Effects of Hura crepitans and its active ingredient, daphne factor F3, on dihydrotestosterone-induced neurotrophin-4 activation and hair retardation.

Neurotrophin (NT)-4 is known to be an inducer of catagen in the hair cycle, but little is known of its role in the pathogenesis of androgenetic alopecia (AGA). We previously studied the gene expression of dermal papilla cells from AGA patients and controls and found that NT-4 was up-regulated in the AGA patients. In the present study, the etiological relationship between NT-4 and androgen, which is one of the causes of AGA, and the effect of an NT-4 inhibitor on hair growth were investigated. We established a NT-4 luciferase reporter assay system using a roughly 2-kb region upstream of the NT-4 transcriptional start site and investigated an accelerating effect of androgen on NT-4 transcription. We also screened for a NT-4 inhibitor by using the NT-4 reporter assay and evaluated the effects of NT-4 inhibitors on hair growth by using dihydrotestosterone (DHT)-implanted mice. The results show that transcriptional activity of NT-4 was accelerated by androgen, and extract of Hura crepitans L. inhibited the DHT-induced NT-4 transcriptional activation and ameliorated the retardation of hair regrowth by DHT-implanted mice. We also isolated the active ingredient in H. crepitans and found its structure to be that of 6,7-epoxy-5-hydroxyresiniferonol-14-(2,4-tetradecadienoate), i.e., daphne factor F3. These findings demonstrated that NT-4 activity accelerated by androgen might contribute to the pathogenesis of AGA and indicated that NT-4 inhibitors such as H. crepitans and daphne factor F3 might have a salutary effect on AGA.