Pomegranate-derived anthocyanin regulates MORs-cAMP/CREB-BDNF pathways in opioid-dependent models and improves cognitive impairments

Norhaslinda Ridzwan, Mimie Noratiqah Jumli, Atif Amin Baig, Mohd Adzim Khalili Rohin, Norhaslinda Ridzwan, Mimie Noratiqah Jumli, Atif Amin Baig, Mohd Adzim Khalili Rohin

Abstract

Background: Pomegranate (Punica granatum) is one of the oldest known edible fruit. Recently, there has been an increased interest in this fruit as a functional food for health benefits due to its use in disease prevention and promotion of overall health wellness.

Objective: This study aims to investigate the effects of pomegranate extract for the development of non-opioid substitution therapy for in-vitro and in-vivo studies.

Materials and methods: Anthocyanin contents consisting of cyanidin 3-glucoside, diglucoside, and pelargonidin 3-glucoside, diglucoside were detected and quantified in pomegranate extract using high-performance liquid chromatography. The optimum dosage of the extract was determined based on the regulation of MORs and cAMP proteins in U-87 cells. Co-treatment of the extract with morphine was performed to evaluate its potency in reducing the concentration levels of MORs and cAMP. For animal studies, rats were divided into two major groups representing both acute and chronic morphine-induced treatments and the Morris water maze (MWM) study was employed after treatment for each rat. The rats were sacrificed after the treatments and serum samples were collected to evaluate the levels of CREB and BDNF.

Results: The results indicated that each of the anthocyanin content tested in the study was present in the pomegranate extract. Additionally, in-vitro studies using pomegranate extract treatment showed that the extract was effective in decreasing the MORs and cAMP protein levels in U-87 cells at a concentration of 0.125 mg/mL. The memory impairment based on the MWM study in rats was also subsequently improved after treatment with pomegranate extract as compared to treatment with morphine. The blood serum derived from the rats treated with pomegranate extract also showed a significant decrease in CREB level and an increase in BDNF as compared to rats treated with morphine.

Conclusion: In conclusion, this study substantiates the potency of pomegranate extract as a non-opioid substitution therapy for in-vitro and in-vivo studies.

Keywords: Brain-derived neurotropic family (BDNF); Cyclic adenosine monophosphate (cAMP); Morphine; Pomegranate; cAMP responsive element binding protein (CREB); μ-opioid receptor (MOR).

Conflict of interest statement

Conflict of interest None.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
The percentages cell viability of human Glioblastoma Multiforme cancer cells (U-87) by morphine sulfate and pomegranate extract. (a) The IC50 value of morphine sulphate was 1.60 (0.06) µg/mL. (b) The IC50 value of pomegranate extract was 0.44 (0.04) mg/mL. Data represent the mean (SD) of three independent experiments. The cell growth of treated group was standardized with untreated control group as A/A0 (%), where A is the value of A570 generated at a given concentration of extracts by MTT assay, A0 is from untreated control group.
Fig. 2
Fig. 2
Dose response study of (a) morphine on MORs; (b) morphine on cAMP; (c) pomegranate extract on MORs; (d) pomegranate extract on cAMP stimulations at 3 and 48 h. Three independent experiments were carried out and the data represent the mean (SD). Paired T-test. ∗p

Fig. 3

Co-treatment study of morphine and…

Fig. 3

Co-treatment study of morphine and pomegranate extract on (a) MORs and (b) cAMP…

Fig. 3
Co-treatment study of morphine and pomegranate extract on (a) MORs and (b) cAMP stimulations at 48 hours incubation. Data represent the mean (SD) of three independent experiments. One-way ANOVA, ∗p

Fig. 4

The MWM study on the…

Fig. 4

The MWM study on the effect of pomegranate extract according to (a) total…

Fig. 4
The MWM study on the effect of pomegranate extract according to (a) total swimming distance (cm) and (b) time latency (s) for acute and chronic morphine induced groups (n = 32). Data represent the mean (SD) of four sessions of trial each day for 4 consecutive days experiments. Paired T-test, ∗p

