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Konzentrationsabhängige Funktionelle Hemmung Der Sauren Sphingomyelinase Durch Antidepressiva

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Konzentrationsabhängige Funktionelle Hemmung Der Sauren Sphingomyelinase Durch Antidepressiva Friedrich-Alexander-Universität Erlangen-Nürnberg Universitätsklinikum Erlangen Psychiatrische und Psychotherapeutische Klinik Direktor: Prof. Dr. Johannes Kornhuber Konzentrationsabhängige funktionelle Hemmung der sauren Sphingomyelinase durch Antidepressiva Inaugural-Dissertation zur Erlangung der Doktorwürde der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg vorgelegt von Sven Städtler aus Kulmbach Gedruckt mit Erlaubnis der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen Nürnberg Dekan: Prof. Dr. med. Dr. h.c. Jürgen Schüttler Referent: Prof. Dr. med. Johannes Kornhuber Korreferent: PD Dr. med. Juan Manuel Maler Tag der Mündlichen Prüfung: 30. März 2011 Meinen Eltern gewidmet Inhaltsverzeichnis 1 Zusammenfassung ..................................................................................................... 7 1.1 Hintergrund und Ziele ........................................................................................ 7 1.2 Material und Methode ........................................................................................ 7 1.3 Ergebnisse .......................................................................................................... 8 1.4 Schlussfolgerungen ............................................................................................ 8 2 Abstract ..................................................................................................................... 9 2.1 Background and Aims ........................................................................................ 9 2.2 Materials and Methods ....................................................................................... 9 2.3 Results ................................................................................................................ 9 2.4 Conclusion ........................................................................................................ 10 3 Sphingolipide als Teil der Zellmembran ................................................................. 11 4 Sphingomyelinasen ................................................................................................. 11 4.1 Die saure Sphingomyelinase ............................................................................ 12 4.1.1 Eigenschaften ............................................................................................ 12 4.1.2 ASM-Hemmung über zellbiologische Mechanismen ............................... 12 4.1.3 Pharmakologische Hemmung der ASM.................................................... 12 4.2 Die ASM generiert das bioaktive Lipid Ceramid ............................................. 15 5 Dysregulierte ASM-Aktivität bei unterschiedlichen Krankheiten .......................... 16 5.1 Reduzierte ASM-Aktivität als Ursache der NPD ............................................. 16 5.2 Tumorerkrankungen zeigen erniedrigte ASM-Aktivität .................................. 17 5.3 Arteriosklerose ................................................................................................. 18 5.4 Diabetes mellitus .............................................................................................. 19 5.5 Wilson-Krankheit ............................................................................................. 19 5.6 Infektionen ........................................................................................................ 20 5.7 Endotoxischer Schock und Inflammation ........................................................ 21 5.8 Emphysem und Cystische Fibrose ................................................................... 21 5.9 Neuropsychiatrische Krankheitsbilder: Depression, Alzheimer, Apoplex....... 22 6 Ziele der Arbeit ....................................................................................................... 23 7 Material und Methoden ........................................................................................... 24 7.1 Material ............................................................................................................ 24 7.1.1 Eukaryote Zellen ....................................................................................... 24 7.1.2 Puffer und Lösungen ................................................................................. 24 7.1.3 Verwendete Wirkstoffe ............................................................................. 25 7.2 Methoden .......................................................................................................... 31 7.2.1 Zellkultur ................................................................................................... 31 7.2.2 Proteinkonzentrationsbestimmung ............................................................ 32 7.2.3 Bestimmung der ASM-Aktivität ............................................................... 33 7.2.4 Statistische Auswertung ............................................................................ 34 8 Ergebnisse ............................................................................................................... 35 8.1 Antidepressiva unterschiedlichster Klassen hemmen die ASM ....................... 35 8.2 Trizyklische Antidepressiva ............................................................................. 36 8.2.1 Amitriptylin ............................................................................................... 36 8.2.2 Desipramin ................................................................................................ 37 8.2.3 Clomipramin ............................................................................................. 38 8.3 Tetrazyklische Antidepressiva ......................................................................... 39 8.3.1 Mianserin .................................................................................................. 39 8.3.2 Maprotilin .................................................................................................. 40 8.4 Selektive-Serotonin-Wiederaufnahme-Hemmer .............................................. 41 8.4.1 Sertralin ..................................................................................................... 41 8.4.2 Paroxetin ................................................................................................... 42 8.4.3 Fluoxetin ................................................................................................... 43 8.4.4 Citalopram ................................................................................................. 44 8.4.5 Alaproclate ................................................................................................ 45 8.5 Selektive-Noradrenalin-Wiederaufnahme-Inhibitoren (NRI) - Reboxetin ...... 46 8.6 Noradrenalin- und selektiver Serotonin-Wiederaufnahmehemmer (NaSSA) – Mirtazapin ................................................................................................................... 47 9 Diskussion ............................................................................................................... 48 9.1 ASM-Inhibtoren finden sich in den unterschiedlichsten Antidepressiva- Klassen ........................................................................................................................ 48 9.2 Bewertung der Ergebnisse ................................................................................ 49 9.3 Lysosomotropismus als mögliche Erklärung der klinischen Latenz von Antidepressiva ............................................................................................................. 53 9.4 Therapeutische Konzentrationen von Antidepressiva hemmen ASM ohne pathologisch zu niedrige ASM-Restaktivität zu erzeugen .......................................... 55 9.5 Spezifische Hemmung der ASM durch therapeutische Konzentrationen Antidepressiva ............................................................................................................. 56 9.6 ASM-Hemmung ist bei vielen Krankheitsbildern von Vorteil......................... 56 9.7 Die verwendeten Antidepressiva hemmen die sekretierte Form der ASM nicht 58 9.8 Vorteile und Limitationen des verwendeten Zellkulturmodells ....................... 58 9.9 Die Chance der erweiterten klinischen Anwendung der ASM-hemmenden Antidepressiva ............................................................................................................. 59 10 Literaturverzeichnis................................................................................................. 61 11 Abkürzungsverzeichnis ........................................................................................... 70 12 Abbildungsverzeichnis ............................................................................................ 72 13 Anhang .................................................................................................................... 73 13.1 Chemikalien .................................................................................................. 73 13.2 Hilfsmittel ..................................................................................................... 74 13.3 Geräte und Apparaturen ................................................................................ 74 13.4 Kommerziell erhältliche Systeme ................................................................. 74 14 Danksagung ............................................................................................................. 75 7 1 Zusammenfassung
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