| Abstract |
The Retinal Pigment Epihtelium (RPE) is a monolayer of cuboidal cells, rich in melanin, located between the photoreceptors and the choriocapillaries. RPE plays an important role in the function of photoreceptors and is involved in the pathophysiology of many ocular diseases such as the age-related macular degeneration (ARMD).
ARMD is the main cause of blindness in ages 65 years or older. There are two forms of the disease; the exudative and the dry form. Exudative ARMD is less common, yet carries a worse prognosis, as it may cause sudden, dramatic loss of vision. The hallmark of the disease is the development of choroidal neovascularization that grows through the RPE and under the retina. Up to now, there is no definite treatment for ARMD. Various treatment modalities have been proposed including LASER photocoagulation, photodynamic therapy and more recently, intraocular injections of anti-VEGF agents.
Somatostatin (SRIF) is a neuropeptide that exerts a diverse number of physiological actions in the peripheral and central nervous system. SRIF’s actions are mediated by five subtypes (sst1-sst5) of specific G-protein coupled receptors. In the retina somatostatin is located in amacrine and ganglion cells. Its role in the retinal circuitry is being extensively studied. There is experimental data to support that somatostatin inhibits the hypoxia-induced retinal neovascularization.
The purpose of the present thesis was to study the presence of SRIF and its receptors and their physiological role in human RPE. We also wanted to study if somatostatin is safe and effective in the treatment of ARMD.
The human RPE cell line D407 was used for all experiments. We detected the presence of all somatostatin receptor subtypes in these cells (sst1-sst5). Of the three synthetases for nitric oxide (NOS), the iNOS was detected in D407. We demonstrated that SRIF, by activating its sst2 receptors, increased NO’s production in a concentration-dependent manner.
We demonstrated also that SRIF decreased cell viability in a concentration-dependent manner. The observed decrease in cell number was partly due to apoptosis via sst1, and sst5 activation. Activation of sst2, sst3 and sst4 receptors led to inhibition of cell growth that did not involve apoptosis, but rather antiproliferative actions. SHP-
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1 was detected in the human RPE cells and sodium orthovanadate reversed somatostatin’s actions.
We designed a pilot, randomized, placebo-controlled, prospective trial to evaluate the role of somatostatin in the treatment of choroidal neovascularization. Twenty eyes of 20 patients were included in the study. Patients were randomly allocated to treatment with lanreotide (Somatuline, Ipsen) (10 eyes) or placebo (10 eyes). Patients received one intramuscular injecton of lanreotide or placebo every 15 days for 6 months. Follow-up lasted for 6 months for the control group and for 12 months for the study group. The changes in visual acuity and fluorescein angiography at 6 months were compared between the two groups. In addition, the changes in the same parameters within the study group, from 6 to 12 months, were studied.
From baseline to 6 months the mean visual acuity and surface area of hyperfluorescence remained stable in the study group, while the intensity of hyperfluorescence decreased. After discontinuation of treatment, deterioration of all three parameters was noted in the study group. Statistical analysis, however, failed to reveal any significant difference from baseline. No adverse events were detected during treatment with lanreotide.
This clinical trial does not provide strong evidence for the effectiveness of SRIF in the treatment of ARMD. However, the trend for stabilization of visual acuity and fluorescein angiography parameters during treatment with lanreotide justifies the design of multicenter trials with larger samples and different drug dosages and/or routes of administration.
The present thesis has formed the base for further study of the mechanisms that are involved in the physiological actions of SRIF in human RPE. It has also given rationale for further study of the role of SRIF in the treatment of ARMD, alone or in combination with other agents (anti-VEGF) or other forms of treatment such as LASER or photodynamic therapy.
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