Aqueous Extract of Pomegranate Alone or in Combination with Citalopram Produces Antidepressant-Like Effects in an Animal Model of Menopause: Participation of Estrogen Receptors

Brenda Valdés-Sustaita, Carolina López-Rubalcava, María Eva González-Trujano, Cristina García-Viguera, Erika Estrada-Camarena, Brenda Valdés-Sustaita, Carolina López-Rubalcava, María Eva González-Trujano, Cristina García-Viguera, Erika Estrada-Camarena

Abstract

It has been reported that the aqueous extract of pomegranate (AE-PG) has polyphenols with estrogenic-like activities. The present work determines if AE-PG alone or in combination with the selective serotonin reuptake inhibitor, citalopram, has antidepressant-like effects. It was also analyzed the participation of estrogen receptors (ER). AE-PG (0.1, 1.0, 10, or 100 mg/kg) was evaluated in ovariectomized female Wistar rats subjected to the forced swimming test. The effects induced by AE-PG were compared with those of citalopram (2.5, 5.0, 10, and 20.0 mg/kg) and 17β-estradiol (E2; 2.5 5.0, and 10 μg/rat). Likewise, the combination of suboptimal doses of AE-PG (0.1 mg/kg) plus citalopram (2.5 mg/kg) was evaluated. To determine if ER participates in the antidepressant-like action of pomegranate, the estrogen antagonist tamoxifen (15 mg/kg) was administered with AE-PG (1 mg/kg). AE-PG produced antidepressant-like actions with a similar behavioral profile induced by citalopram and E2. Suboptimal doses of citalopram plus AE-PG produced antidepressant-like effects. Tamoxifen was able to block AE-PG's antidepressant-like actions. These results confirm the participation of ER in AE-PG's antidepressant-like effects. Furthermore, the additive effects observed with the combined treatment of AE-PG plus citalopram could be advantageous in the treatment of depressive disorders, such as menopause.

Keywords: antidepressant-like action; citalopram; estrogen receptors; ovariectomy; polyphenols; pomegranate fruit.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Behavioral effects produced by the chronic administration (14 days; one administration per day) of the AE-PG (panel (a); n = 7–9 per dose), E2 (panel (b); n = 7–8 per dose), and citalopram (panel (c); n = 8–10 per dose) on the forced swimming test. The figure shows the mean number of counts ± standard error. Dunnett post hoc: * p < 0.05; *** p < 0.001 versus the control group. AE-PG = aqueous extract of pomegranate; E2 = 17β-estradiol.
Figure 2
Figure 2
Behavioral effects of the chronic administration (14 days; one administration per day) of the minimum effective dose of the AE-PG (1.0 mg/kg) with Tmx (15 mg/kg) on the forced swimming test. The figure shows the number of counts ± standard error (n = 6–7 animals per dose). Tukey post hoc: * p < 0.05; *** p < 0.001 versus the corn oil + saline group; ###p < 0.001 versus the AE-PG + corn oil group. AE-PG = aqueous extract of pomegranate; Tmx = Tamoxifen.
Figure 3
Figure 3
Behavioral effects of the simultaneous administration of the suboptimal dose of the AE-PG (0.1 mg/kg) plus the suboptimal dose of the citalopram (2.5 mg/kg) (chronic administration for 14 days; one administration per day) on the forced swimming test. Shown are the mean number of counts ± standard error (n = 10 animals per dose). Tukey post hoc: *** p < 0.001 versus the control group; &&& versus the suboptimal doses groups. AE-PG = aqueous extract of pomegranate.

References

    1. Viladomiu M., Hontecillas R., Lu P., Bassaganya-Riera J. Preventive and prophylactic mechanisms of action of pomegranate bioactive constituents. Evid. Based Complement. Alternat. Med. 2013;2013:789764. doi: 10.1155/2013/789764.
    1. Zhang L.H., Fu Q.J., Zhang Y.H. Composition of anthocyanins in pomegranate flowers and their antioxidant activity. Food Chem. 2011;127:1444–1449. doi: 10.1016/j.foodchem.2011.01.077.
    1. Al-Muammar M.N., Khan F. Obesity: The preventive role of the pomegranate (Punica granatum) Nutrition. 2012;28:595–604. doi: 10.1016/j.nut.2011.11.013.
    1. Gonzalez-Trujano M.E., Pellicer F., Mena P., Moreno D.A., Garcia-Viguera C. Antinociceptive and anti-inflammatory activities of a pomegranate (Punica granatum L.) extract rich in ellagitannins. Int. J. Food Sci. Nutr. 2015;66:395–399. doi: 10.3109/09637486.2015.1024208.
