Molecular and Translational Pharmacology of Melissa officinalis: Targeting Nrf2/ARE, NF-κB/MAPK, and Purinergic Receptors

Yusupovna, Mamatova Irodakhon; Abdujalilovich, Mamajonov Zafar; Rakhmonovich, Askarov Ibragim; Juraevna, Ulugbekova Gulruh

doi:10.48309/ajgc.2026.559064.1865

Molecular and Translational Pharmacology of Melissa officinalis: Targeting Nrf2/ARE, NF-κB/MAPK, and Purinergic Receptors

Document Type : Review Article

Authors

Mamatova Irodakhon Yusupovna ¹

Mamajonov Zafar Abdujalilovich ²

Askarov Ibragim Rakhmonovich ³

Ulugbekova Gulruh Juraevna ²

¹ Department of Biochemistry, Andijan State Medical Institute, Andijan, Uzbekistan

² Department of Anatomy and Clinical Anatomy, Andijan State Medical Institute, Andijan, Uzbekistan

³ Department of Chemistry, Andijan state university, Andijan, Uzbekistan

https://doi.org/10.48309/ajgc.2026.559064.1865

Abstract

Melissa officinalis (lemon balm) (MO) is a medicinal herb traditionally used for neurological, metabolic, and infectious disorders. This review synthesizes evidence on its bioactive compounds and molecular mechanisms, with emphasis on antioxidant, anti-inflammatory, anticancer, metabolic, and neuroprotective effects. A structured literature search was conducted in PubMed, Scopus, and Web of Science (2010–2025) using terms related to MO, phytochemicals, oxidative stress, NF-κB/MAPK, Nrf2/ARE, and purinergic receptors. Eligible studies included in vitro, in vivo, and clinical trials. Bioactive compounds, particularly rosmarinic acid, consistently enhanced Nrf2–ARE–driven antioxidant defense, suppressed NF-κB/MAPK-mediated inflammation, and modulated immune responses via P2X7 inhibition and A2A activation. Flavonoids and essential oils contributed to anxiolytic, anticancer, and antimicrobial effects. Clinical studies confirmed efficacy in anxiety, insomnia, and mild cognitive impairment, although variability of extracts and poor bioavailability remain limitations. MO exhibits multi-target pharmacological potential through modulation of oxidative stress, inflammation, and purinergic signaling. Standardized preparations, bioavailability-enhancing formulations, and biomarker-guided clinical trials are needed to establish its therapeutic utility in neuropsychiatric, inflammatory, and metabolic disorders.

Graphical Abstract

Keywords

Melissa officinalis

Rosmarinic acid

Nrf2/ARE

NF-&kappa

B/MAPK

Purinergic receptors, Neuroprotection

Subjects

Biochemistry

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[1] Shakeri, A., Sahebkar, A., Javadi, B. Melissa officinalis l.–a review of its traditional uses, phytochemistry and pharmacology. Journal of Ethnopharmacology, 2016, 188, 204-228.

[2] Miraj, S., Rafieian-Kopaei, Kiani, S. Melissa officinalis l: A review study with an antioxidant prospective. Journal of Evidence-Based Complementary & Alternative Medicine, 2017, 22(3), 385-394.

[3] Kennedy, D.O., Little, W., Scholey, A.B. Attenuation of laboratory-induced stress in humans after acute administration of melissa officinalis (lemon balm). Biopsychosocial Science and Medicine, 2004, 66(4), 607-613.

[4] Awad, R., Levac, D., Cybulska, P., Merali, Z., Trudeau, V., Arnason, J. Effects of traditionally used anxiolytic botanicals on enzymes of the γ-aminobutyric acid (gaba) system. Canadian Journal of Physiology and Pharmacology, 2007, 85(9), 933-942.

[5] Nasser, M., Tibi, A., Savage-Smith, E. Ibn sina's canon of medicine: 11th century rules for assessing the effects of drugs. Journal of the Royal society of Medicine, 2009, 102(2), 78-80.

[6] Di Pierro, F., Sisti, D., Rocchi, M., Belli, A., Bertuccioli, A., Cazzaniga, M., Palazzi, C.M., Tanda, M.L., Zerbinati, N. Effects of melissa officinalis phytosome on sleep quality: Results of a prospective, double-blind, placebo-controlled, and cross-over study. Nutrients, 2024, 16(23), 4199.

[7] López, V., Martín, S., Gómez-Serranillos, M.P., Carretero, M.E., Jäger, A.K., Calvo, M.I. Neuroprotective and neurological properties of melissa officinalis. Neurochemical Research, 2009, 34(11), 1955-1961.

