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Tesi etd-02172011-113047


Thesis type
Tesi di dottorato di ricerca
Author
PIANO, ILARIA
URN
etd-02172011-113047
Title
Antiapoptotic Strategies in Retinal Degeneration: a Biochemical and Functional Approach
Settore scientifico disciplinare
BIO/09
Corso di studi
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Commissione
tutor Prof.ssa Gargini, Claudia
Parole chiave
  • Retinal Degenerations
Data inizio appello
22/03/2011;
Consultabilità
completa
Riassunto analitico
The sphingolipid ceramide exerts a pro-apoptotic role in variety of cellular and<br>organ systems and increased of de-novo synthesis of ceramide are associated<br>with initiation of cell death. In Retinitis Pigmentosa (RP) photoreceptor death<br>occurs by apoptosis but the individual pathways of this process are unknown.<br>We employed an animal model of RP, the rd10 mutant mouse, to assess the<br>role of ceramide in inherited photoreceptor degeneration. We used Myriocin, a<br>known inhibitor of serine palmitoyltransferase (SPT, the rate-limiting enzyme<br>of ceramide biosynthesis) which was either injected intravitreally in a single<br>dose or administered daily to rd10 mice as eye drops of Solid Lipid Nanoparti-<br>cles (SLNs). Control mice were given intravitreal injections of vehicle alone or<br>unloaded lipid particles, respectively. We found that retinal ceramide levels in<br>rd10 mice double from P14 to P30, the time interval of maximum photoreceptor<br>death in this strain. Intraocular treatment with Myriocin decreases the number<br>of pycnotic photoreceptors in rd10 mice by approximately 50%. Electroretino-<br>gram (ERG) recordings were obtained from animals of various ages chronically<br>treated with Myriocin-SLNs. ERG a-waves persist after P30 in treated mice<br>while these responses are virtually extinct in control littermates. Retinal sec-<br>tions from ERG recorded animals were examined at a confocal microscope to<br>estimate photoreceptor survival. Morphometric analysis of retinas from rd10<br>mice aged P24 (peak of rod apoptosis) up to P30 showed prolonged survival of<br>photoreceptors in treated animals. This study demonstrates in a mammalian<br>model of RP that it is possible to decrease the rate of apoptotic death of pho-<br>toreceptors in vivo by lowering retinal ceramide levels through inhibition of the<br>de-novo biosynthesis of this molecule. Non-invasive, chronic administrations of<br>nanoparticles loaded with SPT inhibitors are effective in prolonging survival<br>and light responsiveness of photoreceptors.<br>
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