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Daphnane Diterpenes from Daphne genkwa Activate Nurr1 and Have a Neuroprotective Effect in an Animal Model of Parkinson’s Disease

Author:
Han, Baek-Soo, Kim, Kyoung-Shim, Kim, Yu Jin, Jung, Hoe-Yune, Kang, Young-Mi, Lee, Kyu-Suk, Sohn, Mi-Jin, Kim, Chun-Hyung, Kim, Kwang-Soo, Kim, Won-Gon
Source:
Journal of natural products 2016 v.79 no.6 pp. 1604-1609
ISSN:
1520-6025
Subject:
Daphne genkwa, Parkinson disease, animal models, brain, cell death, death, diterpenoids, inflammation, intraperitoneal injection, lipopolysaccharides, methanol, neurons, neuroprotective effect, roots, screening, small interfering RNA, stems, transcription (genetics), transcriptional activation, tyrosine 3-monooxygenase
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.
Agid:
5498548