    1. Yuan T., Ma H., Liu W., Niesen D.B., Shah N., Crews R., Rose K.N., Vattem D.A., Seeram N.P. Pomegranate’s Neuroprotective Effects against Alzheimer’s Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites. ACS Chem. Neurosci. 2016;7:26–33. doi: 10.1021/acschemneuro.5b00260.
    1. Viuda-Martos M., Fernandez-Lopez J., Perez-Alvarez J.A. Pomegranate and its Many Functional Components as Related to Human Health: A Review. Compr. Rev. Food Sci. Food Saf. 2010;9:635–654. doi: 10.1111/j.1541-4337.2010.00131.x.
    1. Choi D.W., Kim J.Y., Choi S.H., Jung H.S., Kim H.J., Cho S.Y., Kang C.S., Chang S.Y. Identification of steroid hormones in pomegranate (Punica granatum) using HPLC and GC-mass spectrometry. Food Chem. 2006;96:562–571. doi: 10.1016/j.foodchem.2005.03.010.
    1. Mori-Okamoto J., Otawara-Hamamoto Y., Yamato H., Yoshimura H. Pomegranate extract improves a depressive state and bone properties in menopausal syndrome model ovariectomized mice. J. Ethnopharmacol. 2004;92:93–101. doi: 10.1016/j.jep.2004.02.006.
    1. Van Elswijk D.A., Schobel U.P., Lansky E.P., Irth H., van der Greef J. Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry. 2004;65:233–241. doi: 10.1016/j.phytochem.2003.07.001.
    1. Landete J.M. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Res. Int. 2011;44:1150–1160. doi: 10.1016/j.foodres.2011.04.027.
    1. Larrosa M., Gonzalez-Sarrias A., Garcia-Conesa M.T., Tomas-Barberan F.A., Espin J.C. Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. J. Agric. Food Chem. 2006;54:1611–1620. doi: 10.1021/jf0527403.
    1. Espin J.C., Larrosa M., Garcia-Conesa M.T., Tomas-Barberan F. Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: The evidence so far. Evid. Based Complement. Alternat. Med. 2013;2013:270418. doi: 10.1155/2013/270418.
    1. Heftmann E., Ko S.T., Bennett R.D. Identification of Estrone in Pomegranate Seeds. Phytochemistry. 1966;5:1337–1339. doi: 10.1016/S0031-9422(00)86133-6.
    1. Handley A.P., Williams M. The efficacy and tolerability of SSRI/SNRIs in the treatment of vasomotor symptoms in menopausal women: A systematic review. J. Am. Assoc. Nurse Pract. 2015;27:54–61. doi: 10.1002/2327-6924.12137.
    1. Roberts H., Hickey M. Managing the menopause: An update. Maturitas. 2016;86:53–58. doi: 10.1016/j.maturitas.2016.01.007.
    1. Lethaby A., Marjoribanks J., Kronenberg F., Roberts H., Eden J., Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst. Rev. 2013 doi: 10.1002/14651858.CD001395.pub4.
    1. Shuid A.N., Mohamed I.N. Pomegranate Use to Attenuate Bone Loss in Major Musculoskeletal Diseases: An Evidence-Based Review. Curr. Drug Targets. 2013;14:1565–1578. doi: 10.2174/1389450114666131108155039.
    1. Auerbach L., Rakus J., Bauer C., Gerner C., Ullmann R., Wimmer H., Huber J. Pomegranate seed oil in women with menopausal symptoms: A prospective randomized, placebo-controlled, double-blinded trial. Menopause. 2012;19:426–432. doi: 10.1097/gme.0b013e3182345b2f.
    1. Spilmont M., Leotoing L., Davicco M.J., Lebecque P., Mercier S., Miot-Noirault E., Pilet P., Rios L., Wittrant Y., Coxam V. Pomegranate seed oil prevents bone loss in a mice model of osteoporosis, through osteoblastic stimulation, osteoclastic inhibition and decreased inflammatory status. J. Nutr. Biochem. 2013;24:1840–1848. doi: 10.1016/j.jnutbio.2013.04.005.
    1. Naveen S., Siddalingaswamy M., Singsit D., Khanum F. Anti-depressive effect of polyphenols and omega-3 fatty acid from pomegranate peel and flax seed in mice exposed to chronic mild stress. Psychiatry Clin. Neurosci. 2013;67:501–508. doi: 10.1111/pcn.12100.
    1. Ramirez-Rodriguez G., Vega-Rivera N.M., Oikawa-Sala J., Gomez-Sanchez A., Ortiz-Lopez L., Estrada-Camarena E. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice. J. Pineal Res. 2014;56:450–461. doi: 10.1111/jpi.12136.
