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

Abstract

Ion channel dysfunction has been implicated in several neurological diseases including epilepsy. Cerebral ion channels, and particularly presynaptic channels controlling neurotransmitter release, are among the most important targets of various antiepileptic drugs. In comparison with other parts of the neuron, in presynaptic nerve endings Na+ and Ca2+ channels controlling neurotransmitter release are particularly abundant. However, most studies directed to test the effect of antiepileptic drugs on ion channels are done in preparations suitable for electrophysiological approaches. Because using those approaches in the small sized cerebral nerve endings is almost impossible. 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 Ca2+ 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 Ca2+ channels is eliminated, or such as a high external concentration of K+, that activates cerebral pre-synaptic Ca2+ 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. Because 4aminopyridine exposure may more closely mimic some of the changes that may take place in the epileptic tissue, since in cerebral nerve endings 4-aminopyridine besides increasing the permeability of Na+ and Ca2+ channels, also decreases the permeability of some K+ channels, and by this mean arrests indirectly the Na+/K+ ATPase (Galvan & Sitges, 2004), making even more difficult the limitation of neuronal excitability.