Ethyl-EPA in Huntington disease: potentially relevant mechanism of action.
The pathomechanisms involved in the neuronal dysfunction in Huntington disease (HD) are still unresolved and may be heterogeneous. One potential mechanism might be related to the induction of mitochondrial dysfunction in the CNS. This might lead firstly to neuronal dysfunction and finally to the activation of apoptotic pathways. Several compounds, which should alleviate mitochondrial dysfunction, have been tested in preclinical models as well as in clinical trials of different scale. Recently we reported the efficacy of Ethyl-eicosapentaenoic acid (Ethyl-EPA) in patients with HD. Ethyl-EPA is a polyunsaturated fatty acid from the n-3 group, which is in clinical development for HD and melancholic depression. In our trial with Ethyl-EPA in HD responding patients could be characterized by either a lower CAG repeat number or a chorea-predominant clinical expression of the disease. Here we would like to describe some evidence on the potential mechanism of action of Ethyl-EPA in HD. We specifically focus on pathways, which are known to be influenced in HD and are modified by Ethyl-EPA and which points to an involvement of mitochondrial function as a common target. Some attention is given to the NF-kappa B pathway and the c-Jun amino-terminal kinases (JNK) pathway, which both may lead to an activation of the antiproliferative factor p53 and consequently mitochondrial dysfunction. Further the effects of EPA or Ethyl-EPA in preclinical models of HD are described. The evidence from these studies led to the design of phase III clinical trials, which are ongoing.
Murck
Harald
H
Amarin Neuroscience Ltd, Laurelhill Business Park, Stirling, UK. hmurck@amarin-neuro.com
Manku
Mehar
M
D000818:Animals; D001921:Brain / Q000187:drug effects; D002986:Clinical Trials as Topic; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy*
C035276:eicosapentaenoic acid ethyl ester; D015118:Eicosapentaenoic Acid