Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease.
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.
DeMarch
Zena
Z
Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Laboratory of Neuroanatomy, Rome, Italy.
Giampà
Carmela
C
Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Laboratory of Neuroanatomy, Rome, Italy.
Patassini
Stefano
S
Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Laboratory of Neuroanatomy, Rome, Italy.
Bernardi
Giorgio
G
Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Laboratory of Neuroanatomy, Rome, Italy; University of Rome Tor Vergata, Department of Neuroscience, Rome, Italy.
Fusco
Francesca Romana
FR
Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Laboratory of Neuroanatomy, Rome, Italy. Electronic address: f.fusco@hsantalucia.it.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020889:Rolipram / Q000627:therapeutic use*
D019208:Brain-Derived Neurotrophic Factor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D020889:Rolipram