ABSTRACT
Huntington's disease (HD) is a fatal, neurodegenerative movement disorder that has no cure and few treatment options. In these preclinical studies, we tested the effects of chronic treatment of glatiramer acetate (GA; Copaxone®), an FDA-approved drug used as first-line therapy for MS, in two different HD mouse models, and explored potential mechanisms of action of drug efficacy. Groups of CAG140 knock-in and N171-82Q transgenic mice were treated with GA for up to 1year of age (CAG140 knock-in mice) or 20weeks (N171-82Q mice). Various behavioral assays were measured over the course of drug treatment whereby GA treatment delayed the onset and reduced the severity of HD behavioral symptoms in both mouse models. The beneficial actions of GA were associated with elevated levels of promoter I- and IV-driven brain-derived neurotrophic factor (Bdnf) expression and reduced levels of cytokines, in particular, interleukins IL4 and IL12, in the brains of HD mice. In addition, the GA-induced effects on BDNF, IL4 and IL12 levels were detected in plasma from drug-treated mice and rats, suggesting utility as a peripheral biomarker of treatment effectiveness. These preclinical studies support the use of GA as a relevant clinical therapy for HD patients.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Glatiramer Acetate/pharmacology , Huntington Disease/drug therapy , Huntington Disease/metabolism , Neuroprotective Agents/pharmacology , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Disease Models, Animal , Female , Gene Expression/drug effects , Interleukin-12/metabolism , Interleukin-4/metabolism , Male , Mice, Transgenic , Motor Activity/drug effects , Motor Activity/physiology , Random Allocation , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Deficiencies in brain-derived-neurotrophic-factor have been implicated in the pathogenesis of Huntington's disease (HD). OBJECTIVE: Glatiramer acetate, an FDA- approved drug used for the treatment of multiple sclerosis, has been shown to increase brain-derived-neurotrophic-factor levels in immune cells; hence, we investigated whether it could have similar effects in striatal cells. METHODS: Wild-type and HD striatal cells were treated with glatiramer acetate for 48 hrs. HD transgenic and wild-type mice were injected with glatiramer acetate (1.5 to 1.7 mg/mouse) for five days. These treatments were followed by protein measurements for brain-derived-neurotrophic-factor. RESULTS: Glatiramer acetate elicited concentration-dependent increases in brain-derived-neurotrophic-factor protein levels in wild-type and HD striatal cells and in striatal tissue from N171-82Q transgenic mice. Glatiramer acetate also improved metabolic activity of HD striatal cells, and significantly reduced the early hyperactivity phenotype exhibited by N171-82Q transgenic mice. CONCLUSIONS: These findings suggest that glatiramer acetate may represent a useful therapeutic approach for HD. The excellent safety and tolerability record of this compound makes it an ideal candidate for drug repurposing efforts.