Nurr1, an orphan nuclear receptor involved in the differentiation of dopaminergic neurons in the brain, is a new attractive target for Parkinson’s disease (PD).[1,2] During the screening for Nurr1 activators from natural sources using cell-based assay systems, an methanol extract of the combined stems and roots of Daphne genkwa was found to activate the transcriptional function of Nurr1. Eight daphnane-type diterpenes were isolated as active components from the hexane layer of the extract. The percentage of yuanhuacine (1) in the extract was highest among the diterpenes. Compound 1 and yuanhuadine most strongly enhanced the function of Nurr1. Nurr1-specific siRNA abolished the activity of 1, strongly suggesting that transcriptional activation by 1 occurred through the modulation of Nurr1 function. Additionally, treatment with 1 inhibited 6-hydroxydopamine (6-OHDA)-induced neuronal cell death and lipopolysaccharide (LPS)-induced neuroinflammation. Importantly, the ethanol extract of D. genkwa improved behavioral deficits in a 6-OHDA-lesioned rat model of PD at oral administration (100 mg/kg/day) for 2 weeks. Morever, intraperitoneal administration of 1 (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, Daphne genkwa extract and its active compounds are potential candidates for the treatment of PD.
[1] Kim CH, Han BS, Moon J, Kim DJ, Shin J, Rajan S, Nguyen QT, Sohn M, Kim WG, Han M, Jeong I, Kim KS, Lee EH, Tu Y, Naffin-Olivos JL, Park CH, Ringe D, Yoon HS, Petsko GA, Kim KS. Proc Natl Acad Sci USA 2015; 112: 8756-8761
[2] Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S, Sumi-Ichinose C, Nomura T, Metzger D, Chambon P, Lindqvist E, Larsson NG, Olson L, Bjorklund A, Ichinose H, Perlmann T. J Neurosci 2009; 29: 15923-15932