Dokument

Zusammenfassung:
Der Hypothalamus repräsentiert die wichtigste Komponente des Zentralnervensystems (ZNS) zur Integration afferenter Signalinformationen und zur Regulation der Homöostase von Körperkerntemperatur, Wasser- und Elektrolythaushalt des Extrazellularraumes, circadianer Rhythmik sowie Energiehaushalt. Das wichtigste Kerngebiet (Nucleus) des Hypothalamus zur Steuerung der genannten physiologischen Funktionen stellt der in der supraoptischen Region, in unmittelbarer Nähe zum dritten Hirnventrikel gelegene Nucleus paraventricularis (PVN) dar. Der PVN enthält zahlreiche neurosekretorische Zellen und weist darüber hinaus zahlreiche efferente und afferente neuronale Verknüpfungen zu anderen Struktureinheiten des Gehirns auf. Zusätzlich zum PVN kommt auch dem im Bereich der Commissura anterior gelegenen Nucleus praeopticus medianus (MnPO) eine bedeutende, integrative Funktion bei der Regulation des Wasser- und Elektrolythaushaltes sowie der Körperkerntemperatur zu. Bei der Regulation dieser Prozesse spielt neben klassischen und peptidergen Neurotransmittern auch das gasförmige Signalmolekül Stickstoffmonoxid (NO), produziert unter anderem von der neuronalen Stickstoffmonoxid-Synthase (nNOS), eine wesentliche neuromodulatorische Rolle. Auch für das apelinerge System, bestehend aus den verschiedenen, aktiven Fragmenten des Preproapelins (Apelin36, Apelin17 und Apelin13) und dem G-Protein gekoppelten Rezeptor APJ, wurde bereits ein zentral vermittelter Einfluss unter anderem auf die Temperaturregulation und auf die Kontrolle des Wasser- und Elektrolythaushaltes beschrieben. Eine Expression sowohl der Apelinpeptide als auch des Rezeptors konnte bisher in peripheren Organen sowie im ZNS, und dabei hauptsächlich im Hypothalamus, gezeigt werden. Trotz zahlreicher Expressionsstudien fehlte jedoch bisher eine detaillierte Kartierung der Verteilung des Rezeptorproteins in Hypothalamus und Thalamus. (1) Anhand der in der vorliegenden Arbeit durchgeführten immunhistochemischen Markierungen an coronalen Gehirnschnitten der Ratte wurde deshalb erstmalig eine detaillierte, semiquantitative Kartierung der Expression des APJ Proteins im Hypothalamus erstellt. Diese Untersuchung bestätigt einerseits die bereits auf mRNA-Ebene publizierte APJ-Expression in Strukturen wie PVN und Nucleus supraopticus (SON), konnte jedoch darüber hinaus in vielen Nuclei und/oder deren Substrukturen wie u.a. dem MnPO, dem medialen Teil des „Bed Nucleus“ der Stria terminalis, dem N. praecommissuralis und dem N. dorsomedialis eine APJ-Expression zum ersten Mal auf Proteinebene für einzelne Neurone bzw. deren Pseudopodia nachweisen. (2) Sowohl für den PVN als auch den MnPO wurde bereits eine Expression von nNOS in früheren Studien beschrieben. Zusätzlich dazu konnte in der Fachliteratur eine Vermittlung apelinerger Effekte über NO etwa anhand der Modulation kardiovaskulärer Parameter in der Peripherie postuliert werden. Deshalb wurde in der vorliegenden Arbeit eine mögliche Co-Distribution und -Lokalisation von APJ und nNOS anhand immunhistochemischer Markierungen im Hypothalamus der Ratte untersucht. Dabei konnte u.a. im MnPO eine ausgeprägte Co-Distribution nitrerger Neurone und APJ-immunpositiver Faserstrukturen festgestellt werden. Bei der quantitativen Analyse der Expression von nNOS und APJ in Perikaryen des PVN und des SON hingegen war sogar mit mit ca. 40 % bzw. ca. 50 % markante zelluläre Co-Expression der beiden Moleküle nachweisbar. Aufgrund der ausgeprägten