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Antioxid Redox Signal. 2016 Jul 10;25(2):61-77. doi: 10.1089/ars.2015.6549. Epub 2016 Apr 27.

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease.

Author information

1
1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC , Madrid, Spain .
2
2 Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid, Spain .
3
3 Biogen, Neurology Research , Cambridge, Massachusetts.
4
4 Servicio de Neurobiología-Investigación, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) , Madrid, Spain .
5
5 Department of Neurology, Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medicine Göttingen , Göttingen, Germany .
6
6 Department of Neuropathology and Tissue Bank, Unidad de Investigación Proyecto Alzheimer, Fundación CIEN, Instituto de Salud Carlos III , Madrid, Spain .

Abstract

AIMS:

This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation.

RESULTS:

Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature.

INNOVATION:

These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy.

CONCLUSION:

DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61-77.

PMID:
27009601
PMCID:
PMC4943471
DOI:
10.1089/ars.2015.6549
[Indexed for MEDLINE]
Free PMC Article

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