7.1 Diskussion der Ergebnisse
7.1.9 Blutuntersuchungen ergeben keinen Hinweis auf Immunreaktion
Die Untersuchungen des arterio-venösen Mischblutes der Versuchstiere ergaben keinerlei Hinweise auf Veränderungen der Gesamtleukozyten (WBC, white blood cells), sodass davon ausgegangen werden kann, dass keinerlei systemische Immunreaktion durch ALF-186 aus-gelöst wird oder Infekte der Tiere die dargestellten Ergebnisse verfälscht haben könnten.
8 Zusammenfassung
Der akute ischämische Schlaganfall ist eine der am häufigsten zum Tode führenden Erkran-kungen der westlichen Welt. Überlebende kämpfen häufig mit schweren lebenslangen kör-perlichen Defiziten und sind oft pflegebedürftig. Hinsichtlich der voranschreitenden Alte-rung der Gesellschaft dürften die Inzidenzen und Prävalenzen des AIS in den kommenden Jahren weiter ansteigen. Der PAIS (perioperative acute ischemic stroke) ist ein vor allem nach kardialen oder vaskulären Operationen beobachtetes Phänomen, welchem in der Anäs-thesie und der Intensivmedizin immer mehr Aufmerksamkeit geschenkt wird. Deswegen stellt sich in der modernen Forschung die Frage nach neuen neuroprotektiven Therapiean-sätzen, welche nicht nur präventiv, sondern auch postkonditionell, nach stattgefundener Is-chämie und darauffolgendem Reperfusionsschaden, wirksam sind. Schon seit längerer Zeit ist bekannt, dass das ursprünglich als „Silent Killer“ bekannte Gas Kohlenstoffmonoxid diese neuroprotektiven Eigenschaften besitzt. Aufgrund der Gefahr einer CO-Intoxikation bei inhalativer Gabe, sowie der schon bei niedrigen Konzentrationen beschriebenen zyto-protektiven Wirkung von CO, wird sogenannten CO freisetzenden Molekülen (CORMs), welche oral, i.p. oder i.v. verabreicht werden können und CO in niedrigen, aber wirksamen Konzentrationen am Zielgewebe freisetzen, immer größere Aufmerksamkeit zuteil. ALF-186, einem neueren Vertreter der CORMs, wurden schon antiinflammatorische (Motterlini
& Otterbein, 2010; Sheikh et al., 2011; Onyiah et al., 2013) sowie antiapoptotische bzw.
neuroprotektive Eigenschaften (Schallner et al., 2013) nachgewiesen. Gegenstand dieser Forschungsarbeit war es, erfolgreich zu belegen, dass ALF-186 bei Gabe nach stattgefunde-nem I/R-Schaden (postkonditionell) neuroprotektiv wirksam auf RGZ ist. Nicht nur dieser Zusammenhang konnte erfolgreich bewiesen werden, auch ließ sich belegen, dass bei Hem-mung der sGC die neuroprotektive Wirkung von ALF-186 reduziert wird, was dafürspricht, dass ALF-186 seine zellschützende Wirkung auf RGZ zumindest teilweise mittels der sGC vermittelt. Diese Ergebnisse wurden durch Quantifizierung der morphometrischen Dichte der RGZ erhalten. Mittels Western Blot-Untersuchung konnte außerdem nachgewiesen wer-den, dass die sGC bei Gabe von ALF-186 zudem deutlich erhöht exprimiert wird. Darüber hinaus konnte mittels qRT-PCR ermittelt werden, dass ALF-186 in RGZ auch die propa-poptotischen Regulatorproteine Bax und Caspase 3 senkt, sowie das antiapoptotische Bcl-2-Protein erhöht. Zudem senkt ALF-186 die antiinflammatorischen Marker TNF-α und IL-6 unter Beteiligung der sGC, sowie den Transkriptionsfaktor NF-κB. Auch auf die Chaperone HSP-70 und -90 hat ALF-186 modulierende Einflüsse.
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