Co-Lokalisation und Co-Distribution in PVN und MnPO könnte somit NO als nachgeschaltetes Signalmolekül auch an der Vermittlung zentraler, apelinerger Wirkmechanismen beteiligt sein. (3) Zur in vitro Untersuchung Apelin-induzierter, intrazellulärer Signaltransduktions-mechanismen wurden aufgrund der ausgeprägten APJ-Rezeptorexpression sowohl MnPO- und PVN-spezifische neurogliale Primärkulturen als auch eine primäre Hypophysenzwischen-lappenkultur (HZL) herangezogen. Änderungen der intrazellulären Calciumkonzentration ([Ca2+]i) als wichtigen second oder third messenger konnten für einzelne Zellen durch den Einsatz calciumbindener Fluorophore wie Fura-2 kontinuierlich erfasst werden (=Calcium-Imaging). Sowohl für Neurone als auch Astrozyten der MnPO- und PVN-spezifischen Kulturen ergab sich bei 2-9 % der Zellen, in PVN-spezifischen Mikrogliazellen hingegen bei 12 % eine direkte Responsivität in Form einer transienten Erhöhung der [Ca2+]i nach Stimulation mit der pyroglutamylierten Form von Apelin13 (PyrAp13) (10-6 mol/l). Wie bereits für andere Neuropeptide beschrieben, vermochte PyrAp13 darüber hinaus den Calciumeinstrom des klassischen Neurotransmitters Glutamat in nitrergen und vor allem nicht-nitrergen Zellen sowohl positiv als auch negativ zu modulieren. Diese modulatorische Wirkung könnte somit möglicherweise die zelluläre Grundlage für physiologische Funktionen des apelinergen Systems als neuer Neuromodulator im ZNS darstellen. Neben der Analyse der [Ca2+]i als dem Apelin13 nachgeschalteten Signal wurde in einigen Publikationen auch über die Involvierung der MAP-Kinasen extracellular regulated kinase 1/2 (ERK1/2) im apelinergen Signalweg in peripheren oder transfizierten Zellsystemen berichtet. In der Primärkultur des HZLs mit hoher nativer APJ-Expression konnte in der vorliegenden Arbeit nach apelinerger Stimulation anhand von Western Blot Analysen jedoch keine Aktivierung der ERK1/2 beobachtet werden, möglicherweise bedingt durch eine bereits hohe Phosphorylierung vor der peptidergen Stimulation. (4) Als weiterer wichtiger Aspekt der wissenschaftlichen Arbeit wurden in vivo physiologische Parameter nach intracerebroventrikulärer (i.c.v.) Applikation von PyrAp13 (20 nmol) in der Ratte anhand telemetrischer Datenaufzeichnung untersucht. (A) I.c.v. mikroappliziertes PyrAp13 zeigte dabei keinen signifikanten Einfluss auf durch bakterielles Lipopolysaccharid (LPS, 100 μg/kg Körpergewicht) induzierte Komponenten des sickness behavior wie Anorexie, Adipsie und Lethargie. Jedoch führte es zu einer signifikanten Reduktion des LPS-induzierten Fiebers 3-6 und 6-9 Std. post injectionem und einem signifikanten erniedrigten Plasmaspiegel an Tumornekrosefaktor-α (TNF-α) als prominenten proinflammatorischen Cytokin 2 Std. nach der Injektion. (B) Trotz der hohen Sequenzähnlichkeit von APJ und dem Angiotensin II (AngII)-Rezeptor und einer in vitro bereits gezeigten Interaktion mit diesem, zeigte i.c.v. mikroappliziertes PyrAp13 jedoch in vivo keinen Einfluss auf durch die zentrale AngII-Applikation induzierte Trinkwasseraufnahme bzw. nukleäre Translokation des neuronalen Aktivitätsmarkers und Transkriptionsfaktors c-Fos. (C) Weiterhin zeigte PyrAp13 i.c.v. selbst beim Vergleich der Injektion vor der Aktivitätsphase mit der Inaktivitätsphase der Versuchstiere keinen Einfluss auf die circadiane Rhythmik telemetrisch erfasster Parameter wie Körpertemperatur, lokomotorische Aktivität und Futter- bzw. Wasseraufnahme.

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