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Experimental therapeutics—preclinical
P08 Analysis of Nrf2-downstream targets after fumarate treatment in dorsal root ganglia—an anti-inflammatory therapy in neurodegenerative disease?!
  1. G Ellrichmann1,
  2. C Reick1,2,
  3. R Gold1,
  4. R Nitsch3,
  5. C Saft1,
  6. RA Linker4,
  7. CA Vogelaar3
  1. 1Department of Neurology, St. Josef Hospital, University of Bochum, Bochum, Germany
  2. 2International Graduate School of Neuroscience, University of Bochum, Bochum, Germany
  3. 3Johannes Gutenberg-University Mainz, Institute of Microanatomy and Neurobiology, Mainz, Germany
  4. 4Friedrich-Alexander-University Erlangen, Erlangen, Germany

Abstract

Background Dimethylfumarate (DMF) is a new disease modifying therapy. Several studies have shown convincing data after DMF therapy in both autoimmune inflammatory diseases and neurodegenerative disorders like Huntington's disease (HD). DMF exerts neuroprotective effects via induction of the nuclear factor E2-related factor 2 (Nrf2) and detoxification pathways. Although the exact mechanisms that lead to neurodegeneration are not fully understood the contribution of oxidative stress inducing neurodegeneration is assumed.

Aims To analyse the effects of DMF on axonal growth and regeneration and to describe the influence of DMF on the Nrf2-pathway.

Methods/techniques We thus investigated the efficacy of DMF in HD transgenic mice (R6/2,YAC128). Analysing the underlying mechanisms, we use in vitro techniques for studying effects of DMF on axon growth and regeneration. Getting an idea of downstream mechanisms of DMF, we quantified expression of affected genes by qPCR under different concentrations of DMF (10 35 70 μM) and a various duration of incubation (4 24 48 h). Additionally, we did the same experiments under conditions of oxidative stress (5 μM H2O2).

Results/outcome Treatment with DMF prevented weight loss, attenuated motor impairment and resulted in preservation of morphologically intact neurons as well as in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. Preliminary data indicate the best effects of DMF therapy after incubation of 24 h in a concentration of 35 μM. Effects on axon growth and regeneration could be objectified by higher expression of target genes (Nrf2,HO-1,TXNRD,GstA1,NQO-1) of the Nrf2-pathway after DMF treatment by qPCR and immunohistochemistry.

Conclusions In conclusion, DMF exerts beneficial effects in axon growth and regeneration being effective not only in inflammatory but also in neurodegenerative diseases. Given its excellent side effect profile, further studies with DMF and its downstream pathways are warranted.

  • Dimethylfumarate
  • Nrf2
  • dorsal root ganglia
  • inflammation

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