Publikationsserver der Universitätsbibliothek Marburg
Titel:Neuroprotektive Wirkung von acyliertem und nicht-acyliertem Ghrelin in einem in vitro-Modell der Parkinson-Krankheit
Autor:Wagner, Johanna Claudia
Weitere Beteiligte: Ries, Vincent (PD Dr.)
Veröffentlicht:2015
URI:https://archiv.ub.uni-marburg.de/diss/z2015/0421
DOI: https://doi.org/10.17192/z2015.0421
URN: urn:nbn:de:hebis:04-z2015-04214
DDC: Medizin
Titel (trans.):Acylated and unacylated ghrelin confers neuroprotection to mesencephalic neurons
Publikationsdatum:2015-07-15
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Ghrelin, Ghrelin

Zusammenfassung:
Ghrelin ist ein Polypeptid, welches eine Reihe unterschiedlicher Funktionen erfüllt, wie z.B. die Regulation der Wachstumshormon-Freisetzung, die Regulation der Nahrungsaufnahme, eine prokinetische Wirkung auf den Gastrointestinaltrakt und die Beeinflussung der endokrinen Pankreasfunktion. Im Zusammenhang mit dem idiopathischen Parkinson-Syndrom (IPS) wurde festgestellt, dass Parkinson-Patienten dysregulierte postprandiale Ghrelinkonzentrationen im Blut haben. Zusätzlich konnten neuroprotektive Eigenschaften von acyliertem Ghrelin im Parkinson-Tiermodell nachgewiesen werden, die aber noch nicht detailliert erforscht sind. Ghrelin wird durch die Ghrelin-O-Acyltransferase (GOAT) von der nicht-acylierten in die acylierte Form umgewandelt. Diese Acylierung ist notwendig für die Bindung an den Ghrelinrezeptor GHS-R1a. Die Fragestellung der vorliegenden Arbeit war nun, inwiefern Ghrelin neuroprotektiv wirkt und ob dieser mögliche Effekt auf die acylierte Form beschränkt ist. Die Versuche wurden in Zellkulturen primärer, mesencephaler Neurone aus embryonalen Wistar-Ratten mit einem Gestationsalter von 15 Tagen durchgeführt. Wir führten unsere Experimente stets mit der acylierten und nicht-acylierten Ghrelinform durch. So konnten wir zeigen, dass beide Formen gegenüber einer Behandlung mit dem Neurotoxin MPP+, einem Hemmstoff des Komplexes I der mitochondrialen Atmungskette, neuroprotektiv auf dopaminerge Neurone wirken. Dabei lag das Wirkmaximum von acyliertem Ghrelin bei 0,1 nM und von der nicht-acylierten Form 10-fach höher, also bei 1 nM. Dieser Unterschied der Wirkmaxima wurde auch schon in Versuchen an Pankreaszellen festgestellt. Auch gegenüber dem Neurotoxin 3-Nitropropionsäure (3-NP), welches den Komplex II der Atmungskette hemmt, wirkten beide Ghrelinformen neuroprotektiv, wieder mit dem Wirkmaximum bei 0,1 bzw. 1 nM. Da die Neurotoxizität der 3-NP sich nicht auf dopaminerge Zellen beschränkt wie die des MPP+, untersuchten wir die Wirkung beider Ghrelinformen auf alle weiteren mesencephalen Neurone. Es zeigte sich, dass die Neuroprotektion unabhängig vom neuronalen Phänotyp war. In der Entstehung des IPS spielen eine Reihe von Pathomechanismen eine Rolle, so auch die elektrische Aktivität der dopaminergen Neurone. So führt z.B. ein massiver Kalzium- oder Kaliumeinstrom in die Zelle letztendlich zum Untergang dopaminerger Neurone. Die chronische Einnahme von Kalziumkanal-Blockern (L-Typ, Dihydropyridin-Typ) führt in einer Studie zu einer Reduktion des Erkrankungsrisikos. So stellte sich für uns die Frage, ob die neuroprotektive Eigenschaft von Ghrelin im Zusammenhang mit Ionenströmen stehen könnte. Die Hemmung des L-Typ-Kalziumkanals mit Nicardipin verhinderte die Wirkung von acyliertem und nicht-acyliertem Ghrelin in allen mesencephalen Neuronen. Aus früheren Studien ergab sich die Überlegung, dass die Wirkung von nicht-acyliertem Ghrelin auf einer Umwandlung in die acylierte Form beruht. Dazu haben wir die Wirkung beider Ghrelinformen im Zusammenhang mit dem GHS-R1a-Antagonisten [D-Lys3]-GHRP-6 untersucht. Eine Antagonisierung des Rezeptors führte zu einem Wirkverlust von acyliertem Ghrelin, nicht aber der nicht-acylierten Form. Somit liegt nahe, dass die Wirkung von nicht-acyliertem Ghrelin über einen anderen Mechanismus vermittelt wird. Dies wurde bestätigt durch Versuche mit dem GOAT-Hemmer GO-Tat-CoA, der die Wirkung von nicht-acyliertem Ghrelin nicht abschwächte. Daraus lässt sich schließen, dass die neuroprotektive Wirkung der nicht-acylierten Form nicht auf einer Umwandlung in die acylierte Form zurückzuführen war. Zusammengefasst konnten wir zeigen, dass nicht nur acyliertes, sondern auch nicht-acyliertes Ghrelin eine neuroprotektive Wirkung auf mesencephale Neurone hat. Diese Protektion ist abhängig von L-Typ-Kalziumkanälen, wird aber bei beiden Ghrelinformen über unterschiedliche Mechanismen vermittelt.

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