Nurr1-Activating Daphnane Diterpenes from Daphne genkwa and its Neuroprotective Effect in an Animal Model of Parkinson's Disease

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