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Bio-guided isolation of anti-Alzheimer’s compounds from Phyllanthus niruri and role of niruriflavone in the reversal of aluminum chloride-induced neurobehavioral and biochemical changes in an animal model

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Abstract

Alzheimer’s disease (AD) is one of the chronic neurodegenerative pathologies that lead to memory loss and mental and behavioral changes in elderly people. The senile plaques, neurofibrillary tangles, oxidative stress, increased acetylcholinesterase (AChE), and neuroinflammation by activating 5-lipoxygenases (5-LOX) are important pathological processes in AD. Phyllanthus niruri Linn (PN) earned a lot of attention for phytoconstituents and their medicinal properties. The compounds quercitrin and niruriflavone were isolated by bio-guided fractionation from PN using the in vitro assays. Both compounds showed good docking scores on AChE and 5-LOX targets in the molecular docking studies. AD was induced in rats by 100 mg/kg of oral aluminum chloride (AlCl3) for 42 days. It decreased the antioxidative enzymes and increased lipid peroxidation and AChE activity. Oral administration of niruriflavone reversed the neurobehavioral changes caused by AlCl3. The niruriflavone treatment also restored the antioxidative enzymes and attenuated the AChE and lipid peroxidation. All the evidence suggests that isolated compounds could benefit the population afflicted by AD in a multitargeted manner.

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References

  1. Wang X, Wang W, Li L, Perry G, Lee H, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. 2014;1842:1240–7.

    Article  CAS  Google Scholar 

  2. Carvajal FJ, Inestrosa NC. Interactions of AChE with Aβ aggregates in Alzheimer’s brain: therapeutic relevance of IDN 5706. Front Mol Neurosci. 2011;4:19 https://doi.org/10.3389/fnmol.2011.00019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Garcia-Ayllon MS, Small DH, Avila J, Saez-Valero J. Revisiting the role of acetylcholinesterase in Alzheimer’s disease: crosstalk with P-tau and β-amyloid. Front Mol Neurosci. 2011;4:1–9.

    Article  Google Scholar 

  4. Dzoyem JP, Eloff JN. Anti-inflammatory, anticholinesterase, and antioxidant activity of leaf extracts of twelve plants used traditionally to alleviate pain and inflammation in South Africa. J Ethnopharmacol. 2015;160:194–201. https://doi.org/10.1016/j.jep.2014.11.034.

    Article  CAS  PubMed  Google Scholar 

  5. Joshi Y, Pratico D. Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase. Transl Neurosci. 2014;5:197–202. https://doi.org/10.2478/s13380-014-0225-7.

  6. Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M. Alzheimer’s Disease International. World Alzheimer report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. https://www.alz.co.uk/research/world-report-2015.

  7. Nichols E. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet. 2022;7:E105–25.

    Google Scholar 

  8. Yiannopoulou KG, Papageorgiou SG. Current and future treatments in Alzheimer disease: an update. J Cent Nerv Syst Dis. 2020;12:1179573520907397.

    Article  Google Scholar 

  9. Kim MJ, Rehman SU, Amin FU, Kim MO. Enhanced neuroprotection of anthocyanin-loaded PEG-gold nanoparticles against Aβ1-42-induced neuroinflammation and neurodegeneration via the NF-KB/JNK/GSK3β signaling pathway. Nanomedicine. 2017;13:2533 https://doi.org/10.1016/j.nano.2017.06.022.

    Article  CAS  PubMed  Google Scholar 

  10. Abdel-Aal RA, Assi AA, Kostandy BB. Rivastigmine reverses aluminum-induced behavioral changes in rats. Eur J Pharmacol. 2011;659:169–76. https://doi.org/10.1016/j.ejphar.2011.03.011. PMID: 21440537.

    Article  CAS  PubMed  Google Scholar 

  11. Bagalkotkar G, Sagineedu SR, Saad MS, Stanslas J. Phytochemicals from Phyllanthus niruri Linn. and their pharmacological properties: a review. J Pharm Pharm. 2006;58:1559–70. https://doi.org/10.1211/jpp.58.12.0001. PMID: 17331318.

