Metabolic Fingerprinting of Different Sideritis Taxa Infusions and Their Neurogenic Activity

Abstract

Over the last years, Sideritis extracts were shown to improve memory. However, their potential to promote the generation of new neurons, starting with the neuronal differentiation of neural stem cells, remains unexplored. Therefore, the present study aimed to evaluate the neurogenic effects of different Sideritis infusions in neural stem and precursor cells and their impact on cell viability. Moreover, the metabolic fingerprints were recorded using LC-DAD, LC-HRESIMS, and GC-MS. The neurogenic potential of infusions of the eight Sideritis taxa tested was as potent as the classical neuronal inducer combination of retinoic acid and valproic acid. Further cytotoxicity assays revealed that the IC₅₀ values of the extracts were between 163 and 322 µg/mL. Hierarchical cluster analyses of the metabolic fingerprints unveiled that the two Sideritis taxa with the lowest IC₅₀ values were the most divergent in the analytical techniques used. As the analysis focused on polyphenols, it is reasonable to assume that these compounds are responsible for the effect on the cell viability of SH-SY5Y neuroblastoma cells. This study is the first report on the neurogenic potential of Sideritis taxa and might support the use of Sideritis herbal preparations in the context of neurodegenerative diseases.

Key words

Sideritis - Lamiaceae - neurogenesis - doublecortin - infusions - metabolic fingerprint

