Presentation Abstract

Program#/Poster#: 432.09/O9
Presentation Title: Neuroprotective effects of fumarates against MPTP mouse model of Parkinson's disease
Location: Halls B-H
Presentation time: Monday, Nov 11, 2013, 1:00 PM - 2:00 PM
Topic: ++C.04.m. Neuroprotective mechanisms
Authors: L. YANG1, N. AMMAL KAIDERY1, S. TARANNUM1, N. SMIRNOVA3, M. JIN1, S. WAKADE1, J. MORGAN2, F. BEAL4, R. RATAN3, I. GAZARYAN3, *B. THOMAS1;
1Pharmacol. & Toxicology and Neurol., 2Neurol., Med. Col. of Georgia, AUGUSTA, GA; 3Burke Med. Res. Inst., White Plains, NY; 4Neurol., Weill Med. Col. of Cornell Univ., New York, NY
Abstract: There is substantial evidence from patients and from animal models that oxidative damage plays a major role in the pathogenesis of the dopaminergic neuron degeneration in Parkinson’s disease (PD). Targeting oxidative stress either by providing exogenous antioxidants or by enhancing the endogenous antioxidative capacity has been intensely investigated for PD therapies. The latter includes the activation of nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway which regulates the expression of a battery of genes encoding anti-oxidative and cytoprotective genes. Fumaric acid esters such as dimethyl and mono-methylfumarate have been found to exert neuroprotective effects by activating the Nrf2/ARE signaling pathway. We investigated in vivo pharmacokinetics, effects on Nrf2/ARE signaling both in vitro and in vivo and its ability to block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity and associated oxidative damage and inflammation in mice. We found that dimethyl and mono-methylfumarate activate Nrf2 pathway using a Neh2-luciferase reporter, assessment of mRNA and proteins levels showed upregulation of several cytoprotective and antioxidative genes in discrete mouse brain regions commensurate with its pharmacologic levels in vivo, and in wild type mouse embryonic fibroblasts but not in Nrf2 null mouse embryonic fibroblasts in vitro. Intraperitoneal administration of both dimethyl and mono-methylfumarate at (10, 25, 50, and 100mg/kg) dose dependently protected against acute MPTP (10mg/kg four times every 2 hour) -induced nigrostriatal dopaminergic neurotoxicity assessed by stereological cell counts of total and tyrosine hydroxylase positive neurons of substantia nigra and striatal levels of catecholamines employing HPLC electrochemistry. Dimethyl and mono-methylfumarate blocked against MPTP-induced oxidative damage and inflammation assessed by 3-nitrotyrosine and CD11b immunoreactivity in the nigrostriatal dopaminergic neurons. Our results suggest that fumaric acid esters protect against nigrostriatal dopaminergic neurotoxicity and associated oxidative damage and inflammation by virtue of its ability to activate neuroprotective Nrf2/ARE genetic program.
Disclosures:  L. Yang: None. N. Ammal Kaidery: None. S. Tarannum: None. N. Smirnova: None. M. Jin: None. S. Wakade: None. J. Morgan: None. F. Beal: None. R. Ratan: None. I. Gazaryan: None. B. Thomas: None.
Keyword(s): PARKINSON'S DISEASE
NEUROPROTECTION
ANTIOXIDANT
Support: NIH Grant NS06885
NIH Grant NS062165
Michael J Fox Foundation for Parkinson's disease
Parkinson's Disease Foundation




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