    Article  CAS  Google Scholar 

  12. Manjrekar AP, Jisha V, Bag PP, Adhikary B, Pai MM, Hegde A. et al. Effect of Phyllanthus niruri treatment on liver, kidney, and testes in CCl4 induced hepatotoxic rats. Indian J Exp Biol. 2008;46:514–20.

    CAS  PubMed  Google Scholar 

  13. Anuar N, Markom M, Khairedin S, Johari N. A production and extraction of quercetin and (+)-catechin from Phyllanthus niruri callus culture. Int J Biol Biomol. 2012;6:968–71.

    Google Scholar 

  14. Sharma P, Parmar J, Verma P, Sharma P, Goyal PK. Anti-tumor activity of Phyllanthus niruri (a medicinal plant) on chemical-induced skin carcinogenesis in mice. Asian Pac J Cancer Prev. 2009;10:1089–94. PMID: 20192590.

    PubMed  Google Scholar 

  15. Hardiyanti R, Marpaung L, Adnyana K, Simanjuntak P. Isolation of quercitrin from Dendrophthoe pentandra (l.) miq leaves and its antioxidant and antibacterial activities. Rasayan J Chem. 2019;12:1822–27.

    Article  CAS  Google Scholar 

  16. Utari F, Itam A, Syafrizayanti S, Putri WH, Ninomiya M, Koketsu M. et al. Isolation of flavonol rhamnosides from Pometia pinnata leaves and investigation of α-glucosidase inhibitory activity of flavonol derivatives. J Appl Pharm Sci. 2019;9:53–65.

    Article  CAS  Google Scholar 

  17. Than NN, Fotso S, Poeggeler B, Hardeland R, Laatsch H. Niruriflavone, a new antioxidant flavone sulfonic acid from Phyllanthus niruri. Z für Na turforschung B. 2006;61:57–60. https://doi.org/10.1515/znb-2006-0111.

    Article  Google Scholar 

  18. Andrianto D, Widianti W, Bintang M. Antioxidant and cytotoxic activity of Phyllanthus acidus fruit extracts. IOP Conf Ser Earth Environ Sci. 2017;58:1–5. https://doi.org/10.1088/1755-1315/58/1/012022.

    Article  Google Scholar 

  19. Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Disco. 2021;20:689–709. https://doi.org/10.1038/s41573-021-00233-1.

    Article  CAS  Google Scholar 

  20. Lipinski B. Hydroxyl radical and its scavengers in health and disease. Oxid Med Cell Longev. 2011;2011:809696. https://doi.org/10.1155/2011/809696.

  21. Mossa AT, Nawwar GA. Free radical scavenging and antiacetylcholinesterase activities of Origanum majorana L. essential oil. Hum Exp Toxicol. 2011;30:1501–13. https://doi.org/10.1177/0960327110391686. PMID: 21239482.

    Article  CAS  PubMed  Google Scholar 

  22. Lin CZ, Zhu CC, Hu M, Wu AZ, Bairu ZD, Kangsa SQ. Structure-activity relationships of antioxidant activity in vitro about flavonoids isolated from Pyrethrum tatsienense. J Intercult Ethnopharmacol. 2014;3:123–7. https://doi.org/10.5455/jice.20140619030232.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Noreen H, Semmar N, Farman M, McCullagh JSO. Measurement of total phenolic content and antioxidant activity of aerial parts of medicinal plant Coronopus didymus. Asian Pac J Trop Med. 2017;10:792–801. https://doi.org/10.1016/j.apjtm.2017.07.024. PMID: 28942828.

    Article  CAS  PubMed  Google Scholar 

  24. Joshi YB, Domenico P. The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer’s disease phenotype. Front Mol Neurosci. 2015;8:436. https://doi.org/10.3389/fncel.2014.00436.

  25. Gomes A, Fernandes E, Lima JL, Mira L, Corvo ML. Molecular mechanisms of anti-inflammatory activity mediated by flavonoids. Curr Med Chem. 2008;15:1586–605. https://doi.org/10.2174/092986708784911579. PMID: 18673226.

