Editors' ChoiceParkinson’s Disease

An old drug auditions for a new leading role

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Science Translational Medicine  29 Jun 2016:
Vol. 8, Issue 345, pp. 345ec105
DOI: 10.1126/scitranslmed.aag2116

In 2013, the Food and Drug Administration approved dimethyl fumarate (DMF) for the treatment of multiple sclerosis under the trade name Tecfidera. The neuroprotective action of DMF is thought to involve activation of the Nrf2 pathway leading to enhanced antioxidant function and antiinflammatory effects. A central role for oxidative stress and inflammation in Parkinson’s disease (PD), as well as other neurological disorders, has stoked interest in the broader therapeutic potential of DMF.

Now, new evidence from Ahuja et al. supports a protective effect for DMF against neurodegeneration associated with PD. In their study, these authors used a toxin model of PD in which intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in acute and selective death of nigrostriatal dopaminergic neurons in mice, reminiscent of the pronounced dopaminergic neuronal death observed in the human disease. Treatment with DMF at 50 mg/kg/day prevented neuronal loss in wild-type MPTP-treated mice but not Nrf2-deficient mice, underscoring the importance of Nrf2 activation for the neuroprotective effects of this drug. DMF additionally attenuated the loss of dopamine and its metabolites DOPAC and HVA observed following MPTP administration. Mechanistically, DMF appeared to promote stabilization and nuclear translocation of Nrf2 by modifying its cytosolic interacting partner Keap1. Once in the nucleus, Nrf2 binds to antioxidant response elements found in numerous gene promoters and subsequently acts as a transcription factor. Accordingly, DMF was found to induce expression of an array of genes involved in antioxidant and antiinflammatory responses in the liver and ventral midbrain of wild-type mice while DMF failed to up-regulate these Nrf2 target genes in Nrf2-deficient animals. DMF was additionally reported to stimulate mitochondrial biogenesis and respiration through an Nrf2-dependent mechanism that awaits further clarification. As there is copious evidence suggesting a major role for mitochondrial dysfunction in PD pathogenesis, the beneficial effect of DMF on cell energetics might be an important aspect of its therapeutic potential.

History shows us that drugs demonstrating promise in rodent MPTP models of PD usually exhibit poor efficacy in clinical trials, giving pause to these otherwise encouraging results. It would be instructive to assess whether DMF is protective in additional models of PD to build the foundation toward prospective treatment in patients.

M. Ahuja et al., Distinct Nrf2 signaling mechanisms of fumaric acid esters and their role in neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced experimental Parkinson's-like disease. J. Neurosci. 36, 6332–6351 (2016). [Abstract]

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