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

<h4>Background</h4>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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Carmela Giampà, Daunia Laurenti, Serenella Anzilotti, Giorgio Bernardi, Frank S Menniti, Francesca Romana Fusco
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8bb4ad0208bb4007b0bdcdbb45561208
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:8bb4ad0208bb4007b0bdcdbb45561208
record_format	dspace
spelling	oai:doaj.org-article:8bb4ad0208bb4007b0bdcdbb455612082021-11-18T07:03:14ZInhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.1932-620310.1371/journal.pone.0013417https://doaj.org/article/8bb4ad0208bb4007b0bdcdbb455612082010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20976216/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Carmela GiampàDaunia LaurentiSerenella AnzilottiGiorgio BernardiFrank S MennitiFrancesca Romana FuscoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13417 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Carmela Giampà Daunia Laurenti Serenella Anzilotti Giorgio Bernardi Frank S Menniti Francesca Romana Fusco Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format	article
author	Carmela Giampà Daunia Laurenti Serenella Anzilotti Giorgio Bernardi Frank S Menniti Francesca Romana Fusco
author_facet	Carmela Giampà Daunia Laurenti Serenella Anzilotti Giorgio Bernardi Frank S Menniti Francesca Romana Fusco
author_sort	Carmela Giampà
title	Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.
title_short	Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.
title_full	Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.
title_fullStr	Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.
title_full_unstemmed	Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.
title_sort	inhibition of the striatal specific phosphodiesterase pde10a ameliorates striatal and cortical pathology in r6/2 mouse model of huntington's disease.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/8bb4ad0208bb4007b0bdcdbb45561208
work_keys_str_mv	AT carmelagiampa inhibitionofthestriatalspecificphosphodiesterasepde10aamelioratesstriatalandcorticalpathologyinr62mousemodelofhuntingtonsdisease AT daunialaurenti inhibitionofthestriatalspecificphosphodiesterasepde10aamelioratesstriatalandcorticalpathologyinr62mousemodelofhuntingtonsdisease AT serenellaanzilotti inhibitionofthestriatalspecificphosphodiesterasepde10aamelioratesstriatalandcorticalpathologyinr62mousemodelofhuntingtonsdisease AT giorgiobernardi inhibitionofthestriatalspecificphosphodiesterasepde10aamelioratesstriatalandcorticalpathologyinr62mousemodelofhuntingtonsdisease AT franksmenniti inhibitionofthestriatalspecificphosphodiesterasepde10aamelioratesstriatalandcorticalpathologyinr62mousemodelofhuntingtonsdisease AT francescaromanafusco inhibitionofthestriatalspecificphosphodiesterasepde10aamelioratesstriatalandcorticalpathologyinr62mousemodelofhuntingtonsdisease
_version_	1718423991343906816

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

Ejemplares similares