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The Effects and Mechanisms of Xanthones in Alzheimer’s Disease: A Systematic Review

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Abstract

Xanthones are natural secondary metabolites that possess great potential as neuroprotective agents due to their prominent biological effects on Alzheimer’s disease (AD). However, their underlying mechanisms in AD remain unclear. This study aimed to systematically review the effects and mechanisms of xanthones in cell culture and animal studies, gaining a better understanding of their roles in AD. A comprehensive literature search was conducted in the Medline and Scopus databases using specific keywords to identify relevant articles published up to June 2023. After removing duplicates, all articles were imported into the Rayyan software. The article titles were screened based on predefined inclusion and exclusion criteria. Relevant full-text articles were assessed for biases using the OHAT tool. The results were presented in tables. Xanthones have shown various pharmacological effects towards AD from the 21 preclinical studies included. Cell culture studies demonstrated the anti-cholinesterase activity of xanthones, which protects against the loss of acetylcholine. Xanthones exhibited neuroprotective effects by promoting cell viability, reducing the accumulation of β-amyloid and tau aggregation. The administration of xanthones in animal models resulted in a reduction in neuronal inflammation by decreasing microglial and astrocyte burden. In terms of molecular mechanisms, xanthones prevented neuroinflammation through the modulation of signaling pathways, including TLR4/TAK1/NF-κB and MAPK pathways. Mechanisms such as activation of caspase-3 and -9 and suppression of endoplasmic reticulum stress were also reported. Despite the various neuroprotective effects associated with xanthones, there are limited studies reported on their underlying mechanisms in AD. Further studies are warranted to fully understand their potential roles in AD.

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Data Availability

The articles used for the current study are available from the corresponding author on reasonable request. The result of OHAT bias assessment is available in the supplementary information files.

Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

AMPK:

AMP-activated protein kinase

APP:

Amyloid precursor protein

Aβ:

Amyloid beta

BACE1:

β-Site amyloid precursor protein cleaving enzyme 1

Bax:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2

BuChE:

Butyrylcholinesterase

COX-2:

Cyclooxygenase-2

DNA:

Deoxyribonucleic acid

DPPH:

2,2-Diphenyl-1-picrylhydrazyl

ERS:

Endoplasmic reticulum stress

FDA:

Food and Drug Administration

GSK:

Glycogen synthase kinase

H2O2 :

Hydrogen peroxide

HO:

Heme oxygenase

IgG1:

Immunoglobulin G1

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

LPO:

Lipid peroxide

LPS:

Lipopolysaccharide

MeSH:

Medical Subject Headings

mRNA:

Messenger ribonucleic acid

NF-κB:

Nuclear factor kappa light chain enhancer of activated B cells

NLRP3:

NLR family pyrin domain containing 3

NO:

Nitric oxide

OHAT:

Office of Health Assessment and Translation

PGC-1 α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PICO:

Population, Intervention, Comparison and Outcome

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PRISMA-SR:

Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Systematic Reviews

ROS:

Reactive oxygen species

SIRT1:

Sirtuin 1

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factor alpha

TLR4:

Toll-like receptor-4

References

  1. Guerchet M, Prince M, Prina M (2020) Numbers of people with dementia worldwide: an update to the estimates in the World Alzheimer Report 2015. https://www.alzint.org/u/numbers-people-with-dementia-2017.pdf. Accessed 30 Apr 2023

  2. Adlard PA, Bush AI (2018) Metals and Alzheimer’s disease: how far have we come in the clinic? J Alzheimers Dis 62:1369–1379

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M (2019) Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomed 14:5541–5554

    Article  CAS  Google Scholar 

  4. Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM (2016) Alzheimer’s disease: targeting the cholinergic system. Curr Neuropharmacol 14:101–115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Chen ZR, Huang JB, Yang SL, Hong FF (2022) Role of cholinergic signaling in Alzheimer’s disease. Molecules 27:1816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Kim DH, Brown RT, Ding EL, Kiel DP, Berry SD (2011) Dementia medications and risk of falls, syncope, and related adverse events: meta-analysis of randomized controlled trials. J Am Geriatr Soc 59:1019–1031

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cummings J, Lee G, Nahed P, Kambar M, Zhong K, Fonseca J, Taghva K (2022) Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement 8:e12295

    Article  Google Scholar 

  8. Söderberg L, Johannesson M, Nygren P, Laudon H, Eriksson F, Osswald G, Möller C, Lannfelt L (2023) Lecanemab, aducanumab, and gantenerumab—binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease. Neurotherapeutics 20:195–206

    Article  PubMed  Google Scholar 

  9. Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S (2021) Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther 13:98

