Ursachen der Pharmakoresistenz der Temporallappenepilepsie - Neue Beeinträchtigungen der GABAergen Hemmung

Zusammenfassung

Trotz Einführung zahlreicher neuer Antiepileptika hat sich der Anteil pharmakoresistenter Patienten nur wenig geändert. Es scheint daher, als seien die zellulären Mechanismen der Epilepsie des Menschen und die Pharmakoresistenz nur unzureichend verstanden. An Hirnschnitten des humanen epileptogenen Neokortex konnte gezeigt werden, dass die GABA_A-Antwort bei einigen Neuronen erregend statt hemmend ist und dass GABA_B-Rezeptor vermittelte Effekte vermindert sind, ein Effekt der hochfrequente synaptische Aktivität begünstigt. Diese Veränderungen sind mehr als hinreichend zur Erklärung der schweren pharmakoresistenten Epilepsie. Störungen bzw. Fehlen jedes einzelnen dieser Mechanismen führt in knockout Mäusen zu Epilepsie.

Summary

Despite the considerable increase in available drugs to treat epilepsy, the percentage of patients becoming seizure free has changed very little in the last decade. Thus it seems as if the cellular mechanisms contributing to epileptogenesis and the development of pharmacoresistance in human epilepsy are still poorly understood. Here I briefly review some of our key findings from slices of human epileptogenic cortex: 1. GABA_A-responses are in some neurones excitatory rather than inhibitory, probably due to impaired chloride transport and 2. GABA_B-receptor mediated events are reduced, allowing for higher frequencies of synaptic activity and. These findings obtained in variable proportions of the neurones are more than sufficient to account for the severity of the pharmacoresistant epilepsy these patients suffered. Each mechanism in isolation cause epilepsy in knockout mice.

Key Words

temporal lobe epilepsy - GABA - KCl transport

Literatur

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