A prominent theory for the pathology of Huntington's Disease (HD) involves excitotoxic injury to the striatum. Continuous exposure of ionotropic NMDA receptors to glutamate from the cortex may occur and be excitotoxic in HD and leave striatal neurons vulnerable to damage. Activation of presynaptic mGluR2/3 receptors by an agonist dampens glutamate release from corticostriatal terminals. Treatments that target excitoxicity thus may improve symptoms in HD patients, and it is therefore logical to

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... ursue therapies aimed in this direction. LY379268 is an inviting mGluR2/3 receptor agonist that has been shown to be neuroprotective in hypoxic and ischemic injuries to cultured neurons. Daily subcutaneous injection of 20mg/kg LY379268 had a number of beneficial effects in R6/2 mice, including an 11% improvement in lifespan and numerous locomotor parameters in open field. The motor parameters improved included overall activity, speed, acceleration, and endurance, all of which were normalized until 12 weeks of age, and improved over vehicle-treated R6/2 mice at all ages. Histological analysis revealed a 20% loss of cortical and striatal neurons in R6/2 mice, which was rescued with the administration of LY379268. There was no effect of the drug on neuronal intranuclear inclusions (NIIs) or benefit for ENK+ striatal neuron neurochemistry, but SP+ striatal projection neurons were normalized in their neurochemistry. The data indicate that LY379268 is particularly useful in improving the health and functioning of the direct striatal pathway (i.e. SP+ neurons), which demonstrably improved the voluntary motor behavior in the R6/2 mice.