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](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7772514/bin/gr1.jpg)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7772514/bin/gr2.jpg)
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. 4
The MWM study on the…
Fig. 4
The MWM study on the effect of pomegranate extract according to (a) total…
Fig. 5
Effects of pomegranate extract on…
Fig. 5
Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute…
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- cAMP/PKA-CREB-BDNF signaling pathway in hippocampus mediates cyclooxygenase 2-induced learning/memory deficits of rats subjected to chronic unpredictable mild stress.Luo Y, Kuang S, Li H, Ran D, Yang J. Luo Y, et al. Oncotarget. 2017 May 30;8(22):35558-35572. doi: 10.18632/oncotarget.16009. Oncotarget. 2017. PMID: 28415673 Free PMC article.
- The Promising Pharmacological Effects and Therapeutic/Medicinal Applications of Punica Granatum L. (Pomegranate) as a Functional Food in Humans and Animals.Saeed M, Naveed M, BiBi J, Kamboh AA, Arain MA, Shah QA, Alagawany M, El-Hack MEA, Abdel-Latif MA, Yatoo MI, Tiwari R, Chakraborty S, Dhama K. Saeed M, et al. Recent Pat Inflamm Allergy Drug Discov. 2018;12(1):24-38. doi: 10.2174/1872213X12666180221154713. Recent Pat Inflamm Allergy Drug Discov. 2018. PMID: 29473532 Review.
- Diverse Phytochemicals and Bioactivities in the Ancient Fruit and Modern Functional Food Pomegranate (Punica granatum).Wu S, Tian L. Wu S, et al. Molecules. 2017 Sep 25;22(10):1606. doi: 10.3390/molecules22101606. Molecules. 2017. PMID: 28946708 Free PMC article. Review.
- Plant-derived compounds effectively inhibit the main protease of SARS-CoV-2: An in silico approach.Mahmud S, Afrose S, Biswas S, Nagata A, Paul GK, Mita MA, Hasan MR, Shimu MSS, Zaman S, Uddin MS, Islam MS, Saleh MA. Mahmud S, et al. PLoS One. 2022 Aug 23;17(8):e0273341. doi: 10.1371/journal.pone.0273341. eCollection 2022. PLoS One. 2022. PMID: 35998194 Free PMC article.
- Blueberry Anthocyanins Extract Attenuates Acrylamide-Induced Oxidative Stress and Neuroinflammation in Rats.Fang Z, Luo Y, Ma C, Dong L, Chen F. Fang Z, et al. Oxid Med Cell Longev. 2022 May 23;2022:7340881. doi: 10.1155/2022/7340881. eCollection 2022. Oxid Med Cell Longev. 2022. PMID: 35651724 Free PMC article.
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- Schottke D. Jones & Bartlett Learning; United States of America: 2016. Emergency medical responder: your first response in emergency care.
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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.
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![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7772514/bin/gr3.jpg)
Fig. 4
The MWM study on the…
Fig. 4
The MWM study on the effect of pomegranate extract according to (a) total…
Fig. 5
Effects of pomegranate extract on…
Fig. 5
Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute…
- Effect of XingPiJieYu decoction on spatial learning and memory and cAMP-PKA-CREB-BDNF pathway in rat model of depression through chronic unpredictable stress.Wang C, Guo J, Guo R. Wang C, et al. BMC Complement Altern Med. 2017 Jan 24;17(1):73. doi: 10.1186/s12906-016-1543-9. BMC Complement Altern Med. 2017. PMID: 28118829 Free PMC article.
- Chemical Characterization of Different Sumac and Pomegranate Extracts Effective against Botrytis cinerea Rots.Romeo FV, Ballistreri G, Fabroni S, Pangallo S, Nicosia MG, Schena L, Rapisarda P. Romeo FV, et al. Molecules. 2015 Jun 30;20(7):11941-58. doi: 10.3390/molecules200711941. Molecules. 2015. PMID: 26133760 Free PMC article.
- cAMP/PKA-CREB-BDNF signaling pathway in hippocampus mediates cyclooxygenase 2-induced learning/memory deficits of rats subjected to chronic unpredictable mild stress.Luo Y, Kuang S, Li H, Ran D, Yang J. Luo Y, et al. Oncotarget. 2017 May 30;8(22):35558-35572. doi: 10.18632/oncotarget.16009. Oncotarget. 2017. PMID: 28415673 Free PMC article.
- The Promising Pharmacological Effects and Therapeutic/Medicinal Applications of Punica Granatum L. (Pomegranate) as a Functional Food in Humans and Animals.Saeed M, Naveed M, BiBi J, Kamboh AA, Arain MA, Shah QA, Alagawany M, El-Hack MEA, Abdel-Latif MA, Yatoo MI, Tiwari R, Chakraborty S, Dhama K. Saeed M, et al. Recent Pat Inflamm Allergy Drug Discov. 2018;12(1):24-38. doi: 10.2174/1872213X12666180221154713. Recent Pat Inflamm Allergy Drug Discov. 2018. PMID: 29473532 Review.
