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

Neurobiology of Disease

D.C. Lafferty¹  A. Reiner²  Y.P. Deng³  H.B. Wang³  N. Del Mar³ 

[1] Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA;Corresponding author at: Dept. of Anatomy and Neurobiology, The University of Tennessee Health Science Center, 855 Monroe Ave., Memphis, TN 38163, USA. Fax: [phone].;Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA;

关键词: Huntington's disease;    Therapy;    mGluR2/3;    Striatum;    Akinesia;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 (20 mg/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 10 weeks 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.

【 授权许可】

Unknown