Ultra-pure ethyl-eicosapentaenoic acid (ethyl-EPA), a semi-synthetic ethyl ester of eicosapentaenoic acid, is associated with clinical improvement in motor functioning in Huntington's disease. The aim was to determine the extent to which it might reduce the rate of progress of cerebral atrophy. High-resolution cerebral magnetic resonance imaging scans were acquired at baseline, 6 months and 1 year in up to 34 patients with stage I or II Huntington's disease who took part in a randomized, double-blind, placebo-controlled trial of ethyl-EPA. For each subject and each pair of structural images, the two-timepoint brain volume change was calculated in a double-blind manner. Significant group-level reductions in brain atrophy were observed in the head of the caudate nucleus and the posterior thalamus. These findings show that treatment with ethyl-EPA is associated with significant reduction in brain atrophy, particularly in the caudate and thalamus. No other drug tested in Huntington's disease has shown this effect.
Huntington's Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell1993; 72: 971–983.
2.
KieburtzKMacDonaldMShihC: Trinucleotide repeat length and progression of illness in Huntington's disease. J Med Genet1994; 31: 872–874.
3.
MarderKZhaoHMyersRH and the Huntington Study Group: Rate of functional decline in Huntington's disease. Neurology2000; 54: 452–458.
4.
KirkwoodSCSuJLConneallyPM: Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol2001; 58: 273–278.
5.
SawaAWiegandGWCooperJ: Increased apoptosis of Huntington's disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat Med1999; 5: 1194–1198.
6.
PanovAVGutekunstCALeavittBR: Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci2002; 5: 731–736.
7.
LiuYF: Expression of polyglutamine-expanded huntingtin activates the SEK1–JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J Biol Chem1998; 273: 28873–28877.
8.
YasudaSInoueKHirabayashiM: Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies. Genes Cells1999; 4: 743–756.
9.
MerienneKHelmlingerDPerkinGR: Polyglutamine expansion induces a protein-damaging stress connecting heat shock protein 70 to the JNK pathway. J Biol Chem2003; 278: 16957–16967.
10.
BaeBIXuHIgarashiS: p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron2005; 47: 29–41.
11.
RyanABZeitlinSOScrableH: Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis. Neurobiol Dis2006; 24: 419–427.
12.
QinZHWangYChaseTN: Stimulation of N-methyl-d-aspartate receptors induces apoptosis in rat brain. Brain Res1996; 725: 166–177.
13.
QinZHWangYNakaiM: Transcription factor NF-kB contributes to excitotoxin-induced apoptosis in rat striatum. Mol Pharmacol1998; 53: 33–42.
14.
QinZHChenRWWangY: Nuclear factor kB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci1999; 19: 4023–4033.
15.
SerhanCNChiangN: Endogenous pro-resolving and anti-inflammatory lipid mediators: A new pharmacologic genus. Br J Pharmacol2008; 153: S200–S215.
16.
Ait-SaidFElalamyIWertsC: Inhibition by eicosapentaenoic acid of IL-1β-induced PGHS-2 expression in human microvascular endothelial cells: Involvement of lipoxygenase-derived metabolites and p38 MAPK pathway. Biochim Biophys Acta2003; 1631: 77–84.
17.
TakaderaTYumotoHTozukaY: Prostaglandin E2 induces caspase-dependent apoptosis in rat cortical cells. Neurosci Lett2002; 317: 61–64.
18.
TakaderaTShiraishiYOhyashikiT: Prostaglandin E2 induced caspase-dependent apoptosis possibly through activation of EP2 receptors in cultured hippocampal neurons. Neurochem Int2004; 45: 713–719.
19.
JumpDB: The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem2002; 277: 8755–8758.
20.
MurckHMankuM: Ethyl-EPA in Huntington disease: Potentially relevant mechanism of action. Brain Res Bull2007; 72: 159–164.
21.
LiuGBibusDMBodeAM: Omega 3 but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells. Proc Natl Acad Sci USA2001; 98: 7510–7515.
22.
MoonYPestkaJJ: Deoxynivalenol-induced mitogen-activated protein kinase phosphorylation and IL-6 expression in mice suppressed by fish oil. J Nutr Biochem2003; 14: 717–726.
23.
LoCJChiuKCFuM: Fish oil modulates macrophage P44/P42 mitogen-activated protein kinase activity induced by lipopolysaccharide. J Parenter Enteral Nutr2000; 24: 159–163.
24.
MoonDOKimKCJinCY: Inhibitory effects of eicosapentaenoic acid on lipopolysaccharide-induced activation in BV2 microglia. Int Immunopharmacol2007; 7: 222–229.
25.
MinogueAMLynchAMLoaneDJ: Modulation of amyloid-beta-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid. J Neurochem2007; 103: 914–926.
26.
LoCJChiuKCFuM: Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NFκkB activity. J Surg Res1999; 82: 216–221.
27.
ZhaoYJoshi-BarveSBarveS: Eicosapentaenoic acid prevents LPS-induced TNF-α expression by preventing NF-kB activation. J Am Coll Nutr2004; 23: 71–78.
28.
FrangouSLewisMWollardJ: Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. J Psychopharmacol2007; 21: 435–439.
29.
VaddadiK: Dyskinesias and their treatment with essential fatty acids: A review. Prostaglandins Leukot Essent Fatty Acids1996; 55: 89–94.
30.
VaddadiKSSoosaiEChiuE: A randomized, placebo-controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids. Neuroreport2002; 13: 29–33.
31.
PuriBKBydderGMCounsellSJ: MRI and neuropsychological improvement in Huntington disease following ethyl-EPA. Neuroreport2002; 13: 123–126.
32.
PuriBKLeavittBRHaydenMR: Ethyl-EPA in Huntington's disease: A double-blind, randomized, placebo-controlled trial. Neurology2005; 65: 286–292.
33.
PuriBK: Monomodal rigid-body registration and applications to the investigation of the effects of eicosapentaenoic acid intervention in neuropsychiatric disorders. Prostaglandins Leukot Essent Fatty Acids2004; 71: 177–179.
34.
KoroshetzWJ: Huntington's disease. In: Office Practice of Neurology (SamuelsMAFeskeS, eds). New York: Churchill Livingstone, 1996; pp 654–661.
35.
Huntington Study Group: Unified Huntington's Disease Rating Scale: Reliability and consistency. Mov Disord1996; 11: 136–142.
36.
SmithSMDe StefanoNJenkinsonM: Normalized accurate measurement of longitudinal brain change. J Comput Assist Tomogr2001; 25: 466–475.
37.
SmithSMZhangYJenkinsonM: Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage2002; 17: 479–489.
38.
SmithSMJenkinsonMWoolrichMW: Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage2004; 23 (suppl 1): S208–S219.
JenkinsonMSmithSM: A global optimisation method for robust affine registration of brain images. Med Image Anal2001; 5: 143–156.
41.
JenkinsonMBannisterPBradyM: Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage2002; 17: 825–841.
42.
ZhangYBradyMSmithS: Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging2001; 20: 45–57.
43.
NicollJAR: Neurodegenerative diseases, movement disorders and system degenerations. In: Adams & Graham's Introduction to Neuropathology, 3rd edn (GrahamDINicollJARBoneI, eds). London: Hodder Arnold, 2006; pp 331–344.
44.
DomRMalfroidMBaroF: Neuropathology of Huntington's chorea. Studies of the ventrobasal complex of the thalamus. Neurology1976; 26: 64–68.