Publication History

Received: 29 December 2022

Accepted after revision: 11 April 2023

Accepted Manuscript online:
12 April 2023

Article published online:
23 May 2023

• References

• 1 González-Burgos E, Carretero ME, Gómez-Serranillos MP. Sideritis spp.: uses, chemical composition and pharmacological activities–a review. J Ethnopharmacol 2011; 135: 209-225
• 2 Committee on Herbal Medicinal Products (HMPC). EMA/HMPC/39455/2015. Assessment report on Sideritis scardica Griseb.; Sideritis clandestina (Bory & Chaub.) Hayek; Sideritis raeseri Boiss. & Heldr.; Sideritis syriaca L., herba. Accessed April 25, 2023 at: https://www.ema.europa.eu/en/documents/herbal-report/final-assessment-report-sideritis-scardica-griseb-sideritis-clandestina-bory-chaub-hayek-sideritis_en.pdf
• 3 Aneva I, Zhelev P, Kozuharova E, Danova K, Nabavi SF, Behzad S. Genus Sideritis, section Empedoclia in southeastern Europe and Turkey – studies in ethnopharmacology and recent progress of biological activities. DARU J Pharm Sci 2019; 27: 407-421
• 4 Tsioutsiou EE, Giordani P, Hanlidou E, Biagi M, De Feo V, Cornara L. Ethnobotanical study of medicinal plants used in Central Macedonia, Greece. Evid Based Complement Alternat Med 2019; 2019: 1-22
• 5 Iatrou G, Kokkalou E. Rarity, Conservation, Importance and Ethnopharmacological Knowledge of the Greek Flora. In: Heywood VH, Skoula M. eds. Cahiers Options Méditerranéennes. Chania (Greece): CHEAM; 1997: 65-75
• 6 Läer U, Glombitza KW, Neugebauer M. The essential oil of Sideritis syriaca . Planta Med 1996; 62: 81-82
• 7 Komaitis ME, Falirea A, Voudouris EC. Constituents of the essential oil of Sideritis cretica Βoiss. J Sci Food Agric 1985; 36: 970-972
• 8 Menteli V, Krigas N, Avramakis M, Turland N, Vokou D. Endemic plants of Crete in electronic trade and wildlife tourism: current patterns and implications for conservation. J Biol Res (Thessalon) 2019; 26: 10
• 9 Karousou R, Deirmentzoglou S. The herbal market of Cyprus: Traditional links and cultural exchanges. J Ethnopharmacol 2011; 133: 191-203
• 10 Chalatsa I, Arvanitis DA, Mikropoulou EV, Giagini A, Papadopoulou-Daifoti Z, Aligiannis N, Halabalaki M, Tsarbopoulos A, Skaltsounis LA, Sanoudou D. Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimerʼs disease neuronal cell culture models. J Alzheimers Dis 2018; 64: 787-800
• 11 Heiner F, Feistel B, Wink M. Sideritis scardica extracts inhibit aggregation and toxicity of amyloid-β in Caenorhabditis elegans used as a model for Alzheimerʼs disease. PeerJ 2018; 6: e4683
• 12 Dimpfel W, Feistel B, Schombert L. Opposite neurophysiological findings induced by Sideritis scardica and Sideritis euboa extract in the rat. J Behav Brain Sci 2016; 06: 448-461
• 13 Hofrichter J, Krohn M, Schumacher T, Lange C, Feistel B, Walbroel B, Pahnke J. Sideritis spp. extracts enhance memory and learning in Alzheimerʼs β-amyloidosis mouse models and aged C57Bl/6 mice. J Alzheimers Dis 2016; 53: 967-980
• 14 Wightman EL, Jackson PA, Khan J, Forster J, Heiner F, Feistel B, Suarez CG, Pischel I, Kennedy DO. The acute and chronic cognitive and cerebral blood flow effects of a Sideritis scardica (Greek Mountain Tea) extract: A double blind, randomized, placebo controlled, parallel groups study in healthy humans. Nutrients 2018; 10: 955
• 15 Oberbauer E, Urmann C, Steffenhagen C, Bieler L, Brunner D, Furtner T, Humpel C, Bäumer B, Bandtlow C, Couillard-Despres S, Rivera FJ, Riepl H, Aigner L. Chroman-like cyclic prenylflavonoids promote neuronal differentiation and neurite outgrowth and are neuroprotective. J Nutr Biochem 2013; 24: 1953-1962
