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.
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.



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.
Departments of Pharmacology and Toxicology.
Manuj
0000-0002-4846-8249
M
Ahuja
Departments of Pharmacology and Toxicology.
Navneet
N
Ammal Kaidery
Departments of Pharmacology and Toxicology, Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065, Kunming Biomed International, Yunnan, China 650500.
Lichuan
L
Yang
Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065.
Noel
N
Calingasan
Burke Cornell Medical Center, White Plains, New York 10605, D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia.
Natalya
N
Smirnova
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208.
Arsen
A
Gaisin
College of Pharmacy, University of Illinois, Illinois, Chicago 60612.
Irina N
IN
Gaisina
Burke Cornell Medical Center, White Plains, New York 10605, Department of Chemistry and Physical Sciences, Pace University, Pleasantville, New York 10570.
Irina
I
Gazaryan
Department of Chemistry, Moscow State University, 119991 Moscow, Russia, and Valenta Pharm, 119530 Moscow, Russia.
Dmitry M
DM
Hushpulian
Physiology, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912.
Ismail
I
Kaddour-Djebbar
Physiology, Oral Biology, and Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912.
Wendy B
WB
Bollag
Neurology, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912.
John C
JC
Morgan
Burke Cornell Medical Center, White Plains, New York 10605.
Rajiv R
0000-0002-9081-2701
RR
Ratan
Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065.
Anatoly A
0000-0002-1334-4828
AA
Starkov
Brain and Mind Research Institute Weill Cornell Medicine, Cornell University, New York, New York 10065.
M Flint
MF
Beal
Departments of Pharmacology and Toxicology, Neurology, bthomas1@augusta.edu.
Bobby
B
Thomas
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D015703:Antigens, CD; D005650:Fumarates; D008298:Maleates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; C073341:citraconic acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MPTP; Nrf2; fumarates; inflammation; mitochondria; oxidative stress