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

Corinna Urmann; Eleni Oberbauer; Sébastien Couillard-Després; Ludwig Aigner; Herbert Riepl

doi:10.1055/s-0034-1396243

Planta Medica, Table of Contents

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^*

¹Organic and Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany

,

Eleni Oberbauer^*

²Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria

,

Sébastien Couillard-Després

³Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria

,

Ludwig Aigner

²Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria

,

Herbert Riepl

¹Organic and Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany

› Author Affiliations

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

Full Text

References

References
1 Gage FH. Mammalian neural stem cells. Science 2000; 287: 1433-1438
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
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
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
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
6 Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104-9110
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
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
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
10 Alonso de Lecinana M, Egido JA. Estrogens as neuroprotectants against ischemic stroke. Cerebrovasc Dis 2006; 21 (Suppl. 02) 48-53
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
28 Andrews PW. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro . Dev Biol 1984; 103: 285-293
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
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
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
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
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
34 Wu TS. Flavonoids from root bark of Citrus sinensis and C. nobilis . Phytochem 1989; 28: 3558-3560
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
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
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
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
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
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
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
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
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

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