neurology-2017-scientifictracks-abstracts

6 / 34

Page 39
Notes:
conferenceseries.com
Volume 8, Issue 2 (Suppl) J Neurol Neurophysiol
ISSN: 2155-9562 JNN, an open access journal Neurology 2017
March 27-29, 2017
March 27-29, 2017 Madrid, Spain
11th World Congress on
Neurology and Therapeutics
Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s
disease
Isabel Lastres-Becker
Autonomous University of Madrid, Spain
This preclinical study was aimed at determining if pharmacological targeting of transcription factor NRF2 might provide a disease
modifying therapy in the animal model of Parkinson’s disease (PD) that best reproduces the main hallmark of this pathology,
i.e. α-synucleinopathy, and associated events including nigral dopaminergic cell death, oxidative stress and neuroinflammation.
Pharmacological activation of NRF2 was at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the
treatment of multiple sclerosis, leading to up-regulation of a battery of cytoprotective genes. 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 p62, LC3 and LAMP2 in MN9D, BV2 and IMA 2.1 and with a shift in microglial dynamics towards a less pro-
inflammatory and more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated
with NRF2 expression, NQO1 and SQSTM1/p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective
capacity of the NRF2 signature. 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.
Biography
Isabel Lastres-Becker is Associate Professor at the Autonomous University of Madrid, Spain. Her main focus is to uncover the molecular basis of neurodegenerative
disorders like Parkinson and Alzheimer’s disease, to try to find a therapeutic target to develop a cure
Isabel Lastres-Becker, J Neurol Neurophysiol 2017, 8:2 (Suppl)