8Prenylnaringenin was identified as potent phytoestrogen which imitates most of the effects of estradiol [1]. Endogenous hormones such as estradiol promote neurogenesis, the differentiation of neural stem cells to neurons. Estradiol is furthermore known to ameliorate general behavior in neurodegenerative processes like Parkinson's or Alzheimer's and lowers the risk of inefficient regeneration after cerebral infarction in vitro and in vivo in women [summarized in 2]. In this study it was of interest to investigate whether 8-prenylnaringenin, which is also used in hormone replacement therapy, imitates the differentiation-inducing effect of estradiol on neural adult stem cells. Furthermore, it was of interest to determine if other hop prenylflavonoids e.g. 6prenylnaringenin with almost no estrogen-like activity show a different potential to induce differentiation in vitro. Therefore an assay based on neural precursor cells transiently transfected with a doublecortin promoter construct was used, which was recently shown to indicate neuronal fate and differentiation [3]. Isomers 8prenylnaringenin (1) and 6prenylnaringenin (2) (Figure 1) showed a similar potential in differentiation induction. Furthermore, isomers seem to be less potent than positive control (retinoic and valproic acid), which was also substantiated by immunocytochemistry (Figure 2; c = 10µM). Side-chain elongation (e.g. 8-geranylnaringenin) mediated an improved differentiation activity, although estrogen-like activity was reduced. These results allow the conclusion that the neuro-differentiation activity, measured in the DCX-assay, does not correlate with the estrogen-like activity of the tested prenylflavonoids.

Diseases like Alzheimer's or Parkinson's and also ischemic incidences (“strokes”) are characterized by a loss of neurons due to cell death, resulting in functional deficits. Since the discovery of multi-potent neural stem cells (NSCs) present in the adult human brain (1), considerable interest has arisen in the possibility of regenerative therapies involving exogenous compounds to target differentiation in NSCs.

Prenylflavonoids are an interesting group of natural products with different biological effects dependent on substitution pattern. Recently we showed that certain prenylflavonoids from hops boost the formation of neurons from stem cells (1). By a structure-activity study it was revealed, that pyranoflavonoids potently induce neurogenesis and the pyrano ring is one structural characteristic of this effect.

Hops (Humulus lupulus L.) as medicinal plant is abundant in rare polyphenols. Besides so called bitter-acids important in brewing there are chalcones like xanthohumol and flavanones. Particularly 8-prenylnaringenin, a flavanone is the most prominent prenylflavanone since it is known as a very potent phytoestrogen [1]. Besides 6- or 8-prenylnaringenin, hop extracts yield a number of minor compounds related to each other by ring closure reactions, e.g. 8-prenylnaringenin is formed from desmethylxanthohumol, so are many more. The potency of hop flavonoids to induce at least growth arrest in leucemic cell cultures is nearly equipotent and remarkable [2]. The question addressed in this work was if this effect would be observed even in neuronal neoplastic cells types since hop flavonoids may cross the blood brain barrier [3]. A commercial extract is available enriched in rare prenylflavonoids and xanthohumol. It is prepared mostly from a residue of the CO2 extraction process by solvent extraction. This material was used in a process of various chromatographic techniques to purify pairs of complementary chalcones and flavanones with identical side chains. Xanthohumol and Isoxanthohumol particularly represent such a pair to get some hint of a structure activity relationship. Growth inhibitors frequently induce differentiation in highly proliferating clones. Here some hop flavonoids appeared to be distinghuished since they may have converted proliferation into differentiation.