    Article  CAS  PubMed  Google Scholar 

  26. Alhawarri MB, Dianita R, Razak KNA, Mohamad S, Nogawa T, Wahab HA. Antioxidant, anti-inflammatory, and inhibition of acetylcholinesterase potentials of Cassia timoriensis DC. flowers. Molecules. 2021;26:2594 https://doi.org/10.3390/molecules26092594. PMID: 33946788; PMCID: PMC8125573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nam G, Hong M, Lee J, Lee HJ, Ji Y, Kang J. et al. Multiple reactivities of flavonoids towards pathological elements in Alzheimer’s disease: structure–activity relationship. Chem Sci. 2020;37:10243–54.

    Article  Google Scholar 

  28. Cavallaro V, Braun AE, Ravelo AG, Murray AP. Sulphated flavonoid isolated from Flaveria bidentis and its semisynthetic derivatives as potential drugs for Alzheimer’s disease. In Proceedings of the 17th International Electronic Conference on Synthetic Organic Chemistry. Basel, Switzerland: MDPI; 2013. https://doi.org/10.3390/ecsoc-17-b011.

  29. Figueira I, Garcia G, Pimpão RC, Terrasso AP, Costa I, Almeida AF. et al. Polyphenols journey through blood-brain barrier towards neuronal protection. Sci Rep. 2017;7:11456. https://doi.org/10.1038/s41598-017-11512-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shailima R, Mary RL. Network based approach in the establishment of the relationship between type 2 diabetes mellitus and its complications at the molecular level coupled with molecular docking mechanism. Biomed Res Int. 2016;2016:6068437. https://doi.org/10.1155/2016/6068437.

  31. Bhuvanendran S, Hanapi NA, Ahemad N, Othman I, Yusof SR, Shaikh MF. Embelin, a potent molecule for Alzheimer’s disease: a proof of concept from blood-brain barrier permeability, acetylcholinesterase inhibition and molecular docking studies. Front Neurosci. 2019;13:495 https://doi.org/10.3389/fnins.2019.00495.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Singh NA, Bhardwaj V, Ravi C, Ramesh N, Mandal AKA, Khan ZA. EGCG nanoparticles attenuate aluminum chloride induced neurobehavioral deficits, beta amyloid and tau pathology in a rat model of Alzheimer’s disease. Front Aging Neurosci. 2018;10:244. https://doi.org/10.3389/fnagi.2018.00244.

  33. Thippeswamy AH, Rafiq M, Viswantha GL, Kavya KJ, Anturlikar SD, Patki PS. Evaluation of Bacopa monniera for its synergistic activity with rivastigmine in reversing aluminum-induced memory loss and learning deficit in rats. J Acupunct Meridian Stud. 2013;6:208–13. https://doi.org/10.1016/j.jams.2013.02.004. PMID: 23972243.

    Article  PubMed  Google Scholar 

  34. Kumar A, Prakash A, Dogra S. Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats. Pharm Rep. 2011;63:915–23. https://doi.org/10.1016/s1734-1140(11)70607-7. PMID: 22001979.

    Article  CAS  Google Scholar 

  35. Kakkar V, Kaur IP. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol. 2011;49:2906–13. https://doi.org/10.1016/j.fct.2011.08.006. PMID: 21889563.

    Article  CAS  PubMed  Google Scholar 

  36. Kaizer RR, Corrêa MC, Spanevello RM, Morsch VM, Mazzanti CM, Gonçalves JF. et al. Acetylcholinesterase activation and enhanced lipid peroxidation after long-term exposure to low levels of aluminum on different mouse brain regions. J Inorg Biochem. 2005;99:1865–70. https://doi.org/10.1016/j.jinorgbio.2005.06.015. 16055195.

    Article  CAS  PubMed  Google Scholar 

  37. Kaur A, Gill KD. Possible peripheral markers for chronic aluminium toxicity in Wistar rats. Toxicol Ind Health. 2006;22:39–46. https://doi.org/10.1191/0748233706th242oa. PMID: 16572710.

