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Elektrophysiologische Untersuchungen Zu Einflüssen Von Aus dem Institut für Physiologie, Abt. Neurophysiologie, der Medizinischen Fakultät Charité der Humboldt-Universität zu Berlin DISSERTATION Elektrophysiologische Untersuchungen zu Einflüssen von ionotropen Glutamatantagonisten sowie 5-HT1A-Agonisten auf die Kaliumchlorid-induzierte „spreading depression“ im neokortikalen Hirnschnittpräparat der adulten Ratte Zur Erlangung des akademischen Grades Doctor medicinae (Dr. med.) vorgelegt der Medizinischen Fakultät Charité der Humboldt-Universität zu Berlin von Hagen Krüger aus Magdeburg II Dekan: Prof. Dr. med. Dr. h. c. R. Felix Gutachter: 1. Prof. Dr. med. U. Heinemann, Berlin 2. Prof. Dr. rer. nat. H.-J. Luhmann, Düsseldorf 3. Prof. Dr. med. U. Eysel, Bochum Datum der Promotion: 17. April 2000 III Erklärung an Eides Statt: Ich erkläre an Eides Statt, daß ich die vorliegende Dissertation selbst und ohne unzulässige Hilfe Dritter verfaßt, die benutzte Literatur sowie Hilfsmittel vollständig erwähnt habe und die Dis- sertation noch von keiner anderen Fakultät abgelehnt worden ist. Diese Dissertation stellt auch in Teilen keine Kopie anderer Arbeiten dar. Sofern fremde Abbildungen zur Illustration kopiert wurden, ist dies als Quelle und im Literaturverzeichnis angegeben. Berlin, den 1.7.1999 Hagen Krüger IV Erklärung: Die dieser Arbeit angegebenen Experimente sind nach entsprechender Anleitung durch Herrn Prof. Dr. rer. nat. Heiko J. Luhmann und Herrn Prof. Dr. med. Uwe Heinemann von mir selbst durchgeführt und ausgewertet worden bis auf das Experiment für Abb. 9 und 10, welches ge- meinsam mit Frau Dipl.-Biol. Kristin Raabe durchgeführt wurde. Teile der Arbeit sind bereits publiziert oder in Manuskriptform in Bearbeitung. Die Abbildungs- beschriftungen erfolgten deshalb in englischer Sprache. V Danksagung: Diese Arbeit entstand zwischen dem Oktober 1994 und dem Januar 1997 am Institut für Physio- logie, Abteilung Neurophysiologie, der Medizinischen Fakultät Charité der Humboldt-Universi- tät zu Berlin. Für die Überlassung des Themas und die Übernahme der Arbeit, die hilfsbereite Arbeitsatmo- sphäre, Förderung in verschiedener Form sowie sehr guten Arbeitsbedingungen im Labor möchte ich Herrn Prof. Dr. med. Uwe Heinemann sehr herzlich danken. Mein besonderer Dank gilt Herrn Prof. Dr. rer. nat. Heiko J. Luhmann, ohne dessen exzellente, freundschaftliche Betreuung und effiziente Einführung in wissenschaftliche Arbeitsweisen diese Arbeit nicht entstanden wäre. Die begeisternde, verantwortungsvolle Zusammenarbeit war für das Gelingen von sehr großer Bedeutung. Darüber hinaus hat es mir viel Freude bereitet, am Institut für Physiologie zu arbeiten und ich möchte allen Mitarbeitern für ihre fachkundige Hilfe und die wertvollen Diskussionen danken. Meinen Eltern gebührt für ihre Geduld und fortwährende Unterstützung Dank. Die im Rahmen der vorliegenden Arbeit durchgeführten Untersuchungen wurden mit Mitteln des Ministeriums für Wissenschaft und Forschung des Landes Nordrhein-Westfalen (SFB 194) und der Studentischen Forschungsförderung der Charité unterstützt. VI INHALTSVERZEICHNIS INHALTSVERZEICHNIS.......................................................................................................................VI LISTE DER ABKÜRZUNGEN........................................................................................................... VIII 1. EINLEITUNG.........................................................................................................................................1 1.1 PATHOGENESE UND MECHANISMEN DER ISCHÄMISCHEN ZELLSCHÄDIGUNG....................................2 1.1.1 Exzitotoxizität .............................................................................................................................3 1.1.2 Spreading depression (SD) und Periinfarktdepolarisationen......................................................5 1.1.3 Stickstoffmonoxid (NO) und freie Radikale...............................................................................6 1.1.4 Mitochondriale Dysfunktion.......................................................................................................7 1.1.5 Entzündung und immunologische Faktoren................................................................................8 1.1.6 Thrombozyten und Serotonin......................................................................................................9 1.1.7 Genetische Veränderungen .......................................................................................................10 1.1.8 Wachstumsfaktoren...................................................................................................................11 1.1.9 Apoptose ...................................................................................................................................11 