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

Manuj Ahuja, Navneet Ammal Kaidery, Lichuan Yang, Noel Calingasan, Natalya Smirnova, Arsen Gaisin, Irina N. Gaisina, Irina Gazaryan, Dmitry M. Hushpulian, Ismail Kaddour-Djebbar, Wendy B. Bollag, John C. Morgan, Rajiv R. Ratan, Anatoly A. Starkov, M. Flint Beal, Bobby Thomas

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59 Scopus citations

Abstract

A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response ele-ment 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’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 upregulated mitochondrial biogenesis in vitro in an Nrf2-dependent manner. Despite the in vitro differences, both DMF and MMF exerted similar neuroprotective effects and blocked MPTP neurotoxicity in wild-type but not in Nrf2 null mice. Our data suggest that DMF and MMF exhibit neuroprotective effects against MPTP neurotoxicity because of their distinct Nrf2-mediated antioxidant, anti-inflammatory, and mitochondrial functional/biogenetic effects, but MMF does so without depleting glutathione and inhibiting mitochondrial and glycolytic functions. Given that oxidative damage, neuroinflammation, and mitochondrial dysfunction are all implicated in PD pathogenesis, our results provide preclinical evidence for the development of MMF rather than DMF as a novel PD therapeutic.

Original languageEnglish (US)
Pages (from-to)6332-6351
Number of pages20
JournalJournal of Neuroscience
Volume36
Issue number23
DOIs
StatePublished - Jun 8 2016

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Keywords

  • Fumarates
  • Inflammation
  • MPTP
  • Mitochondria
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ahuja, M., Kaidery, N. A., Yang, L., Calingasan, N., Smirnova, N., Gaisin, A., Gaisina, I. N., Gazaryan, I., Hushpulian, D. M., Kaddour-Djebbar, I., Bollag, W. B., Morgan, J. C., Ratan, R. R., Starkov, A. A., Beal, M. F., & Thomas, B. (2016). 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. Journal of Neuroscience, 36(23), 6332-6351. https://doi.org/10.1523/JNEUROSCI.0426-16.2016