title: The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice.
abstract: Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington's disease (HD) pathogenesis. Since corticostriatal terminals possess mGluR2/3 autoreceptors, whose activation dampens glutamate release, we tested the ability of the mGluR2/3 agonist LY379268 to improve the phenotype in R6/2 HD mice with 120-125 CAG repeats. Daily subcutaneous injection of a maximum tolerated dose (MTD) of LY379268 (20mg/kg) had no evident adverse effects in WT mice, and diverse benefits in R6/2 mice, both in a cohort of mice tested behaviorally until the end of R6/2 lifespan and in a cohort sacrificed at 10weeks of age for blinded histological analysis. MTD LY379268 yielded a significant 11% increase in R6/2 survival, an improvement on rotarod, normalization and/or improvement in locomotor parameters measured in open field (activity, speed, acceleration, endurance, and gait), a rescue of a 15-20% cortical and striatal neuron loss, normalization of SP striatal neuron neurochemistry, and to a lesser extent enkephalinergic striatal neuron neurochemistry. Deficits were greater in male than female R6/2 mice, and drug benefit tended to be greater in males. The improvements in SP striatal neurons, which facilitate movement, are consistent with the improved movement in LY379268-treated R6/2 mice. Our data indicate that mGluR2/3 agonists may be particularly useful for ameliorating the morphological, neurochemical and motor defects observed in HD.
authors.affiliation: Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA. areiner@uthsc.edu
authors.forename: A
authors.initials: A
authors.lastname: Reiner
authors.forename: D C
authors.initials: DC
authors.lastname: Lafferty
authors.forename: H B
authors.initials: HB
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Del Mar
authors.forename: Y P
authors.initials: YP
authors.lastname: Deng
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D017072:Neostriatum / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012737:Sex Factors
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate