Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca2+ channel-mediated release of [3H]glutamate: Comparison with the Na+ channel-mediated release

Antiepileptic Drugs Targeting Cerebral Presynaptic Ion Channels Reduce Cerebral Excitability Decreasing Glutamate Release

“…In a previous study in cerebral nerve endings isolated from the hippocampus we compared the effect of increasing concentrations of several antiepileptic drugs, including carbamazepine, on the release of glutamate induced by veratridine in the absence of external Ca 2+ . Figure 3, adapted from our previous work (Sitges et al, 2007a;2007b), shows that the antiepileptic drugs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine, progressively inhibit glutamate release induced by veratridine in a range from 150 to 1500 µM, whereas the antiepileptic drug topiramate only exerted a modest inhibition (20%) at the highest concentration tested (1500 µM). Interestingly, valproate which mechanism of action has been related to the increase in GABAergic transmission (Loscher 2002) was unable to inhibit glutamate release to veratridine at all, although a very large range of valproate concentrations was tested.…”

“…Figure 6, adapted from Sitges et al (2007b), shows that carbamazepine, phenytoin and oxcarbazepine only reduced in about 30% and 55% glutamate release to high K + at concentrations of 500 µM and 1500 µM, respectively; that lamotrigine and topiramate were even less effective, as at the highest concentration tested (1500 µM) they only exerted a mild reduction (about 25%) of glutamate release to high K + , and that valproate failed to modify the K + response at all. These results indicate that only some of the antiepileptic drugs tested, namely carbamazepine, phenytoin and oxcarbazepine, are able to reduce cerebral presynaptic Ca 2+ channels permeability in some degree at high doses.…”

“…In the present chapter I describe the strategies that we have used for investigating the effects of several compounds known for their anticonvulsant properties, including several of the most commonly used antiepileptic drugs of the first and second generations, as well as of the new potential antiepileptic drug, vinpocetine on cerebral presynaptic ionic channels. For discriminating the effects of those compounds on presynaptic Na + and Ca 2+ channels, we first used depolarizing strategies, such as veratridine that triggers the entrance of Na + by activation of cerebral presynaptic Na + channels even when the participation of Ca 2+ channels is eliminated, or such as a high external concentration of K + , that activates cerebral pre-synaptic Ca 2+ channels even when the participation of Na + channels is eliminated (Sitges & Galindo, 2005;Sitges et al, 2007a;2007b). More recently, we also test the effects of antiepileptic drugs in the cerebral nerve endings in vitro using 4-aminopyridine as depolarizing strategy.…”

“…Thus, as the tetrodotoxin-sensitive fraction of glutamate release induced by 4-aminopyridine requires the presence of external Ca 2+ and is sensitive to presynaptic Ca 2+ channel blockade, the tetrodotoxin-sensitive fraction of glutamate release induced by 4-aminopyridine is expected to be the fraction released from the vesicular pool by exocytosis. This also contrasts with veratridine depolarization, that increases glutamate release in a tetrodotoxin sensitive manner via reversal of the neurotransmitter transporter independently of presynaptic Ca 2+ channels, and with high K + depolarization that increases Ca 2+ and glutamate exocytosis from the vesicular pool in a tetrodotoxin insensitive manner independently of presynaptic Na + channels (Sitges & Galindo, 2005;Sitges et al 2007a;2007b). Moreover, in addition to the tetrodotoxinsensitive increases in Na + , Ca 2+ and glutamate exocytosis, 4-aminopyridine also produces an accumulation of Na + that is tetrodotoxin insensitive and is accompanied by a decrease in the internal concentration of K + , due to inhibition of the Na/K-ATPase that restores K + (Galván & Sitges, 2004).…”

“…Therefore, the changes that may occur in cerebral nerve endings under the excitatory conditions that t a k e p l a c e d u r i n g s e i z u r e s s e e m t o b e m o re closely resembled by 4-aminopyridine; although its mechanism of action is complicated. For instance, in contrast to veratridine, that can increase Na + and glutamate release independently of Ca 2+ channels activation, or in contrast to high K + that can increase Ca 2+ and glutamate release independently of Na + channels activation (Sitges & Galindo, 2005;Sitges et al, 2007a;2007b), 4-aminopyridine is unable to increase Ca 2+ and to induce glutamate exocytosis, when Na + channels are blocked by tetrodotoxin (Tibbs et al, 1989;Heemskerk et al, 1991;Galván & Sitges, 2004;. Thus, as the tetrodotoxin-sensitive fraction of glutamate release induced by 4-aminopyridine requires the presence of external Ca 2+ and is sensitive to presynaptic Ca 2+ channel blockade, the tetrodotoxin-sensitive fraction of glutamate release induced by 4-aminopyridine is expected to be the fraction released from the vesicular pool by exocytosis.…”