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Planta Med 2015; 81(04): 305-311
DOI: 10.1055/s-0034-1396243
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Neurodifferentiating Potential of 8-Prenylnaringenin and Related Compounds in Neural Precursor Cells and Correlation with Estrogen-Like Activity

Corinna Urmann   *
1   Organic and Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany
,
Eleni Oberbauer   *
2   Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
,
Sébastien Couillard-Després
3   Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
,
Ludwig Aigner
2   Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
,
Herbert Riepl
1   Organic and Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany
› Author Affiliations
Further Information

Publication History

received 17 December 2013
revised 31 October 2014

accepted 06 January 2015

Publication Date:
25 February 2015 (online)

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Abstract

Neurodegenerative diseases are an increasing burden for our ageing societies; there is an as yet unmet need for the development of effective therapies. Neurogenesis, i.e., the generation of new neurons in the adult brain from neural stem cells, has received increasing attention since it offers the potential for endogenous brain repair and functional regeneration. Adult neurogenesis is partially under the control of sex hormones such as estradiol, and boosting neurogenesis with estradiol in animals correlates with cognitive improvement. 8-Prenylnaringenin imitates as highly potent phytoestrogen the effects of estradiol. Here, we studied the potential of 8-prenylnaringenin, 6-prenylnaringenin, and related compounds on differentiation induction in vitro using neural precursor cells transiently transfected with a doublecortin promoter luciferase construct, which was recently shown to indicate neuronal fate and differentiation. The flavanones 8-prenylnaringenin and 6-prenylnaringenin showed slight activity in this assay but significant activity by immunostaining. Although the estrogen-like activities of 8-prenylnaringenin and 6-prenylnaringenin are very different, the activity in differentiation induction is similar. Interestingly, also some prenylflavonoids with extended prenyl groups, e.g., a geranyl group, showed increased differentiation activity, while estrogen-like activity is decreased. This allows the conclusion that estrogen-like activity of prenylflavanones does not correlate directly with the activity of differentiation induction in neural precursor cells.

Key words

Humulus lupulus - Cannabaceae - 8-prenylnaringenin - neurogenesis - prenylflavonoids - doublecortin - neural stem cells

* These authors contributed equally to this work.


Supporting Information

 

