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@ARTICLE{Milanese:155465,
      author       = {Milanese, Marco and Bonifacino, Tiziana and Torazza, Carola
                      and Provenzano, Francesca and Kumar, Mandeep and Ravera,
                      Silvia and Zerbo, Arianna Roberta and Frumento, Giulia and
                      Balbi, Matilde and Nguyen, Quynh Tram Julia and Bertola,
                      Nadia and Ferrando, Sara and Viale, Maurizio and Profumo,
                      Aldo and Bonanno, Giambattista},
      title        = {{B}locking glutamate m{G}lu5 receptors with the negative
                      allosteric modulator {CTEP} improves disease course in
                      {SOD}1{G}93{A} mouse model of amyotrophic lateral
                      sclerosis.},
      journal      = {British journal of pharmacology},
      volume       = {178},
      number       = {18},
      issn         = {1476-5381},
      address      = {Malden, MA},
      publisher    = {Wiley},
      reportid     = {DZNE-2021-00664},
      pages        = {3747-3764},
      year         = {2021},
      abstract     = {The pathogenesis of amyotrophic lateral sclerosis (ALS) is
                      not fully clarified, although excessive glutamate (Glu)
                      transmission and the downstream cytotoxic cascades are major
                      mechanisms for motor neuron death. Two metabotropic
                      glutamate receptors (mGlu1 and mGlu5 ) are overexpressed in
                      ALS and regulate cellular disease processes. Expression and
                      function of mGlu5 receptors are altered at early symptomatic
                      stages in the SOD1G93A mouse model of ALS and knockdown of
                      mGlu5 receptors in SOD1G93A mice improved disease
                      progression.We treated male and female SOD1G93A mice with
                      2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine
                      (CTEP), an orally available mGlu5 receptor negative
                      allosteric modulator (NAM), using doses of 2 mg·kg-1 per 48
                      h or 4 mg·kg-1 per 24 h from Day 90, an early symptomatic
                      disease stage. Disease progression was studied by
                      behavioural and histological approaches.CTEP
                      dose-dependently ameliorated clinical features in SOD1G93A
                      mice. The lower dose increased survival and improved motor
                      skills in female mice, with barely positive effects in male
                      mice. Higher doses significantly ameliorated disease
                      symptoms and survival in both males and females, females
                      being more responsive. CTEP also reduced motor neuron death,
                      astrocyte and microglia activation, and abnormal glutamate
                      release in the spinal cord, with equal effects in male and
                      female mice. No differences were also observed in CTEP
                      access to the brain.Our results suggest that mGlu5 receptors
                      are promising targets for the treatment of ALS and highlight
                      mGlu5 receptor NAMs as effective pharmacological tools with
                      translational potential.},
      keywords     = {Amyotrophic Lateral Sclerosis: drug therapy / Animals /
                      Disease Models, Animal / Disease Progression / Female /
                      Glutamic Acid / Male / Mice / Mice, Transgenic / Receptor,
                      Metabotropic Glutamate 5 / Spinal Cord / Superoxide
                      Dismutase / Superoxide Dismutase-1: genetics /
                      2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine
                      (CTEP) (Other) / SOD1G93A mice (Other) / amyotrophic lateral
                      sclerosis (ALS) (Other) / in vivo pharmacological treatment
                      (Other) / metabotropic glutamate receptor 5 (mGlu5 receptor)
                      (Other)},
      cin          = {AG Deleidi},
      ddc          = {610},
      cid          = {I:(DE-2719)1210011},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC8457068},
      pubmed       = {pmid:33931856},
      doi          = {10.1111/bph.15515},
      url          = {https://pub.dzne.de/record/155465},
}