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

Abstract

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.

Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease

“…This reduction over time in the cerebral cortex may be due to the neuronal cell death in the cortex preceding that in the striatum of R6/2 mice (31). The increased PDE4 activity may provide an explanation why rolipram has beneficial effects in the R6/2 model (32,33). Consistent with our novel discovery in vivo, when we evaluated a neuro2a cell model that stably expresses an N-terminal 1-67 amino acid fragment (corresponding to exon 1) of Htt with expanded polyQ (HTT67Q150) (34), we found that PDE4 activity was increased more than 3-fold (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI85594DS1).…”

Alterations in Expression and Function of Phosphodiesterases in Huntington’s Disease

“…If this is true, then inhibition of PDEs early in disease progression represents a valid therapeutic approach to elevate cAMP levels and overcome changes in gene expression, which may contribute to HD pathogenesis. In support of this view, PDE4 inhibition via rolipram has shown beneficial results in mouse www.intechopen.com models of HD (DeMarch et al, 2007;Giampa et al, 2009). Additionally, PDE10A inhibition by TP-10 treatment at 4 weeks of age reduces behavioural and cellular changes associated with HD progression in R6/2 mice (Giampa et al, 2010).…”

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

“…The use of drugs that maintains CREB phosphorylated, like the specific PDE4 and 10 inhibitors rolipram and T10, decreases striatal cell loss after the injection of QUIN in an excitotoxic model of HD [100,117]. Following this research, the same group reported that administration of rolipram in R6/2 mice enhanced the expression of both phosphorylated CREB and BDNF in striatal neurons and ameliorated neurodegeneration, decreased mhtt inclusions preventing the sequestration of CBP, reduced microglia activation and rescue motor function [118,119]. Likewise, beneficial effects of PDE inhibition on cognitive function were also observed in the hippocampus of HD mouse model [101].…”

“…Although PDE10A has been proposed as a therapeutic target for HD based on the observation that pharmacologic inhibition of PDE10A in transgenic HD mice significantly improved behavioral and neuropathologic abnormalities [101,119], some conflicts appear when focusing on HD patients. Earlier work had shown that striatal PDE10A levels in HD mice already decline to minimal levels before onset of motor symptoms [115,116].…”