Fig. 5

Effects of pomegranate extract on…

Fig. 5

Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute…

Fig. 5
Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute and chronic morphine induced group treatments (n=32). Data represent the mean (SD) of three independent experiments.Paired T-test, ∗p
Similar articles
Cited by
References
    1. Caputi F.F., Lattanzio F., Carretta D., Mercatelli D., Candeletti S., Rmualdi P. Morphine and fentanyl differently affect MOP and NOP gene expression in Human Neuroblastoma SH-SY5Y cells. J Mol Neurosci. 2013;51:532–538. doi: 10.1007/s12031-013-0019-3. - DOI - PubMed
    1. Schottke D. Jones & Bartlett Learning; United States of America: 2016. Emergency medical responder: your first response in emergency care.
    1. Chartoff E.H., Connery H.S. It's MOR-e exciting than μ: crosstalk between μ-opioid receptors and glutamatergic transmission in the mesolimbic dopamine system (Review article) Front Pharmacol. 2014;5(116):1–21. doi: 10.3389/fphar.2014.00116. - DOI - PMC - PubMed
    1. Trang T., Al-Hasani R., Salvemini D., Salter M.W., Gutstein H., Cahill C.M. Pain and poppies: the good, the bad, and the ugly of opioid analgesics. J Neurosci. 2015;35:13879–13888. doi: 10.1523/jneurosci.2711-15.2015. - DOI - PMC - PubMed
    1. Gaveriaux-Ruff C. Opiate-induced analgesia: contributions from μ, delta, and kappa opioid receptors mouse mutants. Curr Pharmaceut Des. 2013;19(42):7373–7381. doi: 10.2174/138161281942140105163727. - DOI - PubMed
Show all 59 references
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI
Fig. 3
Fig. 3
Co-treatment study of morphine and pomegranate extract on (a) MORs and (b) cAMP stimulations at 48 hours incubation. Data represent the mean (SD) of three independent experiments. One-way ANOVA, ∗p

Fig. 4

The MWM study on the…

Fig. 4

The MWM study on the effect of pomegranate extract according to (a) total…

Fig. 4
The MWM study on the effect of pomegranate extract according to (a) total swimming distance (cm) and (b) time latency (s) for acute and chronic morphine induced groups (n = 32). Data represent the mean (SD) of four sessions of trial each day for 4 consecutive days experiments. Paired T-test, ∗p

Fig. 5

Effects of pomegranate extract on…

Fig. 5

Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute…

Fig. 5
Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute and chronic morphine induced group treatments (n=32). Data represent the mean (SD) of three independent experiments.Paired T-test, ∗p
Similar articles
Cited by
References
    1. Caputi F.F., Lattanzio F., Carretta D., Mercatelli D., Candeletti S., Rmualdi P. Morphine and fentanyl differently affect MOP and NOP gene expression in Human Neuroblastoma SH-SY5Y cells. J Mol Neurosci. 2013;51:532–538. doi: 10.1007/s12031-013-0019-3. - DOI - PubMed
    1. Schottke D. Jones & Bartlett Learning; United States of America: 2016. Emergency medical responder: your first response in emergency care.
    1. Chartoff E.H., Connery H.S. It's MOR-e exciting than μ: crosstalk between μ-opioid receptors and glutamatergic transmission in the mesolimbic dopamine system (Review article) Front Pharmacol. 2014;5(116):1–21. doi: 10.3389/fphar.2014.00116. - DOI - PMC - PubMed
    1. Trang T., Al-Hasani R., Salvemini D., Salter M.W., Gutstein H., Cahill C.M. Pain and poppies: the good, the bad, and the ugly of opioid analgesics. J Neurosci. 2015;35:13879–13888. doi: 10.1523/jneurosci.2711-15.2015. - DOI - PMC - PubMed
    1. Gaveriaux-Ruff C. Opiate-induced analgesia: contributions from μ, delta, and kappa opioid receptors mouse mutants. Curr Pharmaceut Des. 2013;19(42):7373–7381. doi: 10.2174/138161281942140105163727. - DOI - PubMed
Show all 59 references
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI
Fig. 4
Fig. 4
The MWM study on the effect of pomegranate extract according to (a) total swimming distance (cm) and (b) time latency (s) for acute and chronic morphine induced groups (n = 32). Data represent the mean (SD) of four sessions of trial each day for 4 consecutive days experiments. Paired T-test, ∗p

