The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice

Neurobiol Dis. 2012 Jul;47(1):75-91. doi: 10.1016/j.nbd.2012.03.025. Epub 2012 Mar 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / pharmacology*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / pathology
  • Cohort Studies
  • Disease Models, Animal
  • Female
  • Huntington Disease / drug therapy
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity / drug effects*
  • Neostriatum / chemistry
  • Neostriatum / drug effects*
  • Neostriatum / pathology
  • Neurons / chemistry
  • Neurons / drug effects*
  • Neurons / pathology
  • Receptors, Metabotropic Glutamate / agonists*
  • Sex Factors

Substances

  • Amino Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • LY 379268
  • Receptors, Metabotropic Glutamate