title: A Novel Compound ITC-3 Activates the Nrf2 Signaling and Provides Neuroprotection in Parkinson's Disease Models.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder accompanied by a selective loss of the dopamine(DA)ergic neurons residing in the substantia nigra. There is ample evidence that neuroinflammation and oxidative stress are involved in the pathogenesis of PD. In the present study, we aimed at protecting the DAergic neurons by suppressing these cellular events and generated a novel synthetic isothiocyanate ITC-3. The compound led to elevation of nuclear and total levels of the transcription factor Nrf2 and interacted with its binding protein Keap1 with high affinity, suggesting Nrf2 activation. ITC-3 was able to suppress production of the proinflammatory mediators in lipopolysaccharide-activated BV-2 microglial cells. It also increased mRNA and protein levels of the Nrf2-dependent antioxidant enzymes NAD(P)H quinone oxidoreductase, heme oxygenase-1, and glutamylcysteine ligase in both BV-2 and DAergic neuronal CATH.a cells. The compound protected the DAergic cells against oxidative stress. In vivo, ITC-3 attenuated the loss of tyrosine hydroxylase-immunopositive nigrostriatal DAergic neurons, suppressed microglial activation, and abolished PD-associated motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-elicited animal model of PD. Taken together, ITC-3 may be useful toward development of neuroprotective therapy for PD.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea.
authors.forename: Ji Ae
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 136-791, South Korea.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea.
authors.forename: Se Hee
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea.
authors.forename: Nari
authors.initials: N
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea.
authors.forename: Hye Ri
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 136-791, South Korea.
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 138-736, South Korea. oyhwang@amc.seoul.kr.
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D017879:Isothiocyanates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; C471550:Gcl protein, mouse; D018836:Inflammation Mediators; D017879:Isothiocyanates; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D009687:Nuclear Proteins; C037152:isothiocyanic acid; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse
keywords: Neuroinflammation; Neuroprotection; Oxidative stress; Parkinson’s disease; Substantia nigra