    Article  PubMed  PubMed Central  Google Scholar 

  10. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T (2023) Lecanemab in early Alzheimer’s disease. New Engl J Med 388:9–21

    Article  PubMed  Google Scholar 

  11. Shagufta AI (2016) Recent insight into the biological activities of synthetic xanthone derivatives. Eur J Med Chem 116:267–280

    Article  PubMed  CAS  Google Scholar 

  12. Pinto MM, Sousa ME, Nascimento MS (2005) Xanthone derivatives: new insights in biological activities. Curr Med Chem 12:2517–2538

    Article  PubMed  CAS  Google Scholar 

  13. Wang Y, Xia Z, Xu JR, Wang YX, Hou LN, Qiu Y, Chen HZ (2012) Α-mangostin, a polyphenolic xanthone derivative from mangosteen, attenuates β-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation. Neuropharmacology 62:871–881

    Article  PubMed  CAS  Google Scholar 

  14. Khaw KY, Choi SB, Tan SC, Wahab HA, Chan KL, Murugaiyah V (2014) Prenylated xanthones from mangosteen as promising cholinesterase inhibitors and their molecular docking studies. Phytomedicine 21:1303–1309

    Article  PubMed  CAS  Google Scholar 

  15. Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S (2014) PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res 14:579

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A (2016) Rayyan—a web and mobile app for systematic reviews. Syst Rev 5:210

    Article  PubMed  PubMed Central  Google Scholar 

  17. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71

    Article  PubMed  PubMed Central  Google Scholar 

  18. National Institutes of Environmental Health Sciences (2019) Handbook for conducting a literature-based health assessment using OHAT approach for systematic review and evidence integration. https://ntp.niehs.nih.gov/whatwestudy/assessments/noncancer/handbook/index.html. Accessed 30 Apr 2023

  19. Jung K, Lee B, Han SJ, Ryu JH, Kim DH (2009) Mangiferin ameliorates scopolamine-induced learning deficits in mice. Biol Pharm Bull 32:242–246

    Article  PubMed  CAS  Google Scholar 

  20. Biradar SM, Joshi H, Chheda TK (2012) Neuropharmacological effect of mangiferin on brain cholinesterase and brain biogenic amines in the management of Alzheimer’s disease. Eur J Pharmacol 683:140–147

    Article  PubMed  CAS  Google Scholar 

  21. Du Z, Fanshi F, Lai YH, Chen JR, Hao E, Deng J, Hsiao CD (2019) Mechanism of anti-dementia effects of mangiferin in a senescence accelerated mouse (SAMP8) model. Biosci Rep 39:BSR20190488

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lei LY, Wang RC, Pan YL, Yue ZG, Zhou R, Xie P, Tang ZS (2021) Mangiferin inhibited neuroinflammation through regulating microglial polarization and suppressing NF-κB, NLRP3 pathway. Chin J Nat Med 19:112–119

    PubMed  CAS  Google Scholar 

  23. Chen F, Wang N, Tian X, Su J, Qin Y, He R, He X (2023) The protective effect of mangiferin on formaldehyde-induced HT22 cell damage and cognitive impairment. Pharmaceutics 15:1568

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Reyes-Fermín LM, González-Reyes S, Tarco-Álvarez NG, Hernández-Nava M, Orozco-Ibarra M, Pedraza-Chaverri J (2012) Neuroprotective effect of α-mangostin and curcumin against iodoacetate-induced cell death. Nutr Neurosci 15:34–41

    Article  PubMed  Google Scholar 

  25. Zhao LX, Wang Y, Liu T, Wang YX, Chen HZ, Xu JR, Qiu Y (2017) α-Mangostin decreases β-amyloid peptides production via modulation of amyloidogenic pathway. CNS Neurosci Ther 23:526–534

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Guan H, Li J, Tan X, Luo S, Liu Y, Meng Y, Wu B, Zhou Y, Yang Y, Chen H, Hou L, Qiu Y, Li J (2020) Natural xanthone α-mangostin inhibits lps-induced microglial inflammatory responses and memory impairment by blocking the TAK1/NF-κB signaling pathway. Mol Nutr Food Res 64:e2000096

    Article  PubMed  Google Scholar 

  27. Tiang N, Ahad MA, Murugaiyah V, Hassan Z (2020) Xanthone-enriched fraction of Garcinia mangostana and α-mangostin improve the spatial learning and memory of chronic cerebral hypoperfusion rats. J Pharm Pharmacol 72:1629–1644

    Article  PubMed  CAS  Google Scholar 

  28. Ruankham W, Suwanjang W, Phopin K, Songtawee N, Prachayasittikul V, Prachayasittikul S (2022) Modulatory effects of alpha-mangostin mediated by SIRT1/3-FOXO3a pathway in oxidative stress-induced neuronal cells. Front Nutr 8:714463