Fig. 5

Effects of pomegranate extract on…

Fig. 5

Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute…

Fig. 5
Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute and chronic morphine induced group treatments (n=32). Data represent the mean (SD) of three independent experiments.Paired T-test, ∗p
Similar articles
Cited by
References
    1. Caputi F.F., Lattanzio F., Carretta D., Mercatelli D., Candeletti S., Rmualdi P. Morphine and fentanyl differently affect MOP and NOP gene expression in Human Neuroblastoma SH-SY5Y cells. J Mol Neurosci. 2013;51:532–538. doi: 10.1007/s12031-013-0019-3. - DOI - PubMed
    1. Schottke D. Jones & Bartlett Learning; United States of America: 2016. Emergency medical responder: your first response in emergency care.
    1. Chartoff E.H., Connery H.S. It's MOR-e exciting than μ: crosstalk between μ-opioid receptors and glutamatergic transmission in the mesolimbic dopamine system (Review article) Front Pharmacol. 2014;5(116):1–21. doi: 10.3389/fphar.2014.00116. - DOI - PMC - PubMed
    1. Trang T., Al-Hasani R., Salvemini D., Salter M.W., Gutstein H., Cahill C.M. Pain and poppies: the good, the bad, and the ugly of opioid analgesics. J Neurosci. 2015;35:13879–13888. doi: 10.1523/jneurosci.2711-15.2015. - DOI - PMC - PubMed
    1. Gaveriaux-Ruff C. Opiate-induced analgesia: contributions from μ, delta, and kappa opioid receptors mouse mutants. Curr Pharmaceut Des. 2013;19(42):7373–7381. doi: 10.2174/138161281942140105163727. - DOI - PubMed
Show all 59 references
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Fig. 5
Fig. 5
Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute and chronic morphine induced group treatments (n=32). Data represent the mean (SD) of three independent experiments.Paired T-test, ∗p