[8] Pereira, R.P., Fachinetto, R., de Souza Prestes, A., Puntel, R.L., Santos da Silva, G.N., Heinzmann, B.M., Boschetti, T.K., Athayde, M.L., Bürger, M.E., Morel, A.F. Antioxidant effects of different extracts from melissa officinalis, matricaria recutita and cymbopogon citratus. Neurochemical Research, 2009, 34(5), 973-983.

[9] Colica, C., Di Renzo, L., Aiello, V., De Lorenzo, A., Abenavoli, L. Rosmarinic acid as potential anti-inflammatory agent. Reviews on Recent Clinical Trials, 2018, 13(4), 240-242.

[10] Cases, J., Ibarra, A., Feuillère, N., Roller, M., Sukkar, S.G. Pilot trial of melissa officinalis l. Leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. Mediterranean Journal of Nutrition and Metabolism, 2011, 4(3), 211-218.

[11] Akbarzadeh, M., Dehghani, M., Moshfeghy, Z., Emamghoreishi, M., Tavakoli, P., Zare, N. Effect of melissa officinalis capsule on the intensity of premenstrual syndrome symptoms in high school girl students. Nursing and Midwifery Studies, 2015, 4(2), e27001.

[12] Mathews, I.M., Eastwood, J., Lamport, D.J., Cozannet, R.L., Fanca-Berthon, P., Williams, C.M. Clinical efficacy and tolerability of lemon balm (melissa officinalis l.) in psychological well-being: A review. Nutrients, 2024, 16(20), 3545.

[13] Dastmalchi, K., Dorman, H.D., Oinonen, P.P., Darwis, Y., Laakso, I., Hiltunen, R. Chemical composition and in vitro antioxidative activity of a lemon balm (melissa officinalis l.) extract. LWT-Food Science and Technology, 2008, 41(3), 391-400.

[14] Barros, L., Dueñas, M., Dias, M.I., Sousa, M.J., Santos-Buelga, C., Ferreira, I.C. Phenolic profiles of cultivated, in vitro cultured and commercial samples of melissa officinalis l. Infusions. Food Chemistry, 2013, 136(1), 1-8.

[15] Moradkhani, H., Sargsyan, E., Bibak, H., Naseri, B., Sadat-Hosseini, M., Fayazi-Barjin, A., Meftahizade, H. Melissa officinalis L., a valuable medicine plant: A review. Journal of Medicinal Plants Research, 2010, 4(25), 2753–2759.

[16] Petersen, M., Simmonds, M.S. Rosmarinic acid. Phytochemistry, 2003, 62(2), 121-125.

[17] Souihi, M., Amri, I., Souissi, A., Hosni, K., Ben Brahim, N., Annabi, M. Essential oil and fatty acid composition of melissa officinalis l. Prog. Nutr, 2020, 22(1), 253-258.

[18] Yu, H., Pei, J., Qiu, W., Mei, J., Xie, J. The antimicrobial effect of melissa officinalis l. Essential oil on vibrio parahaemolyticus: Insights based on the cell membrane and external structure. Frontiers in Microbiology, 2022, 13, 812792.

[19] Nuzzo, D. Role of natural antioxidants on neuroprotection and neuroinflammation. Antioxidants, 2021, 10(4), 608.

[20] Spencer, J.P. Flavonoids: Modulators of brain function? British Journal of Nutrition, 2008, 99(E-S1), ES60-ES77.

[21] Azhar, M.K., Anwar, S., Hasan, G.M., Shamsi, A., Islam, A., Parvez, S., Hassan, M.I. Comprehensive insights into biological roles of rosmarinic acid: Implications in diabetes, cancer and neurodegenerative diseases. Nutrients, 2023, 15(19), 4297.

[22] Hase, T., Shishido, S., Yamamoto, S., Yamashita, R., Nukima, H., Taira, S., Toyoda, T., Abe, K., Hamaguchi, T., Ono, K. Rosmarinic acid suppresses alzheimer’s disease development by reducing amyloid β aggregation by increasing monoamine secretion. Scientific Reports, 2019, 9(1), 8711.

[23] Kola, A., Vigni, G., Lamponi, S., Valensin, D. Protective contribution of rosmarinic acid in rosemary extract against copper-induced oxidative stress. Antioxidants, 2024, 13(11), 1419.

[24] Rudrapal, M., Khairnar, S.J., Khan, J., Dukhyil, A.B., Ansari, M.A., Alomary, M.N., Alshabrmi, F.M., Palai, S., Deb, P.K., Devi, R. Dietary polyphenols and their role in oxidative stress-induced human diseases: Insights into protective effects, antioxidant potentials and mechanism (s) of action. Frontiers in Pharmacology, 2022, 13, 806470.

[25] Hussain, T., Tan, B., Yin, Y., Blachier, F., Tossou, M.C., Rahu, N. Oxidative stress and inflammation: What polyphenols can do for us? Oxidative Medicine and Cellular Longevity, 2016, 2016(1), 7432797.

[26] Ma, Q., Role of Nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology, 2013, 53(1), 401-426.

[27] Jadeja, R.N., Upadhyay, K.K., Devkar, R.V., Khurana, S. Naturally occurring Nrf2 activators: Potential in treatment of liver injury. Oxidative Medicine and Cellular Longevity, 2016, 2016(1), 3453926.

[28] L. Suraweera, T., Rupasinghe, H.V., Dellaire, G., Xu, Z. Regulation of Nrf2/ARE pathway by dietary flavonoids: A friend or foe for cancer management? Antioxidants, 2020, 9(10), 973.

[29] Faustino, J.V., Wang, X., Johnson, C.E., Klibanov, A., Derugin, N., Wendland, M.F., Vexler, Z.S. Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. Journal of Neuroscience, 2011, 31(36), 12992-13001.

[30] Choy, K.W., Murugan, D., Leong, X.F., Abas, R., Alias, A., Mustafa, M.R. Flavonoids as natural anti-inflammatory agents targeting nuclear factor-kappa b (nfκb) signaling in cardiovascular diseases: A mini review. Frontiers in Pharmacology, 2019, 10, 1295.

[31] Fürst, R., Zündorf, I. Plant‐derived anti‐inflammatory compounds: Hopes and disappointments regarding the translation of preclinical knowledge into clinical progress. Mediators of Inflammation, 2014, 2014(1), 146832.

[32] Chi, G., Wei, M., Xie, X., Soromou, L., Liu, F., Zhao, S. Suppression of MAPK and Nf-Κb pathways by limonene contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation, 2013, 36(2), 501-511.

[33] Orihuela, R., McPherson, C.A., Harry, G.J. Microglial M1/M2 polarization and metabolic states. British Journal of Pharmacology, 2016, 173(4), 649–665.

[34] Geng, Y., Bush, M., Mosyak, L., Wang, F., Fan, Q.R. Structural mechanism of ligand activation in human GABA_B receptor. Nature, 2013, 504(7479), 254-259.

[35] Kumar, G.P., Khanum, F. Neuroprotective potential of phytochemicals. Pharmacognosy Reviews, 2012, 6(12), 81.

[36] Opazo, C.M., Greenough, M.A., Bush, A.I. Copper: From neurotransmission to neuroproteostasis. Frontiers in Aging Neuroscience, 2014, 6, 143.

[37] Orhan, I., Şener, B., Choudhary, M., Khalid, A. Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some turkish medicinal plants. Journal of Ethnopharmacology, 2004, 91(1), 57-60.

[38] Akhondzadeh, S., Abbasi, S.H. Herbal medicine in the treatment of alzheimer's disease. American Journal of Alzheimer's Disease & Other Dementias®, 2006, 21(2), 113-118.

[39] Spencer, J.P. The impact of fruit flavonoids on memory and cognition. British Journal of Nutrition, 2010, 104(S3), S40-S47.

[40] Di Virgilio, F., Dal Ben, D., Sarti, A.C., Giuliani, A.L., Falzoni, S. The P2X7 receptor in infection and inflammation. Immunity, 2017, 47(1), 15-31.

[41] Burnstock, G. Purine and purinergic receptors. Brain and Neuroscience Advances, 2018, 2, 2398212818817494.

[42] Campagno, K.E., Mitchell, C.H. The P2X₇ receptor in microglial cells modulates the endolysosomal axis, autophagy, and phagocytosis. Frontiers in Cellular Neuroscience, 2021, 15, 645244.

[43] Ribeiro, D.E., Roncalho, A.L., Glaser, T., Ulrich, H., Wegener, G., Joca, S. P2x7 receptor signaling in stress and depression. International Journal of Molecular Sciences, 2019, 20(11), 2778.

[44] Xu, J., Núñez, G. The NLRP3 inflammasome: Activation and regulation. Trends in Biochemical Sciences, 2023, 48(4), 331-344.

[45] Niu, Q., Li, J., Zhang, M., Zhou, P. Natural phytochemicals as P2X7 receptor inhibitors for the treatment of inflammation-related diseases. Italian Journal of Food Science/Rivista Italiana di Scienza degli Alimenti, 2023, 35(2).

[46] Ongini, E., Fredholm, B.B. Pharmacology of adenosine A_2A receptors. Trends in Pharmacological Sciences, 1996, 17(10), 364-372.

[47] Chhabra, P., Linden, J., Lobo, P., Douglas Okusa, M., Lewis Brayman, K. The immunosuppressive role of adenosine A2A receptors in ischemia reperfusion injury and islet transplantation. Current Diabetes Reviews, 2012, 8(6), 419-433.

[48] Allard, D., Turcotte, M., Stagg, J. Targeting A2 adenosine receptors in cancer. Immunology and Cell Biology, 2017, 95(4), 333-339.

[49] Porta, C., Riboldi, E., Ippolito, A., Sica, A. Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology, 2015, 27(4), 237-248.

[50] Biswas, S.K., Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nature Immunology, 2010, 11(10), 889-896.

[51] Yang, L., Han, T., Liu, R., Shi, S., Luan, S., Meng, S. Plant-derived natural compounds: A new frontier in inducing immunogenic cell death for cancer treatment. Biomedicine & Pharmacotherapy, 2024, 177, 117099.

[52] Liu, H.B., Gou, Y., Wang, H.Y., Li, H.M., Wu, W. Temporal changes in climatic variables and their impact on crop yields in southwestern china. International Journal of Biometeorology, 2014, 58(6), 1021-1030.

[53] European Medicines Agency. Community herbal monograph on Melissa officinalis L., folium. London, UK, 2013.

[54] World Health Organization. WHO monographs on selected medicinal plants. Vol. 4. Geneva, World Health Organization, 2009.

[55] Luca, S.V., Macovei, I., Bujor, A., Miron, A., Skalicka-Woźniak, K., Aprotosoaie, A.C., Trifan, A. Bioactivity of dietary polyphenols: The role of metabolites. Critical Reviews in Food Science and Nutrition, 2020, 60(4), 626-659.

[56] Huang, L., Luo, S., Tong, S., Lv, Z., Wu, J. The development of nanocarriers for natural products. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2024, 16(3), e1967.

[57] Cuomo, F., Iacovino, S., Sacco, P., De Leonardis, A., Ceglie, A., Lopez, F. Progress in colloid delivery systems for protection and delivery of phenolic bioactive compounds: Two study cases—hydroxytyrosol and curcumin. Molecules, 2022, 27(3), 921.

[58] Asadi, A., Shidfar, F., Safari, M., Hosseini, A.F., Fallah Huseini, H., Heidari, I., Rajab, A. Efficacy of melissa officinalis l. (lemon balm) extract on glycemic control and cardiovascular risk factors in individuals with type 2 diabetes: A randomized, double‐blind, clinical trial. Phytotherapy Research, 2019, 33(3), 651-659.

[59] Wu, J.Y., Yang, J.L., Hu, J.L., Xu, S., Zhang, X.J., Qian, S.Y., Chen, M.L., Ali, M.A., Zhang, J., Zha, Z. Reporting quality and risk of bias of randomized controlled trials of chinese herbal medicine for multiple sclerosis. Frontiers in Immunology, 2024, 15, 1429895.

[60] Ekor, M. The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Frontiers in Pharmacology, 2014, 4, 177.

[61] Fei, F., Su, N., Li, X., Fei, Z. Neuroprotection mediated by natural products and their chemical derivatives. Neural Regeneration Research, 2020, 15(11), 2008-2015.

[62] Swaroop, A.K., Lalitha, C.M.V.N., Shanmugam, M., Subramanian, G., Natarajan, J., Selvaraj, J. Plant derived immunomodulators; A critical review. Advanced Pharmaceutical Bulletin, 2021, 12(4), 712.

[63] Xin, X., Zong, T., Hu, Z., Jin, L., Zhou, W., Sun, J., Li, G. Discovery of natural compounds and their derivatives against neuroinflammation: Pharmacological mechanisms and structure-activity relationship. Bioorganic Chemistry, 2025, 108934.

[64] Li, Z., Zhao, T., Shi, M., Wei, Y., Huang, X., Shen, J., Zhang, X., Xie, Z., Huang, P., Yuan, K. Polyphenols: Natural food grade biomolecules for treating neurodegenerative diseases from a multi-target perspective. Frontiers in nutrition, 2023, 10, 1139558.

[65] Shin, S.A., Joo, B.J., Lee, J.S., Ryu, G., Han, M., Kim, W.Y., Park, H.H., Lee, J.H., Lee, C.S. Phytochemicals as anti-inflammatory agents in animal models of prevalent inflammatory diseases. Molecules, 2020, 25(24), 5932.