title: Induction of NQO1 and Neuroprotection by a Novel Compound KMS04014 in Parkinson's Disease Models.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of the neurons containing dopamine (DA) in the substantia nigra pars compacta. Lines of evidence suggest that oxidative stress is a major factor contributing to the vulnerability of DA cells and that the enzyme NAD(P)H quinone oxidoreductase (NQO1) provides protection in these cells. In the present study, we report the synthesis of a novel compound KMS04014 and show that it induces NQO1 gene expression and protects DAergic neuronal cells in both cell culture and animal models of PD. In vitro, KMS04014 increased both mRNA and protein levels of NQO1 and induced nuclear translocation of Nrf2 in the DAergic neuronal cell line CATH.a. It also protected the cells against oxidative stress generated by tetrahydrobiopterin, 1-methyl-4-phenylpyridinium (MPP(+)), and H2O2. In vivo, KMS04014 attenuated the loss of tyrosine hydroxylase-immunopositive DAergic neurons in the substantia nigra and reduced degeneration of the nigral neurons and striatal fibers in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, an animal model of PD. Taken together, KMS04014 may be utilized toward development of neuroprotective therapy for PD.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 138-736, South Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Ji Ae
authors.initials: JA
authors.lastname: Lee
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003373:Coumaric Acids / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D020267:MPTP Poisoning / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C000605757:1,2-di(2-methoxy-4-(2-carboxyvinyl))phenoxyethane; D000975:Antioxidants; D003373:Coumaric Acids; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse