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.
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.
Giampà
Carmela
C
Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy.
Middei
Silvia
S
Patassini
Stefano
S
Borreca
Antonella
A
Marullo
Fabrizia
F
Laurenti
Daunia
D
Bernardi
Giorgio
G
Ammassari-Teule
Martine
M
Fusco
Francesca R
FR
D000704:Analysis of Variance; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006816:Huntington Disease / Q000150:complications / Q000235:genetics; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D010320:Parvalbumins / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D021381:Protein Transport / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use*; D018911:Trinucleotide Repeats / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
D010320:Parvalbumins; D010726:Phosphodiesterase Inhibitors; D025801:Ubiquitin; D050882:CREB-Binding Protein; D020889:Rolipram