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wang SN, Li Q, Jing MH, Alba E, Yang XH, Sabaté R, Han YF, Pi RB, Lan WJ, Yang XB, Chen JK (2016) Natural xanthones from Garcinia mangostana with multifunctional activities for the therapy of Alzheimer’s disease. Neurochem Res 41:1806–1817

    Article  PubMed  CAS  Google Scholar 

  30. Hu X, Liu C, Wang K, Zhao L, Qiu Y, Chen H, Hu J, Xu J (2022) Multifunctional anti-Alzheimer’s disease effects of natural xanthone derivatives: a primary structure-activity evaluation. Front Chem 10:842208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Alberdi E, Sánchez-Gómez MV, Ruiz A, Cavaliere F, Ortiz-Sanz C, Quintela-López T, Capetillo-Zarate E, Solé-Domènech S, Matute C (2018) Mangiferin and morin attenuate oxidative stress, mitochondrial dysfunction, and neurocytotoxicity, induced by amyloid beta oligomers. Oxid Med Cell Longev 2018:2856063

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lee Y, Kim S, Oh Y, Kim Y-M, Chin Y-W, Cho J (2019) Inhibition of oxidative neurotoxicity and scopolamine-induced memory impairment by γ-mangostin: in vitro and in vivo evidence. Oxid Med Cell Longev 2019:3640753

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kong C, Jia L, Jia J (2022) γ-Mangostin attenuates amyloid-β42-induced neuroinflammation and oxidative stress in microglia-like BV2 cells via the mitogen-activated protein kinases signaling pathway. Eur J Pharmacol 917:174744

    Article  PubMed  CAS  Google Scholar 

  34. Xiong J, Liu XH, Bui VB, Hong ZL, Wang LJ, Zhao Y, Fan H, Yang GX, Hu JF (2014) Phenolic constituents from the leaves of Cratoxylum formosum ssp. pruniflorum. Fitoterapia 94:114–119

    Article  PubMed  CAS  Google Scholar 

  35. Gao XY, Wang SN, Yang XH, Lan WJ, Chen ZW, Chen JK, Xie JH, Han YF, Pi RB, Yang XB (2016) Gartanin protects neurons against glutamate-induced cell death in HT22 cells: independence of Nrf-2 but involvement of HO-1 and AMPK. Neurochem Res 41:2267–2277

    Article  PubMed  CAS  Google Scholar 

  36. Tonelli M, Catto M, Sabaté R, Francesconi V, Laurini E, Pricl S, Pisani L, Miniero DV, Liuzzi GM, Gatta E (2023) Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer’s disease. Eur J Med Chem 250:115169

    Article  PubMed  CAS  Google Scholar 

  37. Çalış İ, Becer E, Ünlü A, Aydın ZU, Hanoğlu A, Vatansever HS, Dönmez AA (2023) Comparative phytochemical studies on the roots of Polygala azizsancarii and P. peshmenii and neuroprotective activities of the two xanthones. Phytochemistry 210:113650

    Article  PubMed  Google Scholar 

  38. Abdallah HM, El Sayed NS, Sirwi A, Ibrahim SRM, Mohamed GA, Abdel Rasheed NO (2021) Mangostanaxanthone IV ameliorates streptozotocin-induced neuro-inflammation, amyloid deposition, and tau hyperphosphorylation via modulating PI3K/Akt/GSK-3β pathway. Biology 10:1298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Sethiya NK, Mishra SH (2014) Investigation of mangiferin, as a promising natural polyphenol xanthone on multiple targets of Alzheimer’s disease. J Biol Act Prod Nat 4:111–119

    CAS  Google Scholar 

  40. Negi JS, Bisht VK, Singh P, Rawat MSM, Joshi GP (2013) Naturally occurring xanthones: chemistry and biology. J Appl Chem 2013:621459

    Article  Google Scholar 

  41. Chen Y, Bian Y, Wang J-W, Gong T-T, Ying Y-M, Ma L-F, Shan W-G, Xie X-Q, Zhan Z-J (2020) Effects of α-mangostin derivatives on the Alzheimer’s disease model of rats and their mechanism: a combination of experimental study and computational systems pharmacology analysis. ACS Omega 5:9846–9863

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  PubMed  CAS  Google Scholar 

  43. Forman HJ, Fukuto JM, Torres M (2004) Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol 287:C246–C256

    Article  PubMed  CAS  Google Scholar 

  44. Radi E, Formichi P, Battisti C, Federico A (2014) Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis 42(Suppl 3):S125–S152

    Article  PubMed  Google Scholar 

  45. Satoh T, McKercher SR, Lipton SA (2013) Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs. Free Radic Biol Med 65:645–657