• 16 Bieler L, Vogl M, Kirchinger M, Urmann C, Riepl H, Bandtlow C, Klimaschewski L, Aigner L, Couillard-Despres S. The prenylflavonoid ENDF1 overrules central nervous system growth inhibitors and facilitates regeneration of DRG neurons. Front Cell Neurosci 2019; 13: 332
• 17 Urmann C, Bieler L, Priglinger E, Aigner L, Couillard-Despres S, Riepl HM. Neuroregenerative potential of prenyl- and pyranochalcones: A structure–activity study. J Nat Prod 2021; 84: 2675-2682
• 18 Kirchinger M, Bieler L, Tevini J, Vogl M, Haschke-Becher E, Felder TK, Couillard-Després S, Riepl H, Urmann C. Development and characterization of the neuroregenerative Xanthohumol C/hydroxypropyl-β-cyclodextrin complex suitable for parenteral administration. Planta Med 2019; 85: 1233-1241
• 19 Sivandzade F, Cucullo L. Regenerative stem cell therapy for neurodegenerative diseases: An overview. Int J Mol Sci 2021; 22: 2153
• 20 Palop JJ, Chin J, Mucke L. A network dysfunction perspective on neurodegenerative diseases. Nature 2006; 443: 768-773
• 21 Karl C, Couillard-Despres S, Prang P, Munding M, Kilb W, Brigadski T, Plötz S, Mages W, Luhmann H, Winkler J, Bogdahn U, Aigner L. Neuronal precursor-specific activity of a human doublecortin regulatory sequence. J Neurochem 2005; 92: 264-282
• 22 Auld DS, Inglese J. Interferences with Luciferase Reporter Enzymes. In: Markossian S, Grossman A, Brimacombe K, Arkin M, Auld D, Austin C, Baell J, Chung TDY, Coussens NP, Dahlin JL, Devanarayan V, Foley TL, Glicksman M, Gorshkov K, Haas JV, Hall MD, Hoare S, Inglese J, Iversen PW, Kales SC, Lal-Nag M, Li Z, McGee J, McManus O, Riss T, Saradjian P, Sittampalam GS, Tarselli M, Trask jr. OJ, Wang Y, Weidner JR, Wildey MJ, Wilson K, Xia M, Xu X. editors Assay guidance manual. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004
• 23 Encinas M, Iglesias M, Liu Y, Wang H, Muhaisen A, Ceña V, Gallego C, Comella JX. Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells. J Neurochem 2002; 75: 991-1003
• 24 Xicoy H, Wieringa B, Martens GJM. The SH-SY5Y cell line in Parkinsonʼs disease research: A systematic review. Mol Neurodegener 2017; 12: 10
• 25 Kovalevich J, Langford D. Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology. In: Amini S, White MK. editors Neuronal Cell Culture. Totowa, NJ: Humana Press; 2013: 9-21
• 26 Tadić VM, Jeremic I, Dobric S, Isakovic A, Markovic I, Trajkovic V, Bojovic D, Arsic I. Anti-inflammatory, gastroprotective, and cytotoxic effects of Sideritis scardica extracts. Planta Med 2012; 78: 415-427
• 27 Lall N, Chrysargyris A, Lambrechts I, Fibrich B, Blom Van Staden A, Twilley D, de Canha MN, Oosthuizen CB, Bodiba D, Tzortzakis N. Sideritis Perfoliata (Subsp. Perfoliata) nutritive value and its potential medicinal properties. Antioxidants (Basel) 2019; 8: 521
• 28 Lytra K, Tomou EM, Chrysargyris A, Christofi MD, Miltiadous P, Tzortzakis N, Skaltsa H. Bio‐guided investigation of Sideritis cypria methanol extract driven by in Vitro antioxidant and cytotoxic assays. Chem Biodivers 2021; 18: e2000966
• 29 Tomou EM, Lytra K, Chrysargyris A, Christofi MD, Miltiadous P, Corongiu GL, Tziouvelis M, Tzortzakis N, Skaltsa H. Polar constituents, biological effects and nutritional value of Sideritis sipylea Boiss. Nat Prod Res 2022; 36: 4200-4204
• 30 Petreska J, Stefkov G, Kulevanova S, Alipieva K, Bankova V, Stefova M. Phenolic compounds of mountain tea from the Balkans: LC/DAD/ESI/MSn profile and content. Nat Prod Commun 2011; 6: 21-30
• 31 Tomou E, Chatzopoulou P, Skaltsa H. NMR analysis of cultivated Sideritis euboea Heldr. Phytochem Anal 2020; 31: 147-153
• 32 Tomou EM, Papaemmanouil CD, Diamantis DA, Kostagianni AD, Chatzopoulou P, Mavromoustakos T, Tzakos AG, Skaltsa H. Anti-ageing potential of S. euboea Heldr. phenolics. Molecules 2021; 26: 3151
