Withanolide Profile and Acetylcholinesterase Inhibitory Activity of Two Argentinean Jaborosa Species^{[ # ]}

Abstract

Acetylcholinesterase (AChE) inhibitors are still an important option for managing symptoms of mild to moderate Alzheimerʼs disease. In this study, we aimed to evaluate the potential in vitro AChE inhibitory activity of two Argentinian endemic Solanaceae species, Jaborosa bergii and J. runcinata. UHPLC-DAD-HRMS metabolite profiling revealed the presence of withanolides in the active CH₂Cl₂ subextracts. Their fractionation led to the isolation and identification of two known spiranoid withanolides from J. runcinata and three new withanolides with a skeleton similar to that of trechonolide-type withanolides from J. bergii. The known compounds showed moderate AChE inhibitory activity, while the new ones were inactive.

Keywords

Withanolides - Jaborosa bergii - Jaborosa runcinata - Solanaceae - Alzheimerʼs disease - cholinesterase inhibition

• References

• 1 Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimerʼs disease. The Lancet 2021; 397: 1577-1590
• 2 Alzheimerʼs Disease International Dementia Statistics. Accessed September 8, 2023 at: https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/
• 3 Long JM, Holtzman DM. Alzheimer disease: An update on pathobiology and treatment strategies. Cell 2019; 179: 312-339
• 4 Jack jr. CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R. Contributors NIA-AA research framework. Toward a biological definition of alzheimerʼs disease. Alzheimers Dement 2018; 14: 535-562
• 5 U.S. Food and Drug Administration. FDA Grants Accelerated Approval for Alzheimerʼs Disease Treatment. Accessed November 29, 2023 at: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
• 6 U.S. Food and Drug Administration. FDAʼs Decision to Approve New Treatment for Alzheimerʼs Disease. Accessed November 29, 2023 at: https://www.fda.gov/drugs/our-perspective/fdas-decision-approve-new-treatment-alzheimers-disease
• 7 Madnani RS. Alzheimerʼs disease: A mini-review for the clinician. Front Neurol 2023; 14: 1178588
• 8 The Lancet Lecanemab for Alzheimerʼs Disease. Tempering hype and hope. The Lancet 2022; 400: 1899
• 9 Miculas DC, Negru PA, Bungau SG, Behl T, ul Hassan SS, Tit DM. Pharmacotherapy evolution in alzheimerʼs disease: Current framework and relevant directions. Cells 2022; 12: 131
• 10 Tayeb HO, Yang HD, Price BH, Tarazi FI. Pharmacotherapies for alzheimerʼs disease: Beyond cholinesterase inhibitors. Pharmacol Ther 2012; 134: 8-25
• 11 Ng YP, Or TCT, Ip NY. Plant alkaloids as drug leads for alzheimerʼs disease. Neurochem Int 2015; 89: 260-270
• 12 Smyrska-Wieleba N, Mroczek T. Natural inhibitors of cholinesterases: Chemistry, structure–activity and methods of their analysis. Int J Mol Sci 2023; 24: 2722
• 13 Jaborosa Juss. Accessed September 11, 2023: https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:38397-1
• 14 Chiarini FE, Barboza GE. Karyological studies in Jaborosa (Solanaceae). Bot J Linn Soc 2008; 156: 467-478
• 15 Flora Argentina. Accessed September 11, 2023: http://www.floraargentina.edu.ar/
• 16 Alza NP, Richmond V, Baier CJ, Freire E, Baggio R, Murray AP. Synthesis and cholinesterase inhibition of cativic acid derivatives. Bioorg Med Chem 2014; 22: 3838-3849