    Article  PubMed  CAS  Google Scholar 

  46. Carafa V, Rotili D, Forgione M, Cuomo F, Serretiello E, Hailu GS, Jarho E, Lahtela-Kakkonen M, Mai A, Altucci L (2016) Sirtuin functions and modulation: from chemistry to the clinic. Clin Epigenet 8:1–21

    Article  Google Scholar 

  47. Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Azam S, Jakaria M, Kim IS, Kim J, Haque ME, Choi DK (2019) Regulation of toll-like receptor (TLR) signaling pathway by polyphenols in the treatment of age-linked neurodegenerative diseases: focus on TLR4 signaling. Front Immunol 10:1000

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Bumrungpert A, Kalpravidh RW, Chuang CC, Overman A, Martinez K, Kennedy A, McIntosh M (2010) Xanthones from mangosteen inhibit inflammation in human macrophages and in human adipocytes exposed to macrophage-conditioned media. J Nutr 140:842–847

    Article  PubMed  CAS  Google Scholar 

  50. Miron J, Picard C, Frappier J, Dea D, Théroux L, Poirier J (2018) TLR4 gene expression and pro-inflammatory cytokines in Alzheimer’s disease and in response to hippocampal deafferentation in rodents. J Alzheimers Dis 63:1547–1556

    Article  PubMed  CAS  Google Scholar 

  51. Morrison DK (2012) MAP kinase pathways. Cold Spring Harb Perspect Biol 4:a011254

    Article  PubMed  PubMed Central  Google Scholar 

  52. Vinutha B, Prashanth D, Salma K, Sreeja SL, Pratiti D, Padmaja R, Radhika S, Amit A, Venkateshwarlu K, Deepak M (2007) Screening of selected Indian medicinal plants for acetylcholinesterase inhibitory activity. J Ethnopharmacol 109:359–363

    Article  PubMed  CAS  Google Scholar 

  53. Chen WN, Yeong KY (2020) Scopolamine, a toxin-induced experimental model, used for research in Alzheimer’s disease. CNS Neurol Disord Drug Targets 19:85–93

    Article  PubMed  CAS  Google Scholar 

  54. Hampel H, Vassar R, De Strooper B, Hardy J, Willem M, Singh N, Zhou J, Yan R, Vanmechelen E, De Vos A, Nisticò R, Corbo M, Imbimbo BP, Streffer J, Voytyuk I, Timmers M, Tahami Monfared AA, Irizarry M, Albala B, Koyama A, Watanabe N, Kimura T, Yarenis L, Lista S, Kramer L, Vergallo A (2021) The β-secretase BACE1 in Alzheimer’s disease. Biol Psychiatry 89:745–756

    Article  PubMed  CAS  Google Scholar 

  55. Zhu K, Xiang X, Filser S, Marinković P, Dorostkar MM, Crux S, Neumann U, Shimshek DR, Rammes G, Haass C, Lichtenthaler SF, Gunnersen JM, Herms J (2018) Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol Psychiatry 83:428–437

    Article  PubMed  CAS  Google Scholar 

  56. Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71:505–508

    Article  PubMed  Google Scholar 

  57. Qin J, Lan W, Liu Z, Huang J, Tang H, Wang H (2013) Synthesis and biological evaluation of 1,3-dihydroxyxanthone mannich base derivatives as anticholinesterase agents. Chem Cent J 7:78

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zhang Z, Guo J, Cheng M, Zhou W, Wan Y, Wang R, Fang Y, Jin Y, Liu J, Xie SS (2021) Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 213:113154

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, 47500, Subang Jaya, Selangor, Malaysia

    Li Wen Pang, Sharina Hamzah & Hui Yin Yow

  2. Medical Advancement for Better Quality of Life Impact Lab, Taylor’s University, 47500, Subang Jaya, Selangor, Malaysia

    Sharina Hamzah

  3. Department of Pharmaceutical Technology, Faculty of Pharmacy, Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    Sui Ling Janet Tan

  4. School of Biosciences, Faculty of Health and Medical Sciences, Taylor’s University, 47500, Subang Jaya, Selangor, Malaysia

    Siau Hui Mah

  5. Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    Hui Yin Yow

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Conceptualisation: YHY, SH, MSH; writing-original draft preparation: PLW, YHY; writing: PLW, SH, SLJT, MSH, YHY; review and editing: YHY, SLJT. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Hui Yin Yow.

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Pang, L.W., Hamzah, S., Tan, S.L.J. et al. The Effects and Mechanisms of Xanthones in Alzheimer’s Disease: A Systematic Review. Neurochem Res 48, 3485–3511 (2023). https://doi.org/10.1007/s11064-023-04005-8

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