Pharmacology of Glutamate Receptor Antagonists in the Kindling Model

Abstract

Both decrease in GABAergic inhibition and increase in glutamatergic excitation are thought to be critically involved in the cellular mechanisms underlying the initiation and spread of epileptic seizures and the processes that lead to epileptogenesis and, as a consequence, chronic epilepsy.^{3,7,8,17,18,31,34} The kindling model of tem oral lobe epilepsy has been particularly helpful in elucidating the important roles of inhibitory and excitatory synaptic function in the development and spread of epileptic activity.³⁴ Based on findings in the kindling and other models of epilepsy, increasing GABAergic transmission and decreasing glutamatergic transmission have been proposed as promising antiepileptic strategies with potential advantages compared with current therapies.^17,31 Various drugs which selectively potentiate GABAergic transmission have been developed over the last three to four decades and some of them, e.g. vigabatrin, have recently been marketed for treatment of epilepsy.²⁹ In contrast to the long history of the “GABA hypothesis of epilepsy” and GABAergic drugs developed because of this hypothesis,¹⁷ it was not until the development in the early 1980s of subtype-selective excitatory amino acid (EAA) receptor agonists and antagonists that the role of EAA receptor systems in the generation of epileptic activity was fully recognized.³⁴ This initiated an enormous interest in the potential therapeutic use of EAA receptor antagonists in epilepsy and other brain disorders for which an involvement of glutamatergic transmission has been suggested. However, it took several years before systemically active compounds (i.e., compounds which pass the blood-brain-barrier after systemic administration) became available. Furthermore, the vast majority of studies on anticonvulsant effects of such compounds was done in experimental models of acute seizures, while until recently no systematic drug evaluation in chronic models of epilepsy such as kindling was reported.