No abstract

Ion channels are targets of various antiepileptic drugs. In cerebral presynaptic nerve endings Na(+) and Ca(2+) channels are particularly abundant, as they control neurotransmitter release, including the release of glutamate (Glu), the most concentrated excitatory amino acid neurotransmitter in the brain. Several pre-synaptic channels are implicated in the mechanism of action of the pro-convulsive agent, 4-aminopyridine (4-AP). In the present study the effects of levetiracetam and other established and newer (vinpocetine) anti-epileptic drugs, as well as of the anti-depressant, sertraline on the increase in Ca(2+) induced by 4-AP in hippocampal isolated nerve endings were investigated. Also the effects of some of the anti-seizure drugs on the selective increase in Ca(2+) induced by high K(+), or on the selective increase in Na(+) induced by veratridine were tested. Sertraline and vinpocetine effectively inhibited the rise in Ca(2+) induced by 4-AP, which was dependent on the out-in Na(+) gradient and tetrodotoxin sensitive. Carbamazepine, phenytoin, lamotrigine and oxcarbazepine inhibited the rise in Ca(2+) induced by 4-AP too, but at higher concentrations than sertraline and vinpocetine, whereas levetiracetam, valproic acid and topiramate did not. The three latter antiepileptic drugs also failed in modifying other responses mediated by the activation of brain presynaptic Na(+) or Ca(2+) channels, including Glu release. This indicates that levetiracetam, valproic acid and topiramate mechanisms of action are unrelated with a decrease in presynaptic Na(+) or Ca(2+) channels permeability. It is concluded that depolarized cerebral isolated nerve endings represent a useful tool to unmask potential antiepileptic drugs targeting presynaptic Na(+) and/or Ca(2+) channels in the brain; such as vinpocetine or the anti-depressant sertraline, which high effectiveness to control seizures in the animal in vivo has been demonstrated.

No abstract

No abstract

The Ca(2+)-dependent, presumably exocytotic fraction of the [3H]GABA released by depolarization is dissected from the depolarization-induced Na(+)-dependent, carrier-mediated fraction of [3H]GABA release in mouse brain synaptosomes. GABA homoexchange is prevented by the [3H]GABA carrier blocker, DABA. The absence of external Na+ completely abolishes the release of the carrier-mediated, presumably cytoplasmic release of [3H]GABA induced by homoexchange and heteroexchange with GABA and DABA, respectively. The carrier-mediated, Na(+)-dependent fraction of the depolarization-induced release of [3H]GABA is resistant to tetrodotoxin (TTX) but is sensitive to amiloride and verapamil. The Ca(2+)-dependent fraction of the [3H]GABA released by high K+ depolarization is also completely abolished by amiloride (from 300 microM) and sensitive to verapamil (30 microM), but in contrast is insensitive to the absence of external Na+ and to DABA. On the basis of these results we conclude that amiloride and verapamil inhibit high K(+)-induced release of [3H]GABA by antagonizing the entrance of Ca2+ (and possibly Na+ when external Ca2+ is absent) through a population of voltage sensitive presynaptic Ca2+ channels activated by depolarization.