  • References

  • 1 Gage FH. Mammalian neural stem cells. Science 2000; 287: 1433-1438
    CrossrefPubMedGoogle Scholar
  • 2 Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci U S A 1992; 89: 8591-8595
    CrossrefPubMedGoogle Scholar
  • 3 Kirschenbaum B, Nedergaard M, Preuss A, Barami K, Fraser RA, Goldman SA. In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain. Cereb Cortex 1994; 4: 576-589
    CrossrefPubMedGoogle Scholar
  • 4 Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4: 1313-1317
    CrossrefPubMedGoogle Scholar
  • 5 Pincus DW, Keyoung HM, Harrison-Restelli C, Goodman RR, Fraser RA, Edgar M, Sakakibara S, Okano H, Nedergaard M, Goldman SA. Fibroblast growth factor-2/brain-derived neurotrophic factor-associated maturation of new neurons generated from adult human subependymal cells. Ann Neurol 1998; 43: 576-585
    CrossrefPubMedGoogle Scholar
  • 6 Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104-9110
    PubMedGoogle Scholar
  • 7 van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature 2002; 415: 1030-1034
    CrossrefPubMedGoogle Scholar
  • 8 Banasr M, Hery M, Brezun JM, Daszuta A. Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus. Eur J Neurosci 2001; 14: 1417-1424
    CrossrefPubMedGoogle Scholar
  • 9 Tanapat P, Hastings NB, Reeves AJ, Gould E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci 1999; 19: 5792-5801
    PubMedGoogle Scholar
  • 10 Alonso de Lecinana M, Egido JA. Estrogens as neuroprotectants against ischemic stroke. Cerebrovasc Dis 2006; 21 (Suppl. 02) 48-53
    CrossrefPubMedGoogle Scholar
  • 11 Kitaoka M, Kadokawa H, Sugano M, Ichikawa K, Taki M, Takaishi S, Iijima Y, Tsutsumi S, Boriboon M, Akiyama T. Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 1). Isolation of 8-isopentenylnaringenin and an initial study on its structure-activity relationship. Planta Med 1998; 64: 511-515
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Milligan SR, Kalita JC, Heyerick A, Rong H, De Cooman L, De Keukeleire D. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocr Metab 1999; 84: 2249-2252
    CrossrefPubMedGoogle Scholar
  • 13 Kretzschmar G, Zierau O, Wober J, Tischer S, Metz P, Vollmer G. Prenylation has a compound specific effect on the estrogenicity of naringenin and genistein. J Steroid Biochem 2010; 118: 1-6
    PubMedGoogle Scholar
  • 14 Milligan SR, Kalita JC, Pocock V, Van De Kauter V, Stevens JF, Deinzer ML, Rong H, De Keukeleire D. The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavonoids. J Clin Endocr Metab 2000; 85: 4912-4915
    CrossrefPubMedGoogle Scholar
  • 15 Schaefer O, Humpel M, Fritzemeier KH, Bohlmann R, Schleuning WD. 8-Prenyl naringesnin is a potent ER alpha selective phytoestrogen present in hops and beer. J Steroid Biochem 2003; 84: 359-360
    PubMedGoogle Scholar
  • 16 Zierau O, Gester S, Schwab P, Metz P, Kolba S, Wulf M, Vollmer G. Estrogenic activity of the phytoestrogens naringenin, 6-(1, 1-dimethylallyl)naringenin and 8-prenylnaringenin. Planta Med 2002; 68: 449-451
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Miyamoto M, Matsushita Y, Kiyokawa A, Fukuda C, Iijima Y, Sugano M, Akiyama T. Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 2). Estrogenic effects of 8-isopentenylnaringenin on bone metabolism. Planta Med 1998; 64: 516-519
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Rad M, Humpel M, Schaefer O, Schoemaker RC, Schleuning WD, Cohen AF, Burggraaf J. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women. Br J Clin Pharmacol 2006; 62: 288-296
    CrossrefPubMedGoogle Scholar
  • 19 Sehmisch S, Hammer F, Christoffel J, Seidlova-Wuttke D, Tezval M, Wuttke W, Stuermer KM, Stuermer EK. Comparison of the phytohormones genistein, resveratrol and 8-prenylnaringenin as agents for preventing osteoporosis. Planta Med 2008; 74: 794-801
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Zierau O, Kretzschmar G, Moller F, Weigt C, Vollmer G. Time dependency of uterine effects of naringenin type phytoestrogens in vivo . Mol Cell Endocrinol 2008; 294: 92-99
    CrossrefPubMedGoogle Scholar
  • 21 Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2006; 54: 164-175
    CrossrefPubMedGoogle Scholar
  • 22 Erkkola R, Vervarcke S, Vansteelandt S, Rompotti P, De Keukeleire D, Heyerick A. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomed 2010; 17: 389-396
    CrossrefPubMedGoogle Scholar