    Article  CAS  PubMed  Google Scholar 

  38. Chen X, Zhang M, Ahmed M, Surapaneni KM, Veeraraghavan VP, Arulselvan P. Neuroprotective effects of ononin against the aluminium chloride-induced Alzheimer’s disease in rats. Saudi J Biol Sci. 2021;28:4232–9. https://doi.org/10.1016/j.sjbs.2021.06.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Al-Mamary M, Al-Habori M, Al-Zubairi AS. The in vitro antioxidant activity of different types of palm dates (Phoenix dactylifera) syrups. Arab J Chem. 2014;7:964–71.

    Article  CAS  Google Scholar 

  40. Hazra B, Biswas S, Mandal N. Antioxidant and free radical scavenging activity of Spondias pinnata. BMC Complement Alter Med. 2008;8:63 https://doi.org/10.1186/1472-6882-8-63.

    Article  Google Scholar 

  41. Mathew M, Subramanian S. In vitro screening for anti-cholinesterase and antioxidant activity of methanolic extracts of ayurvedic medicinal plants used for cognitive disorders. PLoS One. 2014;9:e86804 https://doi.org/10.1371/journal.pone.0086804.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Chung LY, Soo WK, Chan KY, Mustafa MR, Goh SH, Imiyabir Z. Lipoxygenase inhibiting activity of some Malaysian plants. Pharm Biol. 2009;47:1142–48. https://doi.org/10.3109/13880200903008724.

    Article  Google Scholar 

  43. Ishola AA, Oyinloye BE, Basiru A, Kappo AP. Molecular docking studies of flavonoids from Andrographis paniculata as potential acetylcholinesterase, butyrylcholinesterase and monoamine oxidase inhibitors towards the treatment of neurodegenerative diseases. Biointerface Res Appl Chem. 2020;11:9871–9. https://doi.org/10.33263/BRIAC113.98719879.

    Article  Google Scholar 

  44. Yadavalli R, Peasari JR, Mamindla P, Praveenkumar, Mounika S, Ganugapati J. Phytochemical screening and in silico studies of flavonoids from Chlorella pyrenoidosa. Inf Med Unlocked. 2018;10:89–99.

    Article  Google Scholar 

  45. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984;11:47–60.

    Article  CAS  Google Scholar 

  46. Bhalla P, Garg ML, Dhawan DK. Protective role of lithium during aluminium-induced neurotoxicity. Neurochem Int. 2010;56:256–62. https://doi.org/10.1016/j.neuint.2009.10.009.

    Article  CAS  PubMed  Google Scholar 

  47. Prakash A, Kumar A. Effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage in rats. Basic Clin Pharm Toxicol. 2009;105:98e104.

    Article  Google Scholar 

  48. Cheng L, Pan GF, Sun XB, Huang YX, Peng YS, Zhou LY. Evaluation of anxiolytic-like effect of aqueous extract of asparagus stem in mice. Evid Based Complement Altern Med. 2013;2013:587260 https://doi.org/10.1155/2013/587260. PMID: 24348707; PMCID: PMC3853311.

    Article  Google Scholar 

  49. Ellman GL, Courtney KD, Andres V Jr, feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharm. 1961;7:88–95. https://doi.org/10.1016/0006-2952(61)90145-9. PMID: 13726518.

    Article  CAS  PubMed  Google Scholar 

  50. Luck H. Catalase. In: Bergmeyer HU, editor. Methods of enzymatic analysis. New York: Academic Press; 1971. p. 885–93.

  51. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82:48670–7.

    Article  Google Scholar 

  52. Kono Y. Generation of superoxide radical during auto-oxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys. 1978;186:189–95.

    Article  CAS  Google Scholar 

  53. Wills ED. Mechanism of lipid peroxide formation in animal tissues. Biochem J. 1966;99:667–76.

    Article  CAS  Google Scholar 

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Rajamanickam, G., SL, M. Bio-guided isolation of anti-Alzheimer’s compounds from Phyllanthus niruri and role of niruriflavone in the reversal of aluminum chloride-induced neurobehavioral and biochemical changes in an animal model. Med Chem Res 31, 1740–1753 (2022). https://doi.org/10.1007/s00044-022-02944-5

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