Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 26

NMDA receptor antagonists are potent anticonvulsants in many animal models, suggesting a role for these receptors in epileptogenesis (Patrylo et al., 1999). It is known that enhancing NMDA receptor-mediated excitatory actions (e.g. by lowering extracellular Mg) produces epileptiform activity in experimental models of ‘kindled’ epilepsy (Chapman, 1998, 2000). It has been postulated that NMDA receptors may change after neuronal damage (Rice and DeLorenzo, 1998). New receptors are formed that have either less sensitivity to ambient Mg or more sensitivity to ambient glycine; increased excitability could occur within local circuits where the circuitry itself is not altered (or may occur in addition to circuit alterations) (Meldrum et al., 1999). As it is known that the NMDA receptor is subject to modulation by a variety of endogenous agents, including glycine (as a co-agonist with glutamate), polyamines, steroids, neuropeptides (Vezzani et al., 2000b), pH, the redox state of the receptor, and NO, there are many chronic alterations in NMDA receptors that could underlie long-term changes in excitability and, thereby, epilepsy. Presently, there are no data to support changes in any of these regulatory factors in chronic epilepsy, but it is distinctly possible that alterations in one or more of these will be shown to be responsible for one or another form of inherited epilepsy.

Kindling is the most extensively studied animal model of epileptogenesis, and this has demonstrated the unique importance of NMDA receptors in the creation of seizure activity (Bengzon et al., 1999; Meldrum et al., 1999). In kindling, repeated electrical stimuli in the limbic system lead to a progressive increase of seizure susceptibility. When the animal responds to stimuli with generalized convulsions, it has developed a permanent epileptic condition. Activation of NMDA receptors and levels of NMDA receptor function are critical in kindling epilepsy (Bengzon et al., 1999). Selective NMDA-receptor antagonists retard kindling development and can also, at higher doses, have an anticonvulsant effect (Bengzon et al., 1999; Trist, 2000).