. (c) 2006 Published by Elsevier Ltd.