Study on the Platform of Drug Development of Ophthalmic Disease
| Autor: | Tzu-Ning Liu, 劉子寧 |
|---|---|
| Rok vydání: | 2013 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 101 Age-related macular degeneration (AMD) affects the macula and causes loss of central vision. The prevalence and incidence of AMD increase with age, and it is the leading cause of irreversible blindness in the developed countries. However, therapeutic intervention of AMD remained as an unmet medical need. Maintenance of normal structure and function of the retina is critically dependent on the supporting role of the adjacent retinal pigment epithelium (RPE), and chronic oxidative stress with resultant damage of RPE cells was considered to play a pivotal role in the pathogenesis of AMD. Therefore, we suggest that enhancement or maintenance the functions of RPE cells could be a therapeutic strategy for AMD. The aim of this study is to establish an ophthalmic drug-screening platform for identification of compounds, which can promote the functions of RPE cells and to recover the retina impairment in our animal model. The in vitro analyses were performed to screen for compounds which can promote the functions of RPE cells. Two extracts (ViRa35EH2 and EH-201) from Chinese herbs were demonstrated to increase the phagocytosis activities of RPE. Because the undegraded photoreceptor outer segments can lead to the accumulation of lipofuscin in RPE and defective autophagy is related to this consequence. We then examined whether these compounds can activate autophagy and eliminate A2E, a major fluorophore in RPE lipofuscin, from RPE cells. The results showed that both ViRa35EH2 and EH-201 can enhance the expression of LC-3 and decrease the fluorescent intensities of A2E-loaded RPE cells in a dose dependent manner. Furthermore, the RPE cells were known to secret erythropoietin (EPO) which has been demonstrate to protect the retina from light-induced damage. Our results revealed that EH-201 not only could induce the production of endogenous EPO but also activate PGC-1α and Sirt1 which involves in mitochondria biogenesis. The animal model comprised intravenous injection of sublethal dose of sodium iodate followed by exposure to sublethal level of intense light. Because sodium iodate damages the RPE cells specifically, we used this model to mimic the condition of dry AMD. The retinal functions were then measured by electroretinogram (ERG). Our experiments showed that both extracts could facilitate the recovery of retina from such damage. In conclusion, both ViRa35EH2 and EH-201 could promote the functions of RPE and worked well in our animal model of dry AMD. EH-201 also stimulated EPO production and mitochondria biogenesis. All these results indicated that promotion of RPE function serves as a therapeutic target in the treatment of AMD. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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