• 17 Cavallaro V, Alza NP, Murray MG, Murray AP. Alkaloids from Habranthus tubispathus and H. jamesonii, two amaryllidaceae with acetyl- and butyrylcholinesterase inhibition activity. Nat Prod Commun 2014; 9: 159-162
• 18 Alza NP, Murray AP. Chemical constituents and acetylcholinesterase inhibition of senecio ventanensis cabrera (Asteraceae). Rec Nat Prod 2016; 10: 513-518
• 19 Cavallaro V, Baier CJ, Murray MG, Estévez-Braun A, Murray AP. Neuroprotective effects of Flaveria Bidentis and Lippia Salsa extracts on SH-SY5Y cells. S Afr J Bot 2018; 119: 318-324
• 20 Cirigliano AM, Misico RI. Spiranoid withanolides from Jaborosa Odonelliana and Jaborosa Runcinata . Z Naturforsch B 2005; 60: 867-869
• 21 Cirigliano AM, Veleiro AS, Bonetto GM, Oberti JC, Burton G. Spiranoid withanolides from Jaborosa Runcinata and Jaborosa Araucana . J Nat Prod 1996; 59: 717-721
• 22 García ME, Nicotra VE, Oberti JC, Ríos-Luci C, León LG, Marler L, Li G, Pezzuto JM, van Breemen RB, Padrón JM, Hueso-Falcón I, Estévez-Braun A. Antiproliferative and quinone reductase-inducing activities of withanolides derivatives. Eur J Med Chem 2014; 82: 68-81
• 23 Monteagudo ES, Burton G, Gonzalez CM, Oberti JC, Gros EG. 14β,17β- dihydroxywithanolides from Jaborosa Bergii. Phytochemistry 1988; 27: 3925-3928
• 24 Nicotra VE, Gil RR, Vaccarini C, Oberti JC, Burton G. 15, 21-cyclowithanolides from Jaborosa Bergii. J Nat Prod 2003; 66: 1471-1475
• 25 González U, Nieto-Camacho A, Hernández-Ortega S, Martínez M, Maldonado E. Withanolides from Datura Ceratocaula and Datura Discolor and their acetylcholinesterase inhibitory activity. Fitoterapia 2023; 170: 105655
• 26 Choudhary MI, Nawaz SA, ul-Haq Z, Lodhi MA, Ghayur MN, Jalil S, Riaz N, Yousuf S, Malik A, Gilani AH, ur-Rahman A. Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. Biochem Biophys Res Commun 2005; 334: 276-287
• 27 Xia G, Cao S, Chen L, Qiu F. Natural withanolides, an update. Nat Prod Rep 2022; 39: 784-813
• 28 Chen LX, He H, Qiu F. Natural withanolides: An overview. Nat Prod Rep 2011; 28: 705
• 29 Veleiro AS, Oberti JC, Burton G. Chemistry and Bioactivity of Withanolides from South American Solanaceae. In: Atta-ur-Rehman (ed.): Studies in Natural Products Chemistry, Vol. 32. Amsterdam: Elsevier; 2005: 1019-1052
• 30 Lavie D, Bessalle R, Pestchanker MJ, Gottlieb HE, Frolow F, Giordano OS. Trechonolide A, a new withanolide type from Trechonaetes Laciniata . Phytochemistry 1987; 26: 1791-1795
• 31 Monteagudo ES, Oberti JC, Gros EG, Burton G. A spiranic withanolide from Jaborosa Odonelliana . Phytochemistry 1990; 29: 933-935
• 32 Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7: 88-95
• 33 Blaženović I, Kind T, Ji J, Fiehn O. Software tools and approaches for compound identification of LC-MS/MS data in metabolomics. Metabolites 2018; 8: 31
• 34 Sumner LW, Amberg A, Barrett D, Beale MH, Beger R, Daykin CA, Fan TW, Fiehn O, Goodacre R, Griffin JL, Hankemeier T, Hardy N, Harnly J, Higashi R, Kopka J, Lane AN, Lindon JC, Marriott P, Nicholls AW, Reily MD, Thaden JJ, Viant MR. Proposed minimum reporting standards for chemical analysis: Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI). Metabolomics 2007; 3: 211-221
• 35 Liebisch G, Fahy E, Aoki J, Dennis EA, Durand T, Ejsing CS, Fedorova M, Feussner I, Griffiths WJ, Köfeler H, Merrill Jr AH, Murphy RC, OʼDonnell VB, Oskolkova O, Subramaniam S, Wakelam MJO, Spener F. Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures. J Lipid Res 2020; 61: 1539-1555