title: Daphnane Diterpenes from Daphne genkwa Activate Nurr1 and Have a Neuroprotective Effect in an Animal Model of Parkinson's Disease.
abstract: Nurr1 is an orphan nuclear receptor that is essential for the differentiation and maintenance of dopaminergic neurons in the brain, and it is a therapeutic target for Parkinson's disease (PD). During the screening for Nurr1 activators from natural sources using cell-based assay systems, a methanol extract of the combined stems and roots of Daphne genkwa was found to activate the transcriptional function of Nurr1 at a concentration of 3 μg/mL. The active components were isolated and identified as genkwanine N (1) and yuanhuacin (2). Both compounds 1 and 2 significantly enhanced the function of Nurr1 at 0.3 μM. Nurr1-specific siRNA abolished the activity of 1 and 2, strongly suggesting that transcriptional activation by 1 and 2 occurred through the modulation of Nurr1 function. Additionally, treatment with 1 and 2 inhibited 6-hydroxydopamine (6-OHDA)-induced neuronal cell death and lipopolysaccharide (LPS)-induced neuroinflammation. Moreover, in a 6-OHDA-lesioned rat model of PD, intraperitoneal administration of 2 (0.5 mg/kg/day) for 2 weeks significantly improved behavioral deficits and reduced tyrosine hydroxylase (TH)-positive dopaminergic neuron death induced by 6-OHDA injection and had a beneficial effect on the inflammatory response in the brain. Accordingly, compounds 1 and 2, the first reported Nurr1 activators of natural origin, are potential lead compounds for the treatment of PD.
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Baek-Soo
authors.initials: BS
authors.lastname: Han
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Superbacteria Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Hoe-Yune
authors.initials: HY
authors.lastname: Jung
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kang
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Kyu-Suk
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Superbacteria Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Sohn
authors.affiliation: Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School , Belmont, Massachusetts 02478, United States.|Paean Biotechnology Inc., Daejeon 34031, Republic of Korea.
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School , Belmont, Massachusetts 02478, United States.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Superbacteria Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Republic of Korea.
authors.forename: Won-Gon
authors.initials: WG
authors.lastname: Kim
mesh_terms: D000818:Animals; D032364:Daphne / Q000737:chemistry*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy*; D018517:Plant Roots / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D056910:Republic of Korea; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D004224:Diterpenes; D018696:Neuroprotective Agents; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C011309:mezerein; C029912:Yuanhuacin; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine