Are we ready to repurpose dimethylfumarate for Parkinsons disease | 48966

Journal of Neurology & Neurophysiology

ISSN - 2155-9562

Are we ready to repurpose dimethylfumarate for Parkinsons disease? Lessons learnt from preclinical studies

9th Global Neuroscience Conference

November 21-22, 2016 Melbourne, Australia

Bobby Thomas

Augusta University, USA

Posters & Accepted Abstracts: J Neurol Neurophysiol

Abstract :

A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling, which regulates expression of antioxidant, anti-inflammatory, and cytoprotective genes. Tecfidera, a putative Nrf2 activator, is an oral formulation of dimethylfumarate (DMF) used to treat multiple sclerosis. We compared the effects of DMF and its bioactive metabolite monomethylfumarate (MMF) on Nrf2 signaling and their ability to block 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced experimental Parkinson├ó┬?┬?s disease (PD). We show that in vitro DMF and MMF activate the Nrf2 pathway via S-alkylation of the Nrf2 inhibitor Keap1, and by causing nuclear exit of the Nrf2 repressor Bach1. Nrf2 activation by DMF but not MMF was associated with depletion of glutathione, decreased cell viability, and inhibition of mitochondrial oxygen consumption and glycolysis rates in a dose-dependent manner, whereas MMF increased these activities in vitro. However, both DMF and MMF up-regulated mitochondrial biogenesis in vitro in a Nrf2-dependent manner. Despite the in vitro differences, both DMF and MMF exerted similar neuro-protective effects against MPTP-neurotoxicity in mice, and DMF blocked MPTP-neurotoxicity in wild type but not in Nrf2 null mice and attenuated associated oxidative damage and inflammation. Our data suggest that DMF and MMF exhibit neuroprotective effects against MPTP-neurotoxicity owing to their distinct Nrf2-mediated antioxidant, anti-inflammatory and mitochondrial function/biogenesis, but MMF does so without depleting glutathione and inhibiting mitochondrial and glycolytic functions. Given that oxidative damage, neuroinflammation and mitochondrial dysfunction are implicated in PD pathogenesis, our results provide pre-clinical evidence for the development of MMF rather than DMF as a novel PD therapeutic.

Biography :