PDE inhibition as a therapy for Huntington's disease

Eur J Neurosci. 2009 Mar;29(5):902-10.

Phosphodiesterase type IV inhibition prevents sequestration of CREB binding protein, protects striatal parvalbumin interneurons and rescues motor deficits in the R6/2 mouse model of Huntington's disease.

Giampà C, Middei S, Patassini S, Borreca A, Marullo F, Laurenti D, Bernardi G, Ammassari-Teule M, Fusco FR.

Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy.

Comment in:

The phosphodiesterase type IV inhibitor rolipram increases cAMP response element-binding protein (CREB) phosphorylation and exerts neuroprotective effects in both the quinolinic acid rat model of Huntington's disease (DeMarch et al., 2007) and the R6/2 mouse including sparing of striatal neurons, prevention of neuronal intranuclear inclusion formation and attenuation of microglial reaction (DeMarch et al., 2008). In this study, we sought to determine if rolipram has a beneficial role in the altered distribution of CREB binding protein in striatal spiny neurons and in the motor impairments shown by R6/2 mutants. Moreover, we investigated whether rolipram treatment altered the degeneration of parvalbuminergic interneurons typical of Huntington's disease (Fusco et al., 1999). Transgenic mice and their wild-type controls from a stable colony maintained in our laboratory were treated with rolipram (1.5 mg/kg) or saline daily starting from 4 weeks of age. The cellular distribution of CREB binding protein in striatal spiny neurons was assessed by immunofluorescence, whereas parvalbuminergic neuron degeneration was evaluated by cell counts of immunohistochemically labeled tissue. Motor coordination and motor activity were also examined. We found that rolipram was effective in preventing CREB binding protein sequestration into striatal neuronal intranuclear inclusions, sparing parvalbuminergic interneurons of R6/2 mice, and rescuing their motor coordination and motor activity deficits. Our findings demonstrate the possibility of reversing pharmacologically the behavioral and neuropathological abnormalities of symptomatic R6/2 mice and underline the potential therapeutic value of phosphodiesterase type IV inhibitors in Huntington's disease.

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Thursday, December 3, 2009

PDE4 inhibition in Huntington's disease

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, Giampà 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.
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