Postoperative Untersuchungen in der Epilepsiechirurgie: Enzyme der oxidativen Stresskaskade, Multi-Drug-Transporter und Transmitterrezeptoren

Zusammenfassung

In der vorliegenden Untersuchung wurden bei Patienten mit pharmakoresistenten Formen der fokalen temporalen Epilepsie neurochirurgisch die kortikalen Foki entfernt und das Gewebe histochemisch, immunhistochemisch und rezeptorautoradiographisch untersucht. Da Hirngewebe von derselben Stelle desselben Patienten auch in elektrophysiologischen und neurochemischen Analysen untersucht wurde (siehe andere Beiträge in diesem Band), bieten die koordinierten Studien aller beteiligten Wissenschaftler eine einmalige Chance zur Analyse der zugrunde liegenden pathophysiologischen Mechanismen sowohl auf struktureller als auch funktioneller Ebene. Wir konnten zeigen, dass Enzyme der oxidativen Stresskaskade Veränderungen aufweisen, die ein deutliches Anzeichen dafür sind, dass Superoxidradikale und Metaboliten aus Superoxid und Stickstoffmonoxid zur zerebralen Schädigung und eventuell auch zur Ausweitung der Foki beitragen können. Zudem ließ sich zeigen, dass die Expression und intrazerebrale Verteilung von so genannten Multi-Drug-Transportern, die im Wesentlichen für die Pharmakoresistenz verantwortlich gemacht werden, verändert war. Weiterhin zeigten die exzitatorischen und inhibitorischen Neurotransmittersysteme im epileptischen Gewebe ein Ungleichgewicht mit einer Verschiebung hin zur Übererregbarkeit, da die Dichten der AMPA-, Kainat- und NMDA-Rezeptoren in allen hier untersuchten Epilepsiefällen hochreguliert waren. Die Hochregulierung der NMDA-Rezeptoren war mit dem Auftreten spontan entladender Neuronen im epileptischem Gewebe korreliert. Die GABA_A-Rezeptoren und Benzodiazepinbindungsstellen zeigten dagegen in vielen Fällen eine Abnahme ihrer Dichten im epileptischen Gewebe, wodurch die Imbalance zwischen exzitatorischen und inhibitorischen Transmittersystemen noch weiter verstärkt wird.

Abstract

Brain tissue surgically removed from patients suffering from drug-resistant, focal temporal lobe epilepsy was studied using a variety of histochemical methods such as conventional histochemistry, immunohistochemistry and receptor autoradiography. Since brain tissue from the same site of the same patient was also used for electrophysiological and neurochemical analyses (see other contributions in this volume), coordinated efforts by all participating groups provide a unique chance to study pathological mechanisms associated with epileptic discharges both at functional and structural levels. We found enzymes of the oxidative stress cascade altered in most of the examined biopsies, thus indicating that superoxide radicals as well as NO and superoxide metabolites could play an important role in brain tissue alterations, including the expansion of epileptic foci. Furthermore, the expression and distribution patterns of multi-drug-transporters, to which drug-resistance has been attributed in cases of intractable focal epilepsy, was also found to be impaired in epileptic tissue. However, it remains to be analysed whether alterations of these transporters are the primary cause of epileptic seizures, or whether they develop as a result of pathological changes of the blood-brain barrier associated with the disease. Furthermore, epileptic tissue showed alterations mainly in the glutamatergic and GABAergic systems, characterised by a disturbed balance between the expression of excitatory and inhibitory amino acid transmitter receptors. The densities of AMPA, kainate, and NMDA receptors were found to be increased in all examined biopsies. The up-regulation of the NMDA receptor is correlated with the presence of spontaneously spiking neurons. Contrastingly, the GABA_A receptor and benzodiazepine binding site showed down-regulations of their densities.

Key words

Cerebral cortex - epilepsy - oxidative stress - multi-drug-transporters - transmitter receptors

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