Chroman-like cyclic prenylflavonoids promote neuronal differentiation and neurite outgrowth and are neuroprotective.
Flavonoids target a variety of pathophysiological mechanisms and are therefore increasingly considered as compounds encompassed with therapeutic potentials in diseases such as cancer, diabetes, arteriosclerosis, and neurodegenerative diseases and mood disorders. Hops (Humulus lupulus L.) is rich in flavonoids such as the flavanone 8-prenylnaringenin, which is the most potent phytoestrogen identified so far, and the prenylchalcone xanthohumol, which has potent tumor-preventive, anti-inflammatory and antiviral activities. In the present study, we questioned whether hops-derived prenylflavonoids and synthetic derivatives thereof act on neuronal precursor cells and neuronal cell lines to induce neuronal differentiation, neurite outgrowth and neuroprotection. Therefore, mouse embryonic forebrain-derived neural precursors and Neuro2a neuroblastoma-derived cells were stimulated with the prenylflavonoids of interest, and their potential to activate the promoter of the neuronal fate-specific doublecortin gene and to stimulate neuronal differentiation and neurite outgrowth was analyzed. In this screening, we identified highly "neuroactive" compounds, which we termed "enhancement of neuronal differentiation factors" (ENDFs). The most potent molecule, ENDF1, was demonstrated to promote neuronal differentiation of neural stem cells and neurite outgrowth of cultured dorsal root ganglion neurons and protected neuronal PC12 cells from cobalt chloride-induced as well as cholinergic neurons of the nucleus basalis of Meynert from deafferentation-induced cell death. The results indicate that hops-derived prenylflavonoids such as ENDFs might be powerful molecules to promote neurogenesis, neuroregeneration and neuroprotection in cases of chronic neurodegenerative diseases, acute brain and spinal cord lesion and age-associated cognitive impairments.
Institute of Molecular Regenerative Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria.
Eleni
E
Oberbauer
Corinna
C
Urmann
Carolin
C
Steffenhagen
Lara
L
Bieler
Doris
D
Brunner
Tanja
T
Furtner
Christian
C
Humpel
Bastian
B
Bäumer
Christine
C
Bandtlow
Sebastien
S
Couillard-Despres
Francisco J
FJ
Rivera
Herbert
H
Riepl
Ludwig
L
Aigner
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002642:Chick Embryo; D002839:Chromans / Q000494:pharmacology*; D003035:Cobalt / Q000633:toxicity; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects*; D016501:Neurites / Q000502:physiology*; D055495:Neurogenesis; D009479:Neuropeptides / Q000378:metabolism; D016716:PC12 Cells; D011427:Propiophenones / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured
C119737:8-prenylnaringenin; D002839:Chromans; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D044950:Flavanones; D005419:Flavonoids; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D011427:Propiophenones; D003035:Cobalt; C018021:cobaltous chloride; C104536:xanthohumol
Doublecortin; Humulus lupulus L; NGF; Neural stem cells; Neurite outgrowth; Neuroprotection; Prenylflavonoids; Retinoic acid; Xanthohumol