Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease.
Huntington disease (HD) is an adult-onset neurodegenerative disorder that is characterized by selective degeneration in the striatum. There are currently no treatments that can prevent the progressive decline of motor and cognitive function in HD. In parallel with a human clinical trial, we examined the efficacy of ethyl-EPA treatment in the YAC128 mouse model of HD. Oral delivery of ethyl-EPA to symptomatic YAC128 mice beginning at 7 months of age increased membrane EPA levels 3-fold (P < 0.001) and resulted in a modest but significant improvement in motor dysfunction by 12 months of age as measured by open-field activity (P = 0.01) and performance on the rotarod (P = 0.05). At this age, ethyl-EPA-treated YAC128 mice showed no improvement in striatal volume, striatal neuron counts, striatal neuronal cross-sectional area, or striatal DARPP-32 expression compared to untreated YAC128 mice, thereby indicating no reduction of striatal neuropathology. This result is congruent with modest motor benefits observed in HD patients treated with ethyl-EPA. Overall, this work demonstrates the feasibility of experimental therapeutics in the YAC128 mouse model and suggests that experiments in these mice may be predictive for future human clinical trials.
Van Raamsdonk
Jeremy M
JM
Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4.
Pearson
Jacqueline
J
Rogers
Daniel A
DA
Lu
Ge
G
Barakauskas
Vilte E
VE
Barr
Alasdair M
AM
Honer
William G
WG
Hayden
Michael R
MR
Leavitt
Blair R
BR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006816:Huntington Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013997:Time Factors
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C035276:eicosapentaenoic acid ethyl ester; D015118:Eicosapentaenoic Acid; D010751:Phosphopyruvate Hydratase