References

    1. Caputi F.F., Lattanzio F., Carretta D., Mercatelli D., Candeletti S., Rmualdi P. Morphine and fentanyl differently affect MOP and NOP gene expression in Human Neuroblastoma SH-SY5Y cells. J Mol Neurosci. 2013;51:532–538. doi: 10.1007/s12031-013-0019-3.
    1. Schottke D. Jones & Bartlett Learning; United States of America: 2016. Emergency medical responder: your first response in emergency care.
    1. Chartoff E.H., Connery H.S. It's MOR-e exciting than μ: crosstalk between μ-opioid receptors and glutamatergic transmission in the mesolimbic dopamine system (Review article) Front Pharmacol. 2014;5(116):1–21. doi: 10.3389/fphar.2014.00116.
    1. Trang T., Al-Hasani R., Salvemini D., Salter M.W., Gutstein H., Cahill C.M. Pain and poppies: the good, the bad, and the ugly of opioid analgesics. J Neurosci. 2015;35:13879–13888. doi: 10.1523/jneurosci.2711-15.2015.
    1. Gaveriaux-Ruff C. Opiate-induced analgesia: contributions from μ, delta, and kappa opioid receptors mouse mutants. Curr Pharmaceut Des. 2013;19(42):7373–7381. doi: 10.2174/138161281942140105163727.
    1. Yan K., Chen Y.B., Wu J.R., Li K.D., Cui Y.L. Current rapid onset antidepressants and related animal models. Curr Pharmaceut Des. 2018;24:1–9. doi: 10.2174/1381612824666180727115222.
    1. Taylor A.M., Castonguay A., Ghogha A., Vayssiere P., Pradhan A.A., Xue L. Neuroimmune regulation of GABAergic neurons within the ventral tegmental area during withdrawal from chronic morphine. Neuropsychopharmacology. 2016;41(4):949–959. doi: 10.1038/npp.2015.221.
    1. Ghelardini C., Mannelli L.D.C., Bianchi E. The pharmacological basis of opioids. Clin Cases Miner Bone Metab. 2015;12(3):219–221. doi: 10.11138/ccmbm/2015.12.3.219.
    1. Bell J. Pharmacological maintenance treatments of opiate addiction. Br J Clin Pharmacol. 2014;77(2):253–263. doi: 10.1111/bcp.12051.
    1. Ebrahimie M., Bahmani M., Shirzad H., Rafieian-Kopaie M., Saki K. A review study on the effect of Iranian herbal medicines on opioid withdrawal syndrome. J Evid Based Integr Med. 2015:1–8. doi: 10.1177/2156587215577896.
    1. Ibrahim H.S., Ibrahim S., Iliyasu Z., Umar S.A., Mohd K.R.A. Antioxidant potential of Phoenix dactylifera Linn extract and its effects on calcium channel antagonist in the treatment of withdrawal syndrome in morphine dependent rats. Trop J Nat Prod Res. 2018;2(7):309–313. doi: 10.26538/tjnpr.
    1. Adnan L.H.M., Mohamad N., Che Mat K., Abu Bakar N.H., Hashim S.N., Mohd Shariff M.H. Attenuation of morphine-induced cAMP overshoot by thymoquinone in opioid receptor expressing cells (U87 MG) mediated by chronic morphine treatment. J Eng Appl Sci. 2018;13:8906–8911. doi: 10.3923/jeasci.2018.8906.8911.
    1. Abu Bakar N.H., Hashim S.N., Mohamad N., Husain R., Adnan L.H.M., Shariff H. Role of oxidative stress in opiate withdrawal and dependence: exploring the potential use of honey. J Appl Pharm Sci. 2015;5(12):159–161. doi: 10.7324/japs.2015.501228.
    1. Shiban M.S., Al-Otaibi M.M., Al-Zoreky N.S. Antioxidant activity of pomegranate (Punica granatum L.) fruit peels. Food Nutr Sci. 2012;3:991–996. doi: 10.4236/fns.2012.37131.
    1. Fischer U.A., Carle R., Kammerer D.R. Thermal stability of anthocyanins and colourless phenolics in pomegranate (Punica granatum L.) juices and model solutions. Food Chem. 2013;138:1800–1809. doi: 10.1016/j.foodchem.2012.10.072.
    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(6):635–654. doi: 10.1111/j.1541-4337.2010.00131.x.
    1. Zarfeshany A., Asgary S., Javanmard S.H. Potent health effects of pomegranate. Adv Biomed Res. 2014;3:100. doi: 10.4103/2277-9175.129371.
    1. Mphahlele R., Fawole O.A., Stander M.A., Opara U.L. Preharvest and postharvest factors influencing bioactive compounds in pomegranate (Punica Granatum L.) – a review. Sci Hortic. 2014;178:114–123. doi: 10.1016/j.scienta.2014.08.010.
    1. Gomez-Caravaca A.M., Verardo V., Toselli M., Sequra-Carretero A., Fernandez-Gutierrez A., Caboni M.F. Determination of the major phenolic compounds in pomegranate juices by HPLC-DAD-ESI-MS. J Agric Food Chem. 2013;61(22):5328–5337. doi: 10.1021/jf400684n.
    1. Byrne L.S., Peng J., Sarkar S., Chang S.L. Interleukin-1 β induced up-regulation on opioid receptors in the untreated and morphine-desensitized U87 MG human astrocytoma cells. J Neuroinflammation. 2012;9:1–12. doi: 10.1186/1742-2094-9-252.
