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

Abstract

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.

• 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
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 73 Pg. 163-73 (Jan 2015) ISSN: 1095-953X [Electronic] United States
• PMID: 25160573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
• Benzamides
• HTT protein, human
• Huntingtin Protein
• Nerve Tissue Proteins
• Pyrazoles
• Glutamic Acid
• Extracellular Signal-Regulated MAP Kinases

Topics

• Age Factors
• Animals
• Benzamides (therapeutic use)
• Cell Death (drug effects)
• Cells, Cultured
• Corpus Striatum (cytology)
• Disease Models, Animal
• Embryo, Mammalian
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Glutamic Acid (pharmacology)
• Humans
• Huntingtin Protein
• Huntington Disease (drug therapy, genetics, pathology, physiopathology)
• Mice
• Mice, Transgenic
• Mitochondria (pathology)
• Motor Activity (drug effects, genetics)
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects, pathology)
• Pyrazoles (therapeutic use)
• Recognition, Psychology (drug effects)
• Signal Transduction (drug effects)
• Synapses (pathology, ultrastructure)