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Neurobiol Dis. 2008 Jun;30(3):375-87. Epub 2008 Mar 7.
Beneficial effects of rolipram in the R6/2 mouse model of Huntington's
disease.
DeMarch Z, Giampa C, Patassini S, Bernardi G, Fusco FR.
Santa Lucia Foundation IRCCS Hospital at the European Center for Brain
Research, Laboratory of Neuroanatomy, Rome, Italy.
We have previously showed that rolipram, a phosphodiesterase type IV
inhibitor, displays a neuroprotective effect in a rat quinolinic acid
model of HD [DeMarch Z., Giampa C., Patassini S., Martorana A., Bernardi
G. and Fusco F.R., (2007) Beneficial effects of rolipram in a quinolinic
acid model of striatal excitotoxicity. Neurobiol. Dis. 25:266-273.]. In
this study, we sought to determine if rolipram exerts a neuroprotective
effect in R6/2 mutant mice, which recapitulates, in many aspects, human
HD [Mangiarini L., Sathasivam K., Seller M., Cozens B., Harper A.,
Hetherington C., Lawton M., Trottier Y., Lehrach H., Davies S.W. and
Bates G.P. (1996) Exon 1 of the HD gene with an expanded CAG repeat is
sufficient to cause a progressive neurological phenotype in transgenic
mice. Cell. 87:493-506]. Transgenic mice were treated with rolipram 1.5
mg/kg daily starting from 4 weeks of age. After transcardial perfusion,
histological and immunohistochemical studies were performed. We found
that rolipram-treated R6/2 mice survived longer and displayed less
severe signs of neurological dysfunction than the vehicle treated ones.
Primary outcome measures such as brain volume, striatal atrophy, size
and morphology of striatal neurons, neuronal intranuclear inclusions and
microglial reaction confirmed a neuroprotective effect of the compound.
Rolipram was effective in increasing significantly the levels of
activated CREB and of BDNF the striatal spiny neurons, which might
account for the beneficial effects observed in this model. Our findings
show that rolipram could be considered as a valid therapeutic approach
for HD.
Publication Types:
* Comparative Study
PMID: 18424161 |
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