Inhibition of the Striatal Specific Phosphodiesterase PDE10A Ameliorates Striatal and Cortical Pathology in R6/2 Mouse Model of Huntington's Disease

Abstract

BackgroundHuntington'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.Methodology/Principal FindingsR6/2 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/SignificanceOur 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.

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

“…5 to 8). Reagents that activate the cAMP/PKA pathway in the striatum are therefore beneficial in HD mice, as was reported previously (11,20,34). This cross talk between PKA and the proteasome might be brain area specific or disease stage dependent.…”

“…The cAMP/PKA pathway has long been recognized as fundamentally important to HD pathogenesis and for drug development in HD (11,12,15,20). In the present study, we showed that the activity of PKA in the striatum of two HD mouse models was lower than that observed in their littermate controls (Fig.…”

“…Among substrates of the proteasome, we were interested in the regulatory subunits of PKA (PKA-Rs) because cAMP signaling is deregulated in HD (11,12,15). The PKA holoenzyme consists of two PKA-Rs and two catalytic subunits and is catalytically inactive in the absence of cAMP.…”

Facilitation of Corticostriatal Transmission following Pharmacological Inhibition of Striatal Phosphodiesterase 10A: Role of Nitric Oxide-Soluble Guanylyl Cyclase-cGMP Signaling Pathways

“…(Sancesario et al, 2004;, and Huntington's disease (HD) (Hebb and Robertson, 2007;Giampà et al, 2009Giampà et al, , 2010Kleiman et al, 2011). All of these disorders are associated with abnormal corticostriatal neurotransmission (Shepherd, 2013), a function strongly influenced by striatal cyclic nucleotide signaling (Greengard, 2001).…”

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

“…Selective inhibitors of PDE10A have been reported to be efficacious in preclinical rodent behavioral models of schizophrenia, such as phencyclidine-stimulated hyperlocomotor activity, prepulse inhibition model, and conditioned avoidance response (Siuciak et al, 2006(Siuciak et al, , 2008Grauer et al, 2009). Moreover, the PDE10A inhibitor 2,pyrazol-3-yl]phenoxy]methyl]quinoline) has been demonstrated to ameliorate pathology and locomotor behavior in rat and R6/2 mouse models of Huntington's disease (Giampà et al, 2009(Giampà et al, , 2010.…”