Dokument: Investigations on long-term effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on islet inflammation and beta cell survival in type 1 diabetes
| Titel: | Investigations on long-term effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on islet inflammation and beta cell survival in type 1 diabetes | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=58959 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240502-103851-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Wörmeyer, Laura [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Lammert, Eckhard [Gutachter] Prof. Dr. Meißner, Thomas [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Albeit achievements in identifying people at risk to develop type 1 diabetes mellitus in recent years, none of the current treatment options is able to sustainably prevent type 1 diabetes progression indicating the urgent need for novel agents. On the basis of previous studies of our lab, which revealed anti-diabetic effects of the widely-used over-the-counter cough suppressant dextromethorphan (DXM) in mice and humans with type 2
diabetes, we aimed to investigate whether DXM could also be a potential novel candidate for the preventive treatment of type 1 diabetes. By performing in vitro experiments with isolated mouse and human islets, we could confirm the previously reported islet cell protective characteristics of DXM. Precisely, we demonstrated that by treating islets with dextrorphan (DXO), which is the active metabolite of DXM, pancreatic islets are protected against streptozotocin-induced cell death, a commonly used beta cell-specific toxin. Furthermore, in order to evaluate the anti-diabetic effects of DXM in vivo, we conducted a longterm study with a well-known type 1 diabetes model, the non-obese diabetic (NOD) mouse. Long-term treatment of these mice with DXM via the drinking water reduced blood glucose levels, delayed diabetes onset, and reduced diabetes incidence. Additionally, DXM-treated NOD mice displayed increased residual beta and alpha cell mass, as well as islets numbers. To be specific, at 30 weeks of age, islet numbers were five times higher in NOD mice which had been treated with DXM compared to control NOD mice. These effects were mediated by reduced apoptosis in pancreatic islets, as assessed by the cell death marker cleaved caspase- 3, whereas changes in the rate of islet cell proliferation were not observed. In addition, DXM treatment reduced the amount of infiltrating immune cells into pancreatic islets. Particularly, the numbers of CD8+ and CD4+ T lymphocytes in the immune cell infiltrate were reduced, but not FoxP3+ regulatory T cells. An improvement in inflammation of pancreatic islets was also confirmed by determining the expression of chemokines in pancreatic islets treated with DXO. Several chemokines involved in the attraction of different types of immune cells were expressed at lower levels under standard culture conditions, as well as in an inflammatory environment in the presence of DXO. As a conclusion, the study proved that DXM exerts anti-diabetic effects in type 1 diabetes and should therefore be further investigated as a potential preventive treatment. Considering recently suggested novel approaches for effective disease prevention using combinatory treatments and the fact that DXM improves beta cell function and survival, DXM might be particularly useful in combination with an additional immune-modulating agent. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 02.05.2024 | |||||||
| Dateien geändert am: | 02.05.2024 | |||||||
| Promotionsantrag am: | 23.09.2021 | |||||||
| Datum der Promotion: | 08.02.2022 |
