Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.
BACKGROUND
Huntington's disease is a devastating neurodegenerative condition for which there is no therapy to slow disease progression. The particular vulnerability of striatal medium spiny neurons to Huntington's pathology is hypothesized to result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, and a potential therapeutic approach, we investigated whether inhibition of the striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits and brain pathology in a highly utilized model system, the R6/2 mouse.


RESULTS
R6/2 mice were treated with the highly selective PDE10A inhibitor TP-10 from 4 weeks of age until euthanasia. TP-10 treatment significantly reduced and delayed the development of the hind paw clasping response during tail suspension, deficits in rotarod performance, and decrease in locomotor activity in an open field. Treatment prolonged time to loss of righting reflex. These effects of PDE10A inhibition on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal and cortical cell loss, the formation of striatal neuronal intranuclear inclusions, and the degree of microglial activation that occurs in response to the mutant huntingtin-induced brain damage. Striatal and cortical levels of phosphorylated CREB and BDNF were significantly elevated.


CONCLUSIONS
Our findings provide experimental support for targeting the cAMP and CREB signaling pathways and more broadly transcriptional dysregulation as a therapeutic approach to Huntington's disease. It is noteworthy that PDE10A inhibition in the R6/2 mice reduces striatal pathology, consistent with the localization of the enzyme in medium spiny neurons, and also cortical pathology and the formation of neuronal nuclear inclusions. These latter findings suggest that striatal pathology may be a primary driver of these secondary pathological events. More significantly, our studies point directly to an accessible new therapeutic approach to slow Huntington's disease progression, namely, PDE10A inhibition. There is considerable activity throughout the pharmaceutical industry to develop PDE10A inhibitors for the treatment of basal ganglia disorders. The present results strongly support the investigation of PDE10A inhibitors as a much needed new treatment approach to Huntington's disease.
Giampà
Carmela
C
Santa Lucia Foundation IRCCS Hospital, European Center for Brain Research, Laboratory of Neuroanatomy, Rome, Italy.
Laurenti
Daunia
D
Anzilotti
Serenella
S
Bernardi
Giorgio
G
Menniti
Frank S
FS
Fusco
Francesca Romana
FR
D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000201:enzymology / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*
C528913:2-(4-(pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenoxymethyl)quinoline succinic acid; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases