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Identifier |
000363540 |
Title |
In vivo μελέτη της νευροπροστατευτικής δράσης της σωματοστατίνης στην αμφιβληστροειδική διεγερτοτοξικότητα |
Alternative Title |
In vivo study of the neuroprotective actions of somatostatin in a model of retinal excitotoxic. |
Author
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Κιαγιαδάκη, Φωτεινή
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Thesis advisor
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Θερμού, Κυριακή
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Reviewer
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Τσιλιμπάρης, Μιλτιάδης
Σιγανός, Χαράλαμπος
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Abstract |
An increasing number of clinical and laboratory studies have focused
on the investigation of the pathophysiology and therapy of retinal diseases,
such as diabetic retinopathy, glaucoma and age-related macular
degeneration, that lead to visual impairment and blindness. Ischemia has
been shown to be the underlying cause of these diseases. It leads to
neovascularization and neuronal cell death.
The cascade of events leading to the ischemia induced cell death
involves increases in glutamate, the major excitatory neurotransmitter in
retina, intracellular calcium ions and nitric oxide (NO) levels (Osborne et al.,
2004). The neuropeptide somatostatin has been considered as a possible
therapeutic target because of its well known inhibitory actions on Ca2+
channels and intracellular calcium levels (Reisine, 1990, Tallent et al., 1996).
The aim of the present study was to investigate the neuroprotective
effects of somatostatin in an in vivo model of retinal excitotoxicity, employing
the excitatory amino acid AMPA.
The intravitreal administration of AMPA (42nmol per rat eye) resulted
in a loss of retinal neurons such as cholinergic amacrine, bNOS expressing
amacrine and horizontal cells, 24 hours after its administration. An increase in
apoptosis was also observed in the AMPA treated samples. Somatostatin
levels and the expression of the sst2 and sst5 somatostatin receptor subtypes
were not affected by the AMPA treatment.
Intravitreal co-injection of AMPA with somatostatin or sst2 and sst5
selective analogs protected the retina from the AMPA induced toxicity in a
dose dependent manner. The best protection was afforded by sst2 selective
ligands since immunohistochemical studies showed that AMPA induced retinal
cell loss was fully reversed. TUNEL studies confirmed the above results. The
increase in apoptosis observed in the AMPA treated samples was drastically
reduced in the presence of the somatostatinergic sst2 analogs. Intravitreal
ABSTRACT
- 141 -
injection of the sst2 selective analogs after the administration of AMPA
afforded partial protection.
In order to study the mechanism involved in somatostatin’s
neuroprotective actions against excitotoxicity, the involvement of the
intracellular signaling pathway NO/cGMP was studied. The blockade of NO
synthase and guanylate cyclase, the enzymes that catalyze the synthesis of
nitric oxide and cGMP respectively, reversed the actions of the
somatostatinergic analogs.
These results offer new in vivo evidence supporting that sst2 and sst5
selective ligands, for the first time injected intravitreally, protect the retina
from excitotoxic insults, and reinforce the theory of the involvement of
NO/cGMP signaling in somatostatin’s protective effects.
The present data encourage the therapeutic use of somatostatin either
alone or in combination with other treatments presently applied
(photocoagulation, anti-VEGFs) in the therapeutics of retinal diseases whose
pathophysiology involves ischemia induced neurodegeneration or ischemia
induced neovascularization. Further investigations are essential to study the
pharmacokinetic properties of sst2 and sst5 selective analogs to assess the
best conditions for optimum efficacy.
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Language |
Greek |
Subject |
Ophthalmology |
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Retina |
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Somatostatin |
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excitotoxicity |
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Αμφιβληστροειδής |
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Διεγερτοτοξικότητα |
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Σωματοστατίνη |
Issue date |
2009-12-14 |
Collection
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School/Department--School of Medicine--Department of Medicine--Doctoral theses
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Type of Work--Doctoral theses
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Permanent Link |
https://elocus.lib.uoc.gr//dlib/7/b/5/metadata-dlib-niaipd83ag0smrgre54rvhlnu2_1319706912.tkl
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Views |
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