    1. Estrada-Camarena E., Fernandez-Guasti A., Lopez-Rubalcava C. Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology. 2003;28:830–838. doi: 10.1038/sj.npp.1300097.
    1. Estrada-Camarena E., Fernandez-Guasti A., Lopez-Rubalcava C. Interaction between estrogens and antidepressants in the forced swimming test in rats. Psychopharmacology. 2004;173:139–145. doi: 10.1007/s00213-003-1707-4.
    1. Cryan J.F., Valentino R.J., Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci. Biobehav. Rev. 2005;29:547–569. doi: 10.1016/j.neubiorev.2005.03.008.
    1. Rygula R., Abumaria N., Flugge G., Fuchs E., Ruther E., Havemann-Reinecke U. Anhedonia and motivational deficits in rats: Impact of chronic social stress. Behav. Brain Res. 2005;162:127–134. doi: 10.1016/j.bbr.2005.03.009.
    1. Bogdanova O.V., Kanekar S., D’Anci K.E., Renshaw P.F. Factors influencing behavior in the forced swim test. Physiol. Behav. 2013;118:227–239. doi: 10.1016/j.physbeh.2013.05.012.
    1. Reneric J.P., Lucki I. Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacology. 1998;136:190–197.
    1. Detke M.J., Lucki I. Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: The effects of water depth. Behav. Brain Res. 1996;73:43–46. doi: 10.1016/0166-4328(96)00067-8.
    1. Chaki S., Yoshikawa R., Hirota S., Shimazaki T., Maeda M., Kawashima N., Yoshimizu T., Yasuhara A., Sakagami K., Okuyama S., et al. MGS0039: A potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology. 2004;46:457–467. doi: 10.1016/j.neuropharm.2003.10.009.
    1. Reneric J.P., Bouvard M., Stinus L. In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed. Eur. Neuropsychopharm. 2002;12:159–171. doi: 10.1016/S0924-977X(02)00007-X.
    1. Estrada-Camarena E., Fernandez-Guasti A., Lopez-Rubalcava C. Participation of the 5-HT1A receptor in the antidepressant-like effect of estrogens in the forced swimming test. Neuropsychopharmacology. 2006;31:247–255. doi: 10.1038/sj.npp.1300821.
    1. Mondragon-Jacobo C., Hernandez-Herrera G., Guzman-Maldonado S.H. Agronomical, Physicochemical, and Functional Characterization of Mexican Pomegranates as Compared to Wonderful Pomegranate. Acta Hortic. 2015;1089:299–306. doi: 10.17660/ActaHortic.2015.1089.39.
    1. Girish C., Raj V., Arya J., Balakrishnan S. Evidence for the involvement of the monoaminergic system, but not the opioid system in the antidepressant-like activity of ellagic acid in mice. Eur. J. Pharmacol. 2012;682:118–125. doi: 10.1016/j.ejphar.2012.02.034.
    1. Dellafiora L., Mena P., Cozzini P., Brighenti F., del Rio D. Modelling the possible bioactivity of ellagitannin-derived metabolites. In silico tools to evaluate their potential xenoestrogenic behavior. Food Funct. 2013;4:1442–1451. doi: 10.1039/c3fo60117j.
    1. Walf A.A., Rhodes M.E., Frye C.A. Antidepressant effects of ERβ-selective estrogen receptor modulators in the forced swim test. Pharmacol. Biochem. Behav. 2004;78:523–529. doi: 10.1016/j.pbb.2004.03.023.
    1. Wu Z.M., Ni G.L., Shao A.M., Cui R. Genistein alleviates anxiety-like behaviors in post-traumatic stress disorder model through enhancing serotonergic transmission in the amygdala. Psychiatry Res. 2017;255:287–291. doi: 10.1016/j.psychres.2017.05.051.
    1. Hu P., Ma L., Wang Y.G., Ye F., Wang C., Zhou W.H., Zhao X. Genistein, a dietary soy isoflavone, exerts antidepressant-like effects in mice: Involvement of serotonergic system. Neurochem. Int. 2017;108:426–435. doi: 10.1016/j.neuint.2017.06.002.
    1. Creech R.D., Li Q., Carrasco G.A., Van de Kar L.D., Muma N.A. Estradiol induces partial desensitization of serotonin 1A receptor signaling in the paraventricular nucleus of the hypothalamus and alters expression and interaction of RGSZ1 and G alpha z. Neuropharmacology. 2012;62:2040–2049. doi: 10.1016/j.neuropharm.2012.01.001.
    1. López-Rubalcava C., Vega-Rivera N.M., Páez-Martínez N., Estrada-Camarena E. Participation of the Monoaminergic System in the Antidepressant-Like Actions of Estrogens: A Review in Preclinical Studies. In: Ru-Bans L., editor. Effects of Antidepressants. InTech; London, UK: 2012.
