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Schizophrenie, Entzündung und glutamaterge Neurotransmission: ein pathophysiologisches Modell

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Aktuelle Aspekte der Pathogenese und Therapie der Schizophrenie

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Zusammenfassung

Diese Arbeit soll psychoneuroimmunologische Untersuchungen mit aktuellen Ergebnissen aus pharmakologischen, neurochemischen und genetischen Studien bei Schizophrenie zusammenführen. Schizophrenie ist eine Erkrankung der dopaminergen Neurotransmission, aber die Modulation des dopaminergen Systems durch die glutamaterge Neurotransmission spielt eine wesentliche Rolle. Diese Sicht wird durch Befunde der Neuregulin- und Dysbindin-Gene unterstützt. Diese Gene haben funktionelle Auswirkungen auf das glutamaterge System. Glutamaterge Unterfunktion ist durch den NMDA-Rezeptor-Antagonismus vermittelt. Der einzige bisher nachgewiesene endogene NMDA-Rezeptor-Antagonist ist Kynurenin-Säure. Unabhängig vom NMDA-Rezeptor-Antagonismus blockiert Kynurenin-Säure bereits in geringeren Konzentrationen auch den nikotinergen Acetylcholin-Rezeptor, d.h. höhere Kynurenin-Säure-Spiegel können psychotische Symptome und kognitive Einschränkungen erklären. Kynurenin-Säure-Spiegel wurden bei schizophrenen Patienten im Vergleich zu Kontrollen als höher sowohl im Liquor cerebrospinalis als auch in für die Schizophrenie wesentlichen ZNS-Regionen beschrieben.

Eine Reihe von Befunden legen nahe, dass eine (pränatale) Infektion in die Pathogenese der Schizophrenie involviert ist. Aufgrund eines frühen Sensitivierungsprozesses des Immunsystems oder einer (chronischen) Infektion, die durch das Immunsystem nicht abgewehrt werden kann, kommt es bei der Schizophrenie zu einer Immundysbalance zwischen der Typ-I und der Typ-II Immunantwort. Die Typ-I Immunantwort ist zumindest teilweise gehemmt, während die Typ-II Immunantwort überaktiviert ist. Diese Immunkonstellation ist mit der Hemmung des Enzyms Indoleamin Dioxygenase (IDO) verbunden, denn IDO — die in Astrozyten- und Mikroglia-Zellen lokalisiert ist — wird durch Typ-II Zytokine gehemmt. IDO katalysiert den ersten Schritt im Tryptophan-Metabolismus, die Degradation von Tryptophan zu Kynurenin, ebenso wie die Tryptophan 2,3-Dioxygenase (TDO). Aufgrund der Hemmung von IDO wird Tryptophan-Kynurenin vor allem über TDO metabolisiert, die in Astrozyten lokalisiert ist, nicht in Mikroglia oder anderen ZNS-Zellen. Astrozyten sind besonders bei Schizophrenie aktiviert, was hohe Level von S100B zeigen. Astrozyten haben nicht die enzymatische Ausstattung für den kompletten Kynurenin-Abbau. Aufgrund des Nichtvorhandenseins von Kynurenin-OHase in Astrozyten kann Kynurenin-Säure im ZNS akkumulieren, dementsprechend wurde ein Anstieg der TDO-Aktivität bei Schizophrenie beobachtet. Dieser Mechanismus hat eine Akkumulation von Kynurenin-Säure in kritischen ZNS-Regionen zur Folge. Auf diesem Weg dürfte die Immun-mediierte glutamaterg-dopaminerge Dysregulation zu den klinischen Symptomen der Schizophrenie führen. Therapeutische Konsequenzen, zum Beispiel der Gebrauch von antientzündlichen Cyclooxygenase-II-Inhibitoren, die zusätzlich direkt den Kynurenin-Säure-Spiegel senken, werden diskutiert.

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Müller, N., Schwarz, M.J. (2006). Schizophrenie, Entzündung und glutamaterge Neurotransmission: ein pathophysiologisches Modell. In: Möller, HJ., Müller, N. (eds) Aktuelle Aspekte der Pathogenese und Therapie der Schizophrenie. Springer, Vienna. https://doi.org/10.1007/3-211-29109-1_8

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