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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
Supervisors
tutor Prof.ssa Gargini, Maria 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
organ systems and increased of de-novo synthesis of ceramide are associated
with initiation of cell death. In Retinitis Pigmentosa (RP) photoreceptor death
occurs by apoptosis but the individual pathways of this process are unknown.
We employed an animal model of RP, the rd10 mutant mouse, to assess the
role of ceramide in inherited photoreceptor degeneration. We used Myriocin, a
known inhibitor of serine palmitoyltransferase (SPT, the rate-limiting enzyme
of ceramide biosynthesis) which was either injected intravitreally in a single
dose or administered daily to rd10 mice as eye drops of Solid Lipid Nanoparti-
cles (SLNs). Control mice were given intravitreal injections of vehicle alone or
unloaded lipid particles, respectively. We found that retinal ceramide levels in
rd10 mice double from P14 to P30, the time interval of maximum photoreceptor
death in this strain. Intraocular treatment with Myriocin decreases the number
of pycnotic photoreceptors in rd10 mice by approximately 50%. Electroretino-
gram (ERG) recordings were obtained from animals of various ages chronically
treated with Myriocin-SLNs. ERG a-waves persist after P30 in treated mice
while these responses are virtually extinct in control littermates. Retinal sec-
tions from ERG recorded animals were examined at a confocal microscope to
estimate photoreceptor survival. Morphometric analysis of retinas from rd10
mice aged P24 (peak of rod apoptosis) up to P30 showed prolonged survival of
photoreceptors in treated animals. This study demonstrates in a mammalian
model of RP that it is possible to decrease the rate of apoptotic death of pho-
toreceptors in vivo by lowering retinal ceramide levels through inhibition of the
de-novo biosynthesis of this molecule. Non-invasive, chronic administrations of
nanoparticles loaded with SPT inhibitors are effective in prolonging survival
and light responsiveness of photoreceptors.
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