    1. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1–2):55–63. doi: 10.1016/0022-1759(83)90303-4.
    1. Charan J., Kantharia N.D. How to calculate sample size in animal studies? J Pharmacol Pharmacother. 2013;4(4):303–306. doi: 10.4103/0976-500X.119726.
    1. Patel C., Dadhaniya P., Hingorani L., Soni M.G. Safety assessment of pomegranate fruit extract: acute and subchronic toxicity studies. Food Chem Toxicol. 2008;46:2728–2735. doi: 10.1016/j.fct.2008.04.035.
    1. Organization for Economic Co-operation and Development (OECD) Organization for Economic Co-operation and Development; Paris: France: 2001. OECD guidelines for acute toxicity of chemicals 420.
    1. Vorhees C.V., Williams M.T. Morris Water Maze: procedures for assessing spatial and related forms of learning and memory. Natural Protocol. 2006;1(2):848–858. doi: 10.1038/nprot.2006.116.
    1. Rezvani-Kamran A., Salehi I., Shahidi S., Zarei M., Moradkhani S., Komaki A. Effects of the hydroalcoholic extract of Rosa damascene on learning and memory in male rats consuming a high-fat diet. Pharm Biol. 2017;55(1):2065–2073. doi: 10.1080/13880209.2017.1362010.
    1. William L.S., Julie B.S., Levy K., Robertson S.A., Cistola A.M., Centonze L.A. Use of the anesthetic combination of tiletamine, zolazepam, ketamine, and xylazine for neutering feral cats. J Am Vet Med Assoc. 2002;220(10):1491–1495. doi: 10.2460/javma.2002.220.1491.
    1. Parasuraman S., Raveendran R., Kesavan R. Blood sample collection in small laboratory animals. J Pharmacol Pharmacother. 2010;1(2):87–93. doi: 10.4103/0976-500X.72350.
    1. Eisinger D.A., Ammer H., Schulz R. Chronic morphine treatment inhibits opioid receptor desensitization and internalization. J Neurosci. 2002;22:10192–10200. .
    1. Jamil M.F.A., Subki M.F.M., Lan T.M., Majid M.I.A., Adenan M.I. The effect of mitragynine on cAMP formation and mRNA expression of μ-opioid receptors mediated by chronic morphine treatment in SK-N-SH neuroblastoma cell. J Ethnopharmacol. 2013:135–143. doi: 10.1016/j.jep.2013.03.078.
    1. Sharma S.K., Klee W.A., Nirenberg M. Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc Natl Acad Sci USA. 1975;72(8):3092–3096. doi: 10.1073/pnas.72.8.3092.
    1. Zhang J., Zhang X.Y., Su H., Tao J.Y., Xie Y., Han B. Increased serum brain-derived neurotropic factor levels during opiate withdrawal. Neurosci Lett. 2014;571:61–65. doi: 10.1016/j.neulet.2014.04.048.
    1. Hasnaoui N., Jbir R., Mars M., Trifi M., Kamal-Eldin A., Melgarejo P. Organic acids, sugars and anthocyanin contents in juices of Tunisian pomegranate fruits. Int J Food Prop. 2014;14(4):741–757. doi: 10.1080/10942910903383438.
    1. Mphahlele R.R., Fawole O.A., Mokwena L.M., Opara U.L. Effect of extraction method on chemical, volatile composition and antioxidant properties of pomegranate juice. South Afr J Bot. 2016;103:135–144. doi: 10.1016/j.sajb.2015.09.015.
    1. Chen H., Yu W., Chen G., Meng S., Xiang Z., He N. Anti-nociceptive and anti-bacterial properties of anthocyanins and flavonols from fruits of black and non-black mulberries. Molecules. 2018;23(4):1–13. doi: 10.3390/molecules23010004.
    1. Saad L.B., Hwi K.K., Quah T. Evaluation of the anti-nociceptive effect of the ethanolic extract of Punica Granatum. Afr J Tradit, Complementary Altern Med. 2014;11(3):228–233. doi: 10.4314/ajtcam.v11i3.32.
    1. Ilyas E.I.I., Irawati D., Elfiza D., Nurlaela C., Jusman S.W.A., Kartinah N.T. The potency of Hibiscus Sabdariffa Linn. on decreased memory function related to the level of BDNF and CREB in hippocampus of over-trained rats. Int J Recent Sci Res. 2017;8(5):17097–17103. doi: 10.24327/ijrsr.2017.0805.0281.
    1. Subash S., Essa M.M., Al-Adawi S., Memon M.A., Manivasagam T., Akbar M. Neuro-protective effects of berry fruits on neurodegenerative diseases. Neural Regen Res. 2014;9(16):1557–1566. doi: 10.4103/1673-5374.139483.
    1. Shay J., Elbaz H.A., Kee I., Zielske S.P., Malek M.H., Huttemann M. Molecular mechanisms and therapeutic effects of (-)-epicatechin and other polyphenols in cancer, inflammation, diabetes and neurodegeneration. Oxid Med Cell Longev. 2015:181260. doi: 10.1155/2015/181260.
