title: Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease.
abstract: OBJECTIVE
  Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5-dependent protective pathways are more activated in HD neurons, intracellular Ca²⁺ release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators (PAMs) could activate protective pathways without triggering high levels of Ca²⁺ release and be neuroprotective in HD.
  
  
  METHODS
  We performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca²⁺ release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit.
  
  
  RESULTS
  We find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca²⁺ concentration ([Ca²⁺]i ); and Akt blockage leads to loss of PAM-mediated neuroprotection. Importantly, PAMs' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit.
  
  
  CONCLUSIONS
  mGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD.
authors.affiliation: Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: J G
authors.initials: JG
authors.lastname: Doria
authors.forename: F R
authors.initials: FR
authors.lastname: Silva
authors.forename: J M
authors.initials: JM
authors.lastname: de Souza
authors.forename: L B
authors.initials: LB
authors.lastname: Vieira
authors.forename: T G
authors.initials: TG
authors.lastname: Carvalho
authors.forename: H J
authors.initials: HJ
authors.lastname: Reis
authors.forename: G S
authors.initials: GS
authors.lastname: Pereira
authors.forename: T
authors.initials: T
authors.lastname: Dobransky
authors.forename: F M
authors.initials: FM
authors.lastname: Ribeiro
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists* / Q000378:metabolism
chemical_list: C578936:Grm5 protein, mouse; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D009687:Nuclear Proteins; D064529:Receptor, Metabotropic Glutamate 5; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt