How does tecfidera work

Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, Köhl J, Offermanns S, Wettschureck N, Schwaninger M. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE. J Clin Invest. 2014 1;124(5):2188-92.

Taken orally, the drug dimethyl fumarate (DMF) has been shown to improve functional outcomes for patients with MS; however, it is unclear how DMF mediates a protective effect. DMF and, more so, its active metabolite, monomethyl fumarate, are known agonists of the hydroxycarboxylic acid receptor 2 (HCA₂), a G protein-coupled membrane receptor. Here, we evaluated the contribution of HCA₂ in mediating the protective effect afforded by DMF in EAE, a mouse model of MS. DMF treatment reduced neurological deficit, immune cell infiltration, and demyelination of the spinal cords in wild-type mice, but not in Hca2⁻/⁻ mice, indicating that HCA₂ is required for the therapeutic effect of DMF. In particular, DMF decreased the number of infiltrating neutrophils in a HCA₂-dependent manner, likely by interfering with neutrophil adhesion to endothelial cells and chemotaxis. Together, our data indicate that HCA₂ mediates the therapeutic effects of DMF in EAE. Furthermore, identification of HCA₂ as a molecular target may help to optimize MS therapy.

Tecifidera is a topic being talked about in AVTRIMS 2013. A number of presentations has been talking about Nrf2 as a mechanism and it was even suggested that this could be a bad thing. So I draw your attention to this EAE study which suggest that Tecfideramay work via hydroxycarboxylic acid receptor 2 the niacin receptor and stimulation of this can lead to flushing which is a side effect of tecfidera. in a mouse that lacks this receptor dimethyl fumarate stops working.

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  • Or its effectivness could be due to the fact that it reduces the white blood cell count by 30%. Not too much of a mystery here.

    • Yes you maybe be right, however I understand that the kinetics are not completely correct in that the depletion may occur later than the efficacy

    • A promient pathologist was comparing the histology of EAE and MS and looking at Nrf2 expression and they threw out this idea based on tissue expression…I would argue that the clinical data does not support this idea.

    • Could it be that tecfidera really just works targeting the lymphocytes by decreasing them and via its effect on HCA2?
      If tecfidera were an anti-inflammatory AND (like data from EAE suggests) strong neuroprotective agent, wouldnt you expect a bigger effect on disease progression?

    • Yep possible…The neuroprotective effect in EAE models is generally self-fullfilling because anything that stops the inflammatory response arriving in the CNS will limit nerve loss.

  • I've been on Tecfidera for over a year and we have closely monitored my blood work. No problem at all with lymphocytes. Am I unusual?

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