  • 23 Christoffel J, Rimoldi G, Wuttke W. Effects of 8-prenylnaringenin on the hypothalamo-pituitary-uterine axis in rats after 3-month treatment. J Endocrinol 2006; 188: 397-405
    CrossrefPubMedGoogle Scholar
  • 24 Butterweck V, Brattstroem A, Grundmann O, Koetter U. Hypothermic effects of hops are antagonized with the competitive melatonin receptor antagonist luzindole in mice. J Pharm Pharmacol 2007; 59: 549-552
    CrossrefPubMedGoogle Scholar
  • 25 Gerhäuser C, Alt AP, Klimo K, Knauft J, Frank N, Becker H. Isolation and potential cancer chemopreventive activities of phenolic compounds of beer. Phytochem Rev 2002; 1: 369-377
    CrossrefPubMedGoogle Scholar
  • 26 Karl C, Couillard-Despres S, Prang P, Munding M, Kilb W, Brigadski T, Plotz S, Mages W, Luhmann H, Winkler J, Bogdahn U, Aigner L. Neuronal precursor-specific activity of a human doublecortin regulatory sequence. J Neurochem 2005; 92: 264-282
    CrossrefPubMedGoogle Scholar
  • 27 Possemiers S, Bolca S, Grootaert C, Heyerick A, Decroos K, Dhooge W, De Keukeleire D, Rabot S, Verstraete W, Van de Wiele T. The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine. J Nutr 2006; 136: 1862-1867
    PubMedGoogle Scholar
  • 28 Andrews PW. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro . Dev Biol 1984; 103: 285-293
    CrossrefPubMedGoogle Scholar
  • 29 McCaffery P, Dräger UC. Regulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor. Cytokine Growth Factor Rev 2000; 11: 233-249
    CrossrefPubMedGoogle Scholar
  • 30 Laeng P, Pitts RL, Lemire AL, Drabik CE, Weiner A, Tang H, Thyagarajan R, Mallon BS, Altar CA. The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem 2004; 91: 238-251
    CrossrefPubMedGoogle Scholar
  • 31 Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A 2004; 101: 16659-16664
    CrossrefPubMedGoogle Scholar
  • 32 Diller RA, Riepl HM, Rose O, Frias C, Henze G, Prokop A. Ability of prenylflavanones present in hops to induce apoptosis in a human Burkitt lymphoma cell line. Planta Med 2007; 73: 755-761
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Oberbauer E, Urmann C, Steffenhagen C, Bieler L, Brunner D, Furtner T, Humpel C, Baumer B, Bandtlow C, Couillard-Despres S, Rivera FJ, Riepl H, Aigner L. Chroman-like cyclic prenylflavonoids promote neuronal differentiation and neurite outgrowth and are neuroprotective. J Nutr Biochem 2013; 24: 1953-1962
    CrossrefPubMedGoogle Scholar
  • 34 Wu TS. Flavonoids from root bark of Citrus sinensis and C. nobilis . Phytochem 1989; 28: 3558-3560
    CrossrefPubMedGoogle Scholar
  • 35 Nikolic D, Li YM, Chadwick LR, Grubjesic S, Schwab P, Metz P, van Breemen RB. Metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus), by human liver microsomes. Drug Metab Dispos 2004; 32: 272-279
    CrossrefPubMedGoogle Scholar
  • 36 Sagara Y, Vanhnasy J, Maher P. Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation. J Neurochem 2004; 90: 1144-1155
    CrossrefPubMedGoogle Scholar
  • 37 Effenberger KE, Johnsen SA, Monroe DG, Spelsberg TC, Westendorf JJ. Regulation of osteoblastic phenotype and gene expression by hop-derived phytoestrogens. J Steroid Biochem 2005; 96: 387-399
    PubMedGoogle Scholar
  • 38 Liu RT, Zou LB, Fu JY, Lu QJ. Promotion of rat brain-derived progenitor cell neurogenesis by liquiritigenin treatment: underlying mechanisms. Neurosci Lett 2010; 481: 139-143
    CrossrefPubMedGoogle Scholar
  • 39 Nikolic D, Li Y, Chadwick LR, van Breemen RB. In vitro studies of intestinal permeability and hepatic and intestinal metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus L.). Pharmaceut Res 2006; 23: 864-872
    CrossrefPubMedGoogle Scholar
  • 40 Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med 2004; 36: 592-604
    CrossrefPubMedGoogle Scholar
  • 41 Gester S, Metz P, Zierau O, Vollmer G. An efficient synthesis of the potent phytoestrogens 8-prenylnaringenin and 6-(1, 1-dimethylallyl)naringenin by europium(III)-catalyzed Claisen rearrangement. Tetrahedron 2001; 57: 1015-1018
    CrossrefPubMedGoogle Scholar
  • 42 Tischer S, Metz P. Selective C-6 prenylation of flavonoids via europium(III)-catalyzed Clasien rearrangement and cross-metathesis. Adv Synth Catal 2007; 349: 147-151
    CrossrefPubMedGoogle Scholar
  • 43 Dyer BW, Ferrer FA, Klinedinst DK, Rodriguez R. A noncommercial dual luciferase enzyme assay system for reporter gene analysis. Anal Biochem 2000; 282: 158-161
    CrossrefPubMedGoogle Scholar