    1. Lemini C., Cruz-Lopez B., Martinez-Mota L. Participation of estrogen receptors in the antidepressant-like effect of prolame on the forced swimming test. Pharmacol. Biochem. Behav. 2013;103:659–665. doi: 10.1016/j.pbb.2012.11.004.
    1. Vega Rivera N.M., Tenorio A.G., Fernandez-Guasti A., Estrada-Camarena E. The Post-Ovariectomy Interval Affects the Antidepressant-Like Action of Citalopram Combined with Ethynyl-Estradiol in the Forced Swim Test in Middle Aged Rats. Pharmaceuticals. 2016;9 doi: 10.3390/ph9020021.
    1. Flores-Serrano A.G., Vila-Luna M.L., Alvarez-Cervera F.J., Heredia-Lopez F.J., Gongora-Alfaro J.L., Pineda J.C. Clinical doses of citalopram or reboxetine differentially modulate passive and active behaviors of female Wistar rats with high or low immobility time in the forced swimming test. Pharmacol. Biochem. Behav. 2013;110:89–97. doi: 10.1016/j.pbb.2013.06.003.
    1. Kusmider M., Solich J., Palach P., Dziedzicka-Wasylewska M. Effect of citalopram in the modified forced swim test in rats. Pharmacol. Rep. 2007;59:785–788.
    1. Brosen K., Naranjo C.A. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur. Neuropsychopharm. 2001;11:275–283. doi: 10.1016/S0924-977X(01)00101-8.
    1. Duda-Chodak A., Tarko T., Satora P., Sroka P. Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: A review. Eur. J. Nutr. 2015;54:325–341. doi: 10.1007/s00394-015-0852-y.
    1. Garcia-Munoz C., Vaillant F. Metabolic Fate of Ellagitannins: Implications for Health, and Research Perspectives for Innovative Functional Foods. Crit. Rev. Food Sci. 2014;54:1584–1598. doi: 10.1080/10408398.2011.644643.
    1. Basheer L., Kerem Z. Interactions between CYP3A4 and Dietary Polyphenols. Oxid. Med. Cell. Longev. 2015;2015:854015. doi: 10.1155/2015/854015.
    1. Ahn D., Putt D., Kresty L., Stoner G.D., Fromm D., Hollenberg P.F. The effects of dietary ellagic acid on rat hepatic and esophageal mucosal cytochromes P450 and phase II enzymes. Carcinogenesis. 1996;17:821–828. doi: 10.1093/carcin/17.4.821.
    1. Recamier-Carballo S., Estrada-Camarena E., Reyes R., Fernandez-Guasti A. Synergistic effect of estradiol and fluoxetine in young adult and middle-aged female rats in two models of experimental depression. Behav. Brain Res. 2012;233:351–358. doi: 10.1016/j.bbr.2012.05.034.
    1. Tam L.W., Parry B.L. Does estrogen enhance the antidepressant effects of fluoxetine? J. Affect. Disord. 2003;77:87–92.
    1. Soares C.N., Poitras J.R., Prouty J., Alexander A.B., Shifren J.L., Cohen L.S. Efficacy of citalopram as a monotherapy or as an adjunctive treatment to estrogen therapy for perimenopausal and postmenopausal women with depression and vasomotor symptoms. J. Clin. Psychiat. 2003;64:473–479. doi: 10.4088/JCP.v64n0419.
    1. Contreras C.M., Rodríguez-Landa J.F., Gutiérrez-García A.G. The lowest effective dose of fluoxetine in the forced swim test significantly affects the firing rate of lateral septal nucleus neurons in the rat. J. Psychopharmacol. 2001;15:231–236. doi: 10.1177/026988110101500401.
    1. Mostalac-Preciado C.R., de Gortari P., López-Rubalcava C. Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in th elateral septum: Interactions with the serotonergic system. Behav. Brain Res. 2011;223:88–98. doi: 10.1016/j.bbr.2011.04.008.
    1. Vega-Rivera N.M., Fernández-Guasti A., Ramírez-Rodríguez G., Estrada-Camarena E. Acute stress further decreases the effect of ovariectomy on immobility behavior and hippocampal cell survival in rats. Psychoneuroendocrinology. 2013;38:1407–1417. doi: 10.1016/j.psyneuen.2012.12.008.
    1. Detke M.J., Rickels M., Lucki I. Active Behaviors in the Rat Forced Swimming Test Differentially Produced by Serotonergic and Noradrenergic Antidepressants. Psychopharmacology. 1995;121:66–72. doi: 10.1007/BF02245592.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться