Abstract
The genus Ferulago, from the Apiaceae (Umbelliferae) family, comprised perennial herbs that have long been used as medicinal plants in different countries. Phytochemical and biological investigations of this genus revealed that their neuroprotective activities are mediated by a wide variety of compounds, especially coumarins. In this chapter, we introduced the coumarins from various species of the Ferulago genus, as well as different pathological pathways, and major potential genes linked to Alzheimer’s disease (AD). Moreover, the possible effectiveness of these coumarins on the mentioned proteins and genes was investigated. Amyloid-β (Aβ) and secretase enzymes, tau protein, cholinergic and glutaminergic receptors, and the immune system (microglia) were identified as major key factors in AD management. At the molecular level, bergamottin, imperatorin, and oxypeucedanin could affect the BACE1 and show β-secretase inhibitory activities. Moreover, osthole, a prenylated coumarin, can improve memory function by various mechanisms, including inhibiting tau protein phosphorylation, affecting mRNA expression of BACE1, and reducing Aβ formation. According to the effectiveness of reported coumarins from Ferulago species on AD-related proteins and genes, these species and their coumarins could be considered as novel therapeutic options for AD.
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References
Ahmed, S., Khan, H., Aschner, M., Mirzae, H., Küpeli Akkol, E., & Capasso, R. (2020). Anticancer potential of furanocoumarins: Mechanistic and therapeutic aspects. International Journal of Molecular Sciences, 21(16), 5622.
Albayrak, G., Demir, S., Koyu, H., & Baykan, S. (2022). Anticholinesterase compounds from endemic Prangos uechtritzii. Chemistry & Biodiversity, 19(11), e202200557.
Alhazmi, H. A., & Albratty, M. (2022). An update on the novel and approved drugs for Alzheimer disease. Saudi Pharmaceutical Journal.
Ali, M. Y., Seong, S. H., Reddy, M. R., Seo, S. Y., Choi, J. S., & Jung, H. A. (2017). Kinetics and molecular docking studies of 6-formyl umbelliferone isolated from Angelica decursiva as an inhibitor of cholinesterase and BACE1. Molecules, 22(10), 1604.
Andrews, S. J., Fulton-Howard, B., & Goate, A. (2020). Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease. The Lancet Neurology, 19(4), 326–335.
Badalamenti, N., Ilardi, V., Rosselli, S., & Bruno, M. (2021). The ethnobotany, phytochemistry and biological properties of genus Ferulago—A review. Journal of Ethnopharmacology, 274, 114050.
Baek, S. C., Kang, M.-G., Park, J.-E., Lee, J. P., Lee, H., Ryu, H. W., Park, C. M., Park, D., Cho, M.-L., & Oh, S.-R. (2019). Osthenol, a prenylated coumarin, as a monoamine oxidase A inhibitor with high selectivity. Bioorganic & Medicinal Chemistry Letters, 29(6), 839–843.
Basile, A., Sorbo, S., Spadaro, V., Bruno, M., Maggio, A., Faraone, N., & Rosselli, S. (2009). Antimicrobial and antioxidant activities of coumarins from the roots of Ferulago campestris (Apiaceae). Molecules, 14(3), 939–952.
Bellenguez, C., Grenier-Boley, B., & Lambert, J.-C. (2020). Genetics of Alzheimer’s disease: Where we are, and where we are going. Current Opinion in Neurobiology, 61, 40–48.
Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., & Andrade, V. (2022). New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nature Genetics, 54(4), 412–436.
Bettens, K., Sleegers, K., & Van Broeckhoven, C. (2013). Genetic insights in Alzheimer’s disease. The Lancet Neurology, 12(1), 92–104.
Bourgaud, F., Hehn, A., Larbat, R., Doerper, S., Gontier, E., Kellner, S., & Matern, U. (2006). Biosynthesis of coumarins in plants: A major pathway still to be unravelled for cytochrome P450 enzymes. Phytochemistry Reviews, 5, 293–308.
Budzynska, B., Boguszewska-Czubara, A., Kruk-Slomka, M., Skalicka-Wozniak, K., Michalak, A., Musik, I., Biala, G., & Glowniak, K. (2013). Effects of imperatorin on nicotine-induced anxiety- and memory-related responses and oxidative stress in mice. Physiology & Behavior, 122, 46–55.
Calabrò, M., Rinaldi, C., Santoro, G., & Crisafulli, C. (2021). The biological pathways of Alzheimer disease: A review. AIMS Neuroscience, 8(1), 86.
Choi, G.-Y., Kim, H.-B., Cho, J.-M., Sreelatha, I., Lee, I.-S., Kweon, H.-S., Sul, S., Kim, S. A., Maeng, S., & Park, J.-H. (2023). Umbelliferone ameliorates memory impairment and enhances hippocampal synaptic plasticity in scopolamine-induced Rat model. Nutrients, 15(10), 2351.
Çiçek Kaya, A., Özbek, H., Yuca, H., Yılmaz, G., Bingöl, Z., Kazaz, C., Gülçin, İ., & Güvenalp, Z. (2023). Phytochemical content and enzyme inhibitory effect of Heptaptera triquetra (Vent.) Tutin fruit against acetylcholinesterase and carbonic anhydrase I and II isoenzymes. Chemical Papers, 1–9.
Dall’Acqua, S., Maggi, F., Minesso, P., Salvagno, M., Papa, F., Vittori, S., & Innocenti, G. (2010). Identification of non-alkaloid acetylcholinesterase inhibitors from Ferulago campestris (Besser) Grecescu (Apiaceae). Fitoterapia, 81(8), 1208–1212.
Epifano, F., Molinaro, G., Genovese, S., Ngomba, R. T., Nicoletti, F., & Curini, M. (2008). Neuroprotective effect of prenyloxycoumarins from edible vegetables. Neuroscience Letters, 443(2), 57–60.
Fontana, I. C., Kumar, A., & Nordberg, A. (2023). The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease. Nature Reviews Neurology, 19(5), 278–288.
Gao, C., Shen, X., Tan, Y., & Chen, S. (2022). Pathogenesis, therapeutic strategies and biomarker development based on “omics” analysis related to microglia in Alzheimer’s disease. Journal of Neuroinflammation, 19(1), 1–23.
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., & Iwatsubo, T. (2021a). The amyloid-β pathway in Alzheimer’s disease. Molecular Psychiatry, 26(10), 5481–5503.
Hampel, H., Mesulam, M.-M., Cuello, A. C., Farlow, M. R., Giacobini, E., Grossberg, G. T., Khachaturian, A. S., Vergallo, A., Cavedo, E., & Snyder, P. J. (2018). The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 141(7), 1917–1933.
Hampel, H., Vassar, R., De Strooper, B., Hardy, J., Willem, M., Singh, N., Zhou, J., Yan, R., Vanmechelen, E., & De Vos, A. (2021b). The β-secretase BACE1 in Alzheimer’s disease. Biological Psychiatry, 89(8), 745–756.
Hung, W.-L., Suh, J. H., & Wang, Y. (2017). Chemistry and health effects of furanocoumarins in grapefruit. Journal of Food and Drug Analysis, 25(1), 71–83.
Javaid, S. F., Giebel, C., Khan, M. A., & Hashim, M. J. (2021). Epidemiology of Alzheimer’s disease and other dementias: Rising global burden and forecasted trends. F1000Research, 10, 425.
Jiang, S., Li, Y., Zhang, C., Zhao, Y., Bu, G., Xu, H., & Zhang, Y.-W. (2014). M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neuroscience Bulletin, 30, 295–307.
Joghataee, S., Mohammad-zadeh, M., Amin, B., Jafari, F., Tondar, M., & Gholami, O. (2020). Auraptene has neuroprotective and memory enhancing effects in a rat model of Alzheimer’s disease. Neurology Asia, 25(3).
Kang, S. Y., Lee, K. Y., Park, M. J., Kim, Y. C., Markelonis, G. J., Oh, T. H., & Kim, Y. C. (2003). Decursin from Angelica gigas mitigates amnesia induced by scopolamine in mice. Neurobiology of Learning and Memory, 79(1), 11–18.
Karakaya, S., Koca, M., Kılıc, C. S., & Coskun, M. (2018). Antioxidant and anticholinesterase activities of Ferulago syriaca Boiss. and F. isaurica Peșmen growing in Turkey. Medicinal Chemistry Research, 27, 1843–1850.
Kong, L. D., Tan, R. X., Woo, A. Y. H., & Cheng, C. H. K. (2001). Inhibition of rat brain monoamine oxidase activities by psoralen and isopsoralen: Implications for the treatment of affective disorders. Pharmacology & Toxicology, 88(2), 75–80.
Kontogiorgis, C., Detsi, A., & Hadjipavlou-Litina, D. (2012). Coumarin-based drugs: A patent review (2008–present). Expert Opinion on Therapeutic Patents, 22(4), 437–454.
Kowalczyk, J., Skalicka-Wozniak, K., Budzynska, B., El Sayed, N., Espargaró, A., & Sabate, R. (2022). Coumarin derivatives against amyloid-beta 40–42 peptide and protein. Current Issues in Pharmacy and Medical Sciences, 35(2), 67–74.
Kunkle, B. W., Schmidt, M., Klein, H.-U., Naj, A. C., Hamilton-Nelson, K. L., Larson, E. B., Evans, D. A., De Jager, P. L., Crane, P. K., & Buxbaum, J. D. (2021). Novel Alzheimer disease risk loci and pathways in African American individuals using the African genome resources panel: A meta-analysis. JAMA Neurology, 78(1), 102–113.
Küpeli Akkol, E., Genç, Y., Karpuz, B., Sobarzo-Sánchez, E., & Capasso, R. (2020). Coumarins and coumarin-related compounds in pharmacotherapy of cancer. Cancers, 12(7), 1959.
Kurach, Ł, Kulczycka-Mamona, S., Kowalczyk, J., Skalicka-Woźniak, K., Boguszewska-Czubara, A., El Sayed, N., Osmani, M., Iwaniak, K., & Budzyńska, B. (2021). Mechanisms of the procognitive effects of xanthotoxin and umbelliferone on LPS-induced amnesia in mice. International Journal of Molecular Sciences, 22(4), 1779.
Lacy, A., & O’kennedy, R. (2004). Studies on coumarins and coumarin-related compounds to determine their therapeutic role in the treatment of cancer. Current Pharmaceutical Design, 10(30), 3797–3811.
Li, L., Li, W., Jung, S.-W., Lee, Y.-W., & Kim, Y.-H. (2011). Protective effects of decursin and decursinol angelate against amyloid β-protein-induced oxidative stress in the PC12 cell line: The role of Nrf2 and antioxidant enzymes. Bioscience, Biotechnology, and Biochemistry, 75(3), 434–442.
Liu, J., Chang, L., Song, Y., Li, H., & Wu, Y. (2019). The role of NMDA receptors in Alzheimer’s disease. Frontiers in Neuroscience, 13, 43.
Liu, J., Zuo, X., Huang, M., Fang, J., Li, W., Shi, Q., Wang, Q., & Liang, Y. (2023). Multifunctional Gomisin B enhances cognitive function in APP/PS1 transgenic mice by regulating Aβ clearance and neuronal apoptosis. Biomedicine & Pharmacotherapy, 166, 115423.
Liu, S.-L., Wang, C., Jiang, T., Tan, L., **ng, A., & Yu, J.-T. (2016). The role of Cdk5 in Alzheimer’s disease. Molecular Neurobiology, 53, 4328–4342.
Marumoto, S., & Miyazawa, M. (2010). β-Secretase inhibitory effects of furanocoumarins from the root of Angelica dahurica. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 24(4), 510–513.
Marumoto, S., & Miyazawa, M. (2012). Structure–activity relationships for naturally occurring coumarins as β-secretase inhibitor. Bioorganic & Medicinal Chemistry, 20(2), 784–788.
Mazimba, O. (2017). Umbelliferone: Sources, chemistry and bioactivities review. Bulletin of Faculty of Pharmacy, Cairo University, 55(2), 223–232.
Nandi, A., Counts, N., Chen, S., Seligman, B., Tortorice, D., Vigo, D., & Bloom, D. E. (2022). Global and regional projections of the economic burden of Alzheimer’s disease and related dementias from 2019 to 2050: A value of statistical life approach. EClinicalMedicine, 51.
Ogunwa, T. H. (2019). Interaction studies of Angelica polymorpha and Beilschmiedia pulverulenta phytochemicals with acetylcholinesterase as anti-Alzheimer’s disease target. International Journal of Computational Biology and Drug Design, 12(1), 80–99.
Okuyama, S., Minami, S., Shimada, N., Makihata, N., Nakajima, M., & Furukawa, Y. (2013). Anti-inflammatory and neuroprotective effects of auraptene, a citrus coumarin, following cerebral global ischemia in mice. European Journal of Pharmacology, 699(1–3), 118–123.
Okuyama, S., Nakashima, T., Nakamura, K., Shinoka, W., Kotani, M., Sawamoto, A., Nakajima, M., & Furukawa, Y. (2018). Inhibitory effects of auraptene and naringin on astroglial activation, tau hyperphosphorylation, and suppression of neurogenesis in the hippocampus of streptozotocin-induced hyperglycemic mice. Antioxidants, 7(8), 109.
Peng, X.-L., Hou, L., Xu, S.-H., Hua, Y., Zhou, S.-J., Zhang, Y., Zheng, Y.-P., Fu, Y.-H., Xu, Q., & Zhang, L.-S. (2014). Novel APP K724M mutation causes Chinese early-onset familial Alzheimer’s disease and increases amyloid-β42 to amyloid-β40 ratio. Neurobiology of Aging, 35(11), 2657, e2651–2657, e2656.
Pimenova, A. A., Raj, T., & Goate, A. M. (2018). Untangling genetic risk for Alzheimer’s disease. Biological Psychiatry, 83(4), 300–310.
Pluta, R., & Ułamek-Kozioł, M. (2020). Tau protein-targeted therapies in Alzheimer’s disease: Current state and future perspectives. Exon Publications, 69–82.
Ramakrishnan, V., Husain, R. A., & Ahmed, S. S. (2017). PSEN1 gene polymorphisms in Caucasian Alzheimer’s disease: A meta-analysis. Clinica Chimica Acta, 473, 65–70.
Rezaee, R., Behravan, E., Behravan, J., Soltani, F., Naderi, Y., Emami, B., & Iranshahi, M. (2014). Antigenotoxic activities of the natural dietary coumarins umbelliferone, herniarin and 7-isopentenyloxy coumarin on human lymphocytes exposed to oxidative stress. Drug and Chemical Toxicology, 37(2), 144–148.
Santamaría, T. Z., Gómez, P. Y., Galindo, I. F., González, M. G., Vázquez, A. O., & López, M. L. (2022). Pharmacogenetic studies in Alzheimer disease. Neurología (English Edition), 37(4), 287–303.
Sarker, S. D., & Nahar, L. (2017). Progress in the chemistry of naturally occurring coumarins. Progress in the Chemistry of Organic Natural Products, 106, 241–304.
Sayas, C. L., & Ávila, J. (2021). GSK-3 and tau: A key duet in Alzheimer’s disease. Cells, 10(4), 721.
Seo, W. D., Kim, J. Y., Ryu, H. W., Kim, J. H., Han, S.-I., Ra, J.-E., Seo, K. H., Jang, K. C., & Lee, J. H. (2013). Identification and characterisation of coumarins from the roots of Angelica dahurica and their inhibitory effects against cholinesterase. Journal of Functional Foods, 5(3), 1421–1431.
Singh, L., & Bhatti, R. (2023). Signaling pathways involved in the neuroprotective effect of osthole: Evidence and mechanisms. Molecular Neurobiology, 1–19.
Singh, S., Agrawal, N., & Goyal, A. (2024). Role of alpha-7-nicotinic acetylcholine receptor in Alzheimer’s disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders).
Somani, G., Kulkarni, C., Shinde, P., Shelke, R., Laddha, K., & Sathaye, S. (2015). In vitro acetylcholinesterase inhibition by psoralen using molecular docking and enzymatic studies. Journal of Pharmacy & Bioallied Sciences, 7(1), 32.
Süzgeç-Selçuk, S., & Dikpınar, T. (2021). Phytochemical evaluation of the Ferulago genus and the pharmacological activities of its coumarin constituents. Journal of Herbal Medicine, 25, 100415.
Tahami Monfared, A. A., Byrnes, M. J., White, L. A., & Zhang, Q. (2022). Alzheimer’s disease: Epidemiology and clinical progression. Neurology and Therapy, 11(2), 553–569.
Thakur, A., Sharma, R., Jaswal, V. S., Nepovimova, E., Chaudhary, A., & Kuca, K. (2020). Psoralen: A biologically important coumarin with emerging applications. Mini Reviews in Medicinal Chemistry, 20(18), 1838–1845.
Yamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016). Apolipoprotein E as a therapeutic target in Alzheimer’s disease: A review of basic research and clinical evidence. CNS Drugs, 30(9), 773–789.
Yuan, X.-Z., Sun, S., Tan, C.-C., Yu, J.-T., & Tan, L. (2017). The role of ADAM10 in Alzheimer’s disease. Journal of Alzheimer’s Disease, 58(2), 303–322.
Zagaja, M., Andres-Mach, M., Patrzylas, P., Pyrka, D., Szpringer, M., Florek-Łuszczki, M., Żółkowska, D., Skalicka-Woźniak, K., & Łuszczki, J. J. (2016). Influence of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of various novel antiepileptic drugs against maximal electroshock-induced seizures in mice. Fitoterapia, 115, 86–91.
Zhang, X., Li, Y., Xu, H., & Zhang, Y.-W. (2014). The γ-secretase complex: From structure to function. Frontiers in Cellular Neuroscience, 8, 427.
Zhang, Y.-W., Thompson, R., Zhang, H., & Xu, H. (2011). APP processing in Alzheimer’s disease. Molecular Brain, 4, 1–13.
Zhou, F., & Wang, D. (2017). The associations between the MAPT polymorphisms and Alzheimer’s disease risk: A meta-analysis. Oncotarget, 8(26), 43506.
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Dabaghian, F. et al. (2024). Gene-Based Management of Alzheimer’s Disease: Role of Coumarins of Ferulago Genus. In: Kumar, L., Bharadvaja, N., Singh, R., Anand, R. (eds) Medicinal and Aromatic Plants. Sustainable Landscape Planning and Natural Resources Management. Springer, Cham. https://doi.org/10.1007/978-3-031-60117-0_14
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