1.2 SPREADING DEPRESSION (SD) ..........................................................................................................12 1.3 REZEPTOREN UND FUNKTION DER SYNAPTISCHEN TRANSMISSION IM NEOKORTEX.......................17 1.4 FRAGESTELLUNG ..............................................................................................................................22 2. MATERIAL UND METHODEN ........................................................................................................24 2.1 AUFBAU DES NEOKORTEX................................................................................................................24 2.2 NEOKORTIKALE HIRNSCHNITTPRÄPARATION ..................................................................................26 2.3 INTERFACE-MEßKAMMER.................................................................................................................28 2.4 VERWENDETE TESTSUBSTANZEN .....................................................................................................29 2.5. ELEKTROPHYSIOLOGISCHE ABLEITTECHNIK...................................................................................31 2.5.1 Synaptisch-evozierte Feldpotentiale .........................................................................................33 2.5.2 Induktion der Spreading depression (SD).................................................................................34 2.6 UNTERSUCHUNGSPARAMETER UND STATISTISCHE AUSWERTUNG ..................................................34 3. ERGEBNISSE.......................................................................................................................................37 3.1 FUNKTIONELLE EIGENSCHAFTEN DER REPETITIVEN SPREADING DEPRESSION IN VITRO .................37 3.1.1 Ausbreitungsmuster der spreading depression in vitro.............................................................37 3.1.2 Funktionelle Eigenschaften der repetitiven spreading depression............................................39 3.2 EINFLUß DER REPETITIVEN SD AUF DIE SYNAPTISCHE TRANSMISSION ...........................................43 3.3 PHARMAKOLOGISCHE UNTERSUCHUNGEN ZUR ROLLE VON GLUTAMATREZEPTOREN ...................46 3.3.1 Pharmakologische Blockade des AMPA-Glutamatrezeptors mit NBQX.................................46 VII 3.3.2 Nicht-kompetitive Blockade des NMDA-Glutamatrezeptors durch Ketamin ..........................49 3.3.3 Gleichzeitige Blockade der NMDA- und AMPA-Glutamatrezeptoren ....................................52 3.4 PHARMAKOLOGISCHE UNTERSUCHUNGEN ZUR ROLLE DES 5-HT1A-SEROTONINREZEPTORS .........55 3.4.1 Effekte von 8-OH-DPAT ..........................................................................................................55 3.4.2 Effekte von BAY x 3702...........................................................................................................61 4. DISKUSSION........................................................................................................................................67 4.1 SPREADING DEPRESSION IN VITRO UND IN VIVO ..............................................................................67 4.2 EINFLUß DER REPETITIVEN SD AUF DIE SYNAPTISCHE TRANSMISSION ...........................................71 4.3 ROLLE DES AMPA-GLUTAMATREZEPTORS......................................................................................74 4.4 ZUR FUNKTION DES NMDA-GLUTAMATREZEPTORS .......................................................................75 4.5 ROLLE DES 5-HT1A-SEROTONINREZEPTORS .....................................................................................77 4.6 ZUM AUSBREITUNGSMECHANISMUS DER SPREADING DEPRESSION .................................................80 5. ZUSAMMENFASSUNG ......................................................................................................................82 6. LITERATURVERZEICHNIS.............................................................................................................84 7. VERÖFFENTLICHUNGSNACHWEIS ............................................................................................96 Publikationen .....................................................................................................................................96 Symposiumsbeiträge ..........................................................................................................................96 8. CURRICULUM VITAE.......................................................................................................................97 9. ABSTRACT...........................................................................................................................................98 VIII LISTE
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