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Articles, Neurobiology of Disease

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 and Bobby Thomas
Journal of Neuroscience 8 June 2016, 36 (23) 6332-6351; DOI: https://doi.org/10.1523/JNEUROSCI.0426-16.2016
Manuj Ahuja
1Departments of Pharmacology and Toxicology,
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Navneet Ammal Kaidery
1Departments of Pharmacology and Toxicology,
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Lichuan Yang
1Departments of Pharmacology and Toxicology,
7Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065,
12Kunming Biomed International, Yunnan, China 650500,
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Noel Calingasan
7Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065,
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Natalya Smirnova
8Burke Cornell Medical Center, White Plains, New York 10605,
9D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia,
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Arsen Gaisin
10Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208,
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Irina N. Gaisina
11College of Pharmacy, University of Illinois, Illinois, Chicago 60612,
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Irina Gazaryan
8Burke Cornell Medical Center, White Plains, New York 10605,
13Department of Chemistry and Physical Sciences, Pace University, Pleasantville, New York 10570,
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Dmitry M. Hushpulian
14Department of Chemistry, Moscow State University, 119991 Moscow, Russia, and
15Valenta Pharm, 119530 Moscow, Russia
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Ismail Kaddour-Djebbar
3Physiology,
6Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912,
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Wendy B. Bollag
3Physiology,
4Oral Biology, and
5Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912,
6Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912,
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John C. Morgan
2Neurology,
6Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912,
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Rajiv R. Ratan
8Burke Cornell Medical Center, White Plains, New York 10605,
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Anatoly A. Starkov
7Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065,
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M. Flint Beal
7Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065,
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Bobby Thomas
1Departments of Pharmacology and Toxicology,
2Neurology,
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Abstract

A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element 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.

SIGNIFICANCE STATEMENT Almost two centuries since its first description by James Parkinson, Parkinson's disease (PD) remains an incurable disease with limited symptomatic treatment. The current study provides preclinical evidence that a Food and Drug Administration-approved drug, dimethylfumarate (DMF), and its metabolite monomethylfumarate (MMF) can block nigrostriatal dopaminergic neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD. We elucidated mechanisms by which DMF and its active metabolite MMF activates the redox-sensitive transcription factor nuclear-factor-E2-related factor 2 (Nrf2) to upregulate antioxidant, anti-inflammatory, mitochondrial biosynthetic and cytoprotective genes to render neuroprotection via distinct S-alkylating properties and depletion of glutathione. Our data suggest that targeting Nrf2-mediated gene transcription using MMF rather than DMF is a promising approach to block oxidative stress, neuroinflammation, and mitochondrial dysfunction for therapeutic intervention in PD while minimizing side effects.

  • fumarates
  • inflammation
  • mitochondria
  • MPTP
  • Nrf2
  • oxidative stress
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The Journal of Neuroscience: 36 (23)
Journal of Neuroscience
Vol. 36, Issue 23
8 Jun 2016
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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
Journal of Neuroscience 8 June 2016, 36 (23) 6332-6351; DOI: 10.1523/JNEUROSCI.0426-16.2016

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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
Journal of Neuroscience 8 June 2016, 36 (23) 6332-6351; DOI: 10.1523/JNEUROSCI.0426-16.2016
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Keywords

  • fumarates
  • inflammation
  • mitochondria
  • MPTP
  • Nrf2
  • oxidative stress

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