The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein (htt), leading to motor dysfunction, cognitive decline, psychiatric alterations, and death. The metabotropic glutamate recepto...

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Main Authors: J.G. Doria, J.M. de Souza, J.N. Andrade, H.A. Rodrigues, I.M. Guimaraes, T.G. Carvalho, C. Guatimosim, T. Dobransky, F.M. Ribeiro
Format: Article
Language:English
Published: Elsevier 2015-01-01
Series:Neurobiology of Disease
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Online Access:http://www.sciencedirect.com/science/article/pii/S0969996114002526
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author J.G. Doria
J.M. de Souza
J.N. Andrade
H.A. Rodrigues
I.M. Guimaraes
T.G. Carvalho
C. Guatimosim
T. Dobransky
F.M. Ribeiro
author_facet J.G. Doria
J.M. de Souza
J.N. Andrade
H.A. Rodrigues
I.M. Guimaraes
T.G. Carvalho
C. Guatimosim
T. Dobransky
F.M. Ribeiro
author_sort J.G. Doria
collection DOAJ
description Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein (htt), leading to motor dysfunction, cognitive decline, psychiatric alterations, and death. The metabotropic glutamate receptor 5 (mGluR5) has been implicated in HD and we have recently demonstrated that mGluR5 positive allosteric modulators (PAMs) are neuroprotective in vitro. In the present study we demonstrate that the mGluR5 PAM, CDPPB, is a potent neuroprotective drug, in vitro and in vivo, capable of delaying HD-related symptoms. The HD mouse model, BACHD, exhibits many HD features, including neuronal cell loss, htt aggregates, motor incoordination and memory impairment. However, chronic treatment of BACHD mice with CDPPB 1.5 mg/kg s.c. for 18 weeks increased the activation of cell signaling pathways important for neuronal survival, including increased AKT and ERK1/2 phosphorylation and augmented the BDNF mRNA expression. CDPPB chronic treatment was also able to prevent the neuronal cell loss that takes place in the striatum of BACHD mice and decrease htt aggregate formation. Moreover, CDPPB chronic treatment was efficient to partially ameliorate motor incoordination and to rescue the memory deficit exhibited by BACHD mice. Importantly, no toxic effects or stereotypical behavior were observed upon CDPPB chronic treatment. Thus, CDPPB is a potential drug to treat HD, preventing neuronal cell loss and htt aggregate formation and delaying HD symptoms.
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spelling doaj.art-a2efad2760cf4c769989ad08bbe609512022-12-21T18:19:42ZengElsevierNeurobiology of Disease1095-953X2015-01-0173163173The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's diseaseJ.G. Doria0J.M. de Souza1J.N. Andrade2H.A. Rodrigues3I.M. Guimaraes4T.G. Carvalho5C. Guatimosim6T. Dobransky7F.M. Ribeiro8Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDB Biotech, Kosice 040 11, SlovakiaDepartamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil; Corresponding author at: Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, Ave. Antonio Carlos 6627, Belo Horizonte, MG 31270-901, Brazil.Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein (htt), leading to motor dysfunction, cognitive decline, psychiatric alterations, and death. The metabotropic glutamate receptor 5 (mGluR5) has been implicated in HD and we have recently demonstrated that mGluR5 positive allosteric modulators (PAMs) are neuroprotective in vitro. In the present study we demonstrate that the mGluR5 PAM, CDPPB, is a potent neuroprotective drug, in vitro and in vivo, capable of delaying HD-related symptoms. The HD mouse model, BACHD, exhibits many HD features, including neuronal cell loss, htt aggregates, motor incoordination and memory impairment. However, chronic treatment of BACHD mice with CDPPB 1.5 mg/kg s.c. for 18 weeks increased the activation of cell signaling pathways important for neuronal survival, including increased AKT and ERK1/2 phosphorylation and augmented the BDNF mRNA expression. CDPPB chronic treatment was also able to prevent the neuronal cell loss that takes place in the striatum of BACHD mice and decrease htt aggregate formation. Moreover, CDPPB chronic treatment was efficient to partially ameliorate motor incoordination and to rescue the memory deficit exhibited by BACHD mice. Importantly, no toxic effects or stereotypical behavior were observed upon CDPPB chronic treatment. Thus, CDPPB is a potential drug to treat HD, preventing neuronal cell loss and htt aggregate formation and delaying HD symptoms.http://www.sciencedirect.com/science/article/pii/S0969996114002526CDPPBMetabotropic glutamate receptorsHuntington's diseaseBDNFNeuroprotectionMemory and cognition
spellingShingle J.G. Doria
J.M. de Souza
J.N. Andrade
H.A. Rodrigues
I.M. Guimaraes
T.G. Carvalho
C. Guatimosim
T. Dobransky
F.M. Ribeiro
The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
Neurobiology of Disease
CDPPB
Metabotropic glutamate receptors
Huntington's disease
BDNF
Neuroprotection
Memory and cognition
title The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
title_full The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
title_fullStr The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
title_full_unstemmed The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
title_short The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
title_sort mglur5 positive allosteric modulator cdppb ameliorates pathology and phenotypic signs of a mouse model of huntington s disease
topic CDPPB
Metabotropic glutamate receptors
Huntington's disease
BDNF
Neuroprotection
Memory and cognition
url http://www.sciencedirect.com/science/article/pii/S0969996114002526
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