    1. Serohijos A.W., Yin S., Ding F., Gauthier J., Gibson D.G., Maixner W. Structural basis for μ-opioid receptor binding and activation. Structure (London, England: 1993) 2001;19(11):1683–1690. doi: 10.1016/j.str.2011.08.003.
    1. Chan K.C., Huang H.P., Ho H.H., Huang C.N., Lin M.C., Wang C.J. Mulberry polyphenols induce cell cycle arrest of vascular smooth muscle cells by inducing NO production and activating AMPK and p53. J Funct Foods. 2015;15:604–613. doi: 10.1016/j.jff.2015.03.033.
    1. Ayranci E., Erkan N. Radical scavenging capacity of methanolic Phillyrea latifolia L. extract: anthocyanin and phenolic acids composition of fruits. Molecules. 2013;18:1798–1810. doi: 10.3390/molecules18021798.
    1. Chan H.C.S., McCarthy D., Li J., Palczewski K., Yuan S. Designing safer analgesics via μ-opioid receptor pathways. Trends Pharmacol Sci. 2017;38(11):1016–1037. doi: 10.1016/j.tips.2017.08.004.
    1. Duncker S.C., Philippe D., Martin-Paschoud C., Moser M., Mercenier A., Nutten S. Nigella sativa (black cumin) seed extract alleviates symptoms of allergic diarrhea in mice, involving opioid receptors. PLoS One. 2012;7(6) doi: 10.1371/journal.pone.0039841.
    1. Khor B.S., Jamil M.F., Adenan M.I., Shu-Chien A.C. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebra fish. PLoS One. 2011;6(12):1–8. doi: 10.1371/journal.pone.0028340.
    1. Biedermann L., Mwinyi J., Scharl M., Frei P., Zeitz J., Kullak-Ublick G.A. Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis – an open pilot study. J Crohn Colitis. 2013;7:271–279. doi: 10.1016/j.crohns.2012.07.010.
    1. Spencer J.P.E. The impact of flavonoids on memory: physiological and molecular considerations. Chem Soc Rev. 2009;38:1155–1161. doi: 10.1039/b800422f.
    1. Singh M., Arseneault M., Sanderson T., Murthy V., Ramassamy C. Challenges for research on polyphenols from foods in Alzheimer's disease: bioavailability, metabolism, and cellular and molecular mechanisms. J Agric Food Chem. 2008;56:4855–4873. doi: 10.1021/jf0735073.
    1. Nettiksimmons J., Decarli C., Landau S., Beckett L. Biological heterogeneity in Alzheimer's Disease Neuroimaging Initiative (ADNI) amnestic mild cognitive impairment. Alzheimers Dement. 2014;10(5):511–521. doi: 10.1016/j.jalz.2013.09.003.
    1. Socci V., Tempesta D., Desideri G., Gennaro L.G., Ferrara M. Enhancing human cognition with cocoa flavonoids. Front Nutr. 2017;4(19):1–7. doi: 10.3389/fnut.2017.00019.
    1. Angeloni C., Pirola L., Vauzour D., Muraldi T. Dietary polyphenols and their effects on cell biochemistry and pathophysiology. Oxid Med Cell Longev. 2012:1–3. doi: 10.1155/2012/583901.
    1. Numakawa T., Suzuki S., Kumamaru E., Adachi N., Richards M., Kunugi H. BDNF function and intracellular signaling in neurons. Histol Histopathol. 2010;25(2):237–258. doi: 10.14670/HH-25.237.
    1. Maher P., Akaishi T., Abe K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci USA. 2006;103:16568–16573. doi: 10.1073/pnas.0607822103.
    1. Morris R.G.M. An attempt to dissociate ‘spatial-mapping’ and ‘working-memory’ theories of hippocampal function. Neurobiology of the Hippocampus. 1993:405–432. doi: 10.1038/nprot.2006.116.
    1. Moser E.I., Krobert K.A., Moser M.B., Morris R.G.M. Impaired spatial learning after saturation of long-term potentiation. Science. 1998;281:2038–2042. doi: 10.1126/science.281.5385.2038.
    1. Rocha-Gonzalez H.I., Ambriz-Tututi M., Granados-Soto V. Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther. 2008;14:234–247. doi: 10.1111/j.1755-5949.2008.00045.x.
    1. McGhie T.K., Walton M.C. The bioavailability and absorption of anthocyanins: towards a better understanding. Mol Nutr Food Res. 2007;51(6):702–713. doi: 10.1002/mnfr.200700092.
    1. Vanzo A., Scholz M., Gasperotti M., Tramer F., Passamonti S., Vrhovsek U. Metabonomic investigation of rat tissues following intravenous administration of cyanidin 3-glucoside at a physiologically relevant dose. Metabolomics. 2013;9:88–100. doi: 10.1007/s11306-012-0430-8.
    1. Kalt W., Blumberg J.B., McDonald J.E., Vinqvist-Tymchuk M.R., Fillmore S.A.E., Graf B.A. Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs. J Agric Food Chem. 2008;56(3):705–712. doi: 10.1021/jf071998l.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