- Diverse Phytochemicals and Bioactivities in the Ancient Fruit and Modern Functional Food Pomegranate (Punica granatum).Wu S, Tian L. Wu S, et al. Molecules. 2017 Sep 25;22(10):1606. doi: 10.3390/molecules22101606. Molecules. 2017. PMID: 28946708 Free PMC article. Review.
- Plant-derived compounds effectively inhibit the main protease of SARS-CoV-2: An in silico approach.Mahmud S, Afrose S, Biswas S, Nagata A, Paul GK, Mita MA, Hasan MR, Shimu MSS, Zaman S, Uddin MS, Islam MS, Saleh MA. Mahmud S, et al. PLoS One. 2022 Aug 23;17(8):e0273341. doi: 10.1371/journal.pone.0273341. eCollection 2022. PLoS One. 2022. PMID: 35998194 Free PMC article.
- Blueberry Anthocyanins Extract Attenuates Acrylamide-Induced Oxidative Stress and Neuroinflammation in Rats.Fang Z, Luo Y, Ma C, Dong L, Chen F. Fang Z, et al. Oxid Med Cell Longev. 2022 May 23;2022:7340881. doi: 10.1155/2022/7340881. eCollection 2022. Oxid Med Cell Longev. 2022. PMID: 35651724 Free PMC article.
-
- Schottke D. Jones & Bartlett Learning; United States of America: 2016. Emergency medical responder: your first response in emergency care.
- Full Text Sources
- Research Materials
NCBI Literature Resources
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.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Fig. 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7772514/bin/gr4.jpg)
Fig. 5
Effects of pomegranate extract on…
Fig. 5
Effects of pomegranate extract on (a) CREB and (b) BDNF levels of acute…
- Effect of XingPiJieYu decoction on spatial learning and memory and cAMP-PKA-CREB-BDNF pathway in rat model of depression through chronic unpredictable stress.Wang C, Guo J, Guo R. Wang C, et al. BMC Complement Altern Med. 2017 Jan 24;17(1):73. doi: 10.1186/s12906-016-1543-9. BMC Complement Altern Med. 2017. PMID: 28118829 Free PMC article.
- Chemical Characterization of Different Sumac and Pomegranate Extracts Effective against Botrytis cinerea Rots.Romeo FV, Ballistreri G, Fabroni S, Pangallo S, Nicosia MG, Schena L, Rapisarda P. Romeo FV, et al. Molecules. 2015 Jun 30;20(7):11941-58. doi: 10.3390/molecules200711941. Molecules. 2015. PMID: 26133760 Free PMC article.
- cAMP/PKA-CREB-BDNF signaling pathway in hippocampus mediates cyclooxygenase 2-induced learning/memory deficits of rats subjected to chronic unpredictable mild stress.Luo Y, Kuang S, Li H, Ran D, Yang J. Luo Y, et al. Oncotarget. 2017 May 30;8(22):35558-35572. doi: 10.18632/oncotarget.16009. Oncotarget. 2017. PMID: 28415673 Free PMC article.
- The Promising Pharmacological Effects and Therapeutic/Medicinal Applications of Punica Granatum L. (Pomegranate) as a Functional Food in Humans and Animals.Saeed M, Naveed M, BiBi J, Kamboh AA, Arain MA, Shah QA, Alagawany M, El-Hack MEA, Abdel-Latif MA, Yatoo MI, Tiwari R, Chakraborty S, Dhama K. Saeed M, et al. Recent Pat Inflamm Allergy Drug Discov. 2018;12(1):24-38. doi: 10.2174/1872213X12666180221154713. Recent Pat Inflamm Allergy Drug Discov. 2018. PMID: 29473532 Review.
- Diverse Phytochemicals and Bioactivities in the Ancient Fruit and Modern Functional Food Pomegranate (Punica granatum).Wu S, Tian L. Wu S, et al. Molecules. 2017 Sep 25;22(10):1606. doi: 10.3390/molecules22101606. Molecules. 2017. PMID: 28946708 Free PMC article. Review.
- Plant-derived compounds effectively inhibit the main protease of SARS-CoV-2: An in silico approach.Mahmud S, Afrose S, Biswas S, Nagata A, Paul GK, Mita MA, Hasan MR, Shimu MSS, Zaman S, Uddin MS, Islam MS, Saleh MA. Mahmud S, et al. PLoS One. 2022 Aug 23;17(8):e0273341. doi: 10.1371/journal.pone.0273341. eCollection 2022. PLoS One. 2022. PMID: 35998194 Free PMC article.
- Blueberry Anthocyanins Extract Attenuates Acrylamide-Induced Oxidative Stress and Neuroinflammation in Rats.Fang Z, Luo Y, Ma C, Dong L, Chen F. Fang Z, et al. Oxid Med Cell Longev. 2022 May 23;2022:7340881. doi: 10.1155/2022/7340881. eCollection 2022. Oxid Med Cell Longev. 2022. PMID: 35651724 Free PMC article.
-
- Schottke D. Jones & Bartlett Learning; United States of America: 2016. Emergency medical responder: your first response in emergency care.
- Full Text Sources
- Research Materials
![Fig. 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7772514/bin/gr5.jpg)
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Source: PubMed