• 33 Charami MT, Lazari D, Karioti A, Skaltsa H, Hadjipavlou-Litina D, Souleles C. Antioxidant and antiinflammatory activities of Sideritis perfoliata subsp. perfoliata (Lamiaceae). Phytother Res 2008; 22: 450-454
• 34 Pljevljakušić D, Šavikin K, Janković T, Zdunić G, Ristić M, Godjevac D, Konić-Ristić A. Chemical properties of the cultivated Sideritis raeseri Boiss. & Heldr. subsp. raeseri . Food Chem 2011; 124: 226-233
• 35 Papaefstathiou G, Aligiannis N, Fokialakis N, Skaltsounis L. Metabolic profiling and antioxidant activity of Sideritis species growing in southeast europe. Planta Med 2014; 80: P2B105
• 36 Chrysargyris A, Kloukina C, Vassiliou R, Tomou EM, Skaltsa H, Tzortzakis N. Cultivation strategy to improve chemical profile and anti-oxidant activity of Sideritis perfoliata L. subsp. perfoliata . Ind Crops Prod 2019; 140: 111694
• 37 Axiotis E, Petrakis EA, Halabalaki M, Mitakou S. Phytochemical profile and biological activity of endemic Sideritis sipylea Boiss. in North Aegean Greek islands. Molecules 2020; 25: 2022
• 38 Hanoğlu DY, Hanoğlu A, Yusufoğlu H, Demirci B, Can Baser KH, Calis I, Yavuz DÖ. Phytochemical investigation of endemic Sideritis cypria post. Rec Nat Prod 2019; 14: 105-115
• 39 Petreska J, Stefova M, Ferreres F, Moreno DA, Tomás-Barberán FA, Stefkov G, Kulevanova S, Gil-Izquierdo A. Potential bioactive phenolics of Macedonian Sideritis species used for medicinal “Mountain Tea”. Food Chem 2011; 125: 13-20
• 40 Pihan LA, Peter S, Vollmer G, Meier B, Wolfram E. HPTLC fingerprint authentication of selected Sideritis spp. using a pharmacognostic approach. Planta Med 2021; 87: 1152-1166
• 41 Gil MI, Ferreres F, Marrero A, Tomás-Lorente F, Tomas-Barberan FA. Distribution of flavonoid aglycones and glycosides in Sideritis species from the Canary Islands and Madeira. Phytochemistry 1993; 34: 227-232
• 42 Tomás-Barberan FA, Gil MI, Ferreres F, Tomás-Lorente F. Flavonoid p-coumaroylglucosides and 8-hydroxyflavone allosylglucosides in some labiatae. Phytochemistry 1992; 31: 3097-3102
• 43 Trikka F, Michailidou S, Makris AM, Argiriou A. Biochemical fingerprint of Greek Sideritis spp.: Implications for potential drug discovery and advanced breeding strategies. Med Aromat Plants 2019; 8
• 44 Schummer C, Delhomme O, Appenzeller BM, Wennig R, Millet M. Comparison of MTBSTFA and BSTFA in derivatization reactions of polar compounds prior to GC/MS analysis. Talanta 2009; 77: 1473-1482
• 45 Ruiz-Matute AI, Hernández-Hernández O, Rodríguez-Sánchez S, Sanz ML, Martínez-Castro I. Derivatization of carbohydrates for GC and GC-MS analyses. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879: 1226-1240
• 46 Żyżelewicz D, Kulbat-Warycha K, Oracz J, Żyżelewicz K. Polyphenols and other bioactive compounds of Sideritis plants and their potential biological activity. Molecules 2020; 25: 3763
• 47 Aksenov AA, Laponogov I, Zhang Z, Doran SLF, Belluomo I, Veselkov D, Bittremieux W, Nothias LF, Nothias-Esposito M, Maloney KN, Misra BB, Melnik AV, Smirnov A, Du X, Jones 2nd KL, Dorrestein K, Panitchpakdi M, Ernst M, van der Hooft JJJ, Gonzalez M, Carazzone C, Amézquita A, Callewaert C, Morton JT, Quinn RA, Bouslimani A, Orio AA, Petras D, Smania AM, Couvillion SP, Burnet MC, Nicora CD, Zink E, Metz TO, Artaev V, Humston-Fulmer E, Gregor R, Meijler MM, Mizrahi I, Eyal S, Anderson B, Dutton R, Lugan R, Boulch PL, Guitton Y, Prevost S, Poirier A, Dervilly G, Le Bizec B, Fait A, Persi NS, Song C, Gashu K, Coras R, Guma M, Manasson J, Scher JU, Barupal DK, Alseekh S, Fernie AR, Mirnezami R, Vasiliou V, Schmid R, Borisov RS, Kulikova LN, Knight R, Wang M, Hanna GB, Dorrestein PC, Veselkov K. Auto-deconvolution and molecular networking of gas chromatography-mass spectrometry data. Nat Biotechnol 2021; 39: 169-173