Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.

摘要: Background Huntington's disease is a devastating neurodegenerative condition for which there no therapy to slow progression. The particular vulnerability of striatal medium spiny neurons Huntington's pathology hypothesized result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, potential therapeutic approach, we investigated whether inhibition striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits brain highly utilized model system, R6/2 mouse. Methodology/Principal Findings R6/2 mice were treated with selective inhibitor TP-10 4 weeks age until euthanasia. treatment significantly reduced delayed development hind paw clasping response during tail suspension, rotarod performance, decrease locomotor activity an open field. Treatment prolonged time loss righting reflex. These effects on function reflected significant amelioration pathology, including reduction cortical cell loss, formation neuronal intranuclear inclusions, degree microglial activation that occurs mutant huntingtin-induced damage. Striatal levels phosphorylated BDNF elevated. Conclusions/Significance Our findings provide experimental support targeting pathways more broadly as approach disease. It noteworthy reduces consistent localization enzyme neurons, also nuclear inclusions. latter suggest may be primary driver secondary pathological events. More significantly, our studies point directly accessible new progression, namely, inhibition. There considerable throughout pharmaceutical industry develop inhibitors basal ganglia disorders. present results strongly investigation much needed