Publikationsserver der Universitätsbibliothek Marburg
Titel:Effekte des MAP Kinase Inhibitors CNI-1493 auf Amyloid beta behandelte primäre mikrogliäre und neuronale Zellen
Autor:Sankowski, Roman
Weitere Beteiligte: Dodel, Richard (Prof. Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/1040
DOI: https://doi.org/10.17192/z2012.1040
URN: urn:nbn:de:hebis:04-z2012-10409
DDC: Medizin
Titel (trans.):Effects of the MAP Kinase Inhibitor CNI-1493 on Amyloid beta treated primary microglial and neuronal Cells
Publikationsdatum:2012-12-14
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Neuroinflammation, Amyloid <beta->, purinerges Signaling, MAP Kinasen Inhibitor, P2Y2 Rezeptor, Nervenzelle, Alzheimer-Krankheit, Mikroglia

Zusammenfassung:
Der Morbus Alzheimer (AD) ist eine fortschreitende neurodegenerative Erkrankung des zentralen Nervensystems, die vor allem ältere Bevölkerungsgruppen betrifft (mit einer Prävalenz von ca. 6% bei den über 65-Jährigen) und schließlich zu schwerer Behinderung führt. Lösliche und unlösliche Aggregate von Amyloid β (Aβ) und Tau-Protein spielen bei der Pathogenese der Erkrankung eine wesentliche Rolle. Sie verursachen zunächst eine Störung der Neuronenfunktion und führen im weiteren Verlauf zur Neurodegeneration. Dabei kommt es in den betroffenen Hirnabschnitten zu einer sekundären Aktivierung glialer Zellen – der sogenannten Neuroinflammation. Diese trägt im weiteren Verlauf zusätzlich zur Neurodegeneration bei. Die vorliegende Arbeit untersucht die Effekte von CNI-1493 auf Aβ-behandelte primäre Neuronen und Mikroglia. CNI-1493 ist ein tetravalentes Guanylhydrazon, das die Phosphorylierung der p38-MAP Kinase inhibiert. Dabei wirkt es entzündungshemmend, indem es unter anderem die Freisetzung von Zytokinen aus Monozyten und Makrophagen inhibiert. CNI-1493 wurde bereits in einem transgenen Alzheimer-Mausmodell getestet, wo es eine Verbesserung kognitiver Leistungen und Abnahme von Aβ-Plaques in den behandelten Tieren bewirkte. An primären neuronalen Mischkulturen, die mit Aβ behandelt wurden, konnte nach Vorbehandlung mit CNI-1493 die Hochregulation des purinergen Nucleotidrezeptors der Klasse P2Y2 (P2Y2R) nachgewiesen werden. Dieser Rezeptor ist inflammationsregulierend. Mehrere Publikationen konnten zeigen, dass vor allem erhöhte IL-1β Spiegel die Expression des P2Y2R induzieren. Seine Aktivierung kann mehrere positive Effekte auf die AD-Pathologie bedeuten. Desweiteren wurde die mikrogliäre Ausschüttung von Zytokinen nach Behandlung von primärer Mikroglia mit Aβ mittels ELISA bestimmt. Eine Behandlung mit CNI-1493 (2,5 µM) führte dabei zu einer Abnahme der Aβ-bedingten proinflammatorischen Zytokine Interleukin 6 (IL-6) und Tumor Nekrose Faktor α (TNF α). Gleichzeitig war ein deutlicher Anstieg des ebenfalls proinflammatorischen Interleukin-1β (IL-1β) zu beobachten. Die durch CNI-1493 bedingte Abnahme von TNF α und IL-6 bei gleichzeitiger Zunahme des IL-1β ist ein bisher nicht beschriebener Effekt. Wir vermuten, dass die von uns zuvor im Mausmodell beschriebenen neuroprotektiven Effekte von CNI-1493 nicht nur auf der Suppression von TNF α und IL-6, sondern auch auf der Induktion der neuroprotektiven Wirkung von IL-1β beruhen. Diese Ergebnisse stehen in einer Reihe mit Publikationen über eine protektive Wirkung von IL-1β im Rahmen der Alzheimer-Pathologie.

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