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image of Phytoconstituents as Potential Therapeutics against Enzymatic Targets for Neurodegenerative Diseases

Abstract

Neurodegenerative diseases are brought on by the loss of function of nerve cells in the brain or peripheral nervous system and afflict millions of people worldwide. Parkinson's disease and Alzheimer's disease are the two most common neurodegenerative diseases. These neurodegenerative diseases are multi-factorial, progressive, age-related, and influenced by two factors: genetic and environmental. Successful treatment of neurodegenerative diseases is yet a challenging task due to lack of selectivity, toxicity, and the growth of multi-drug-resistant cells to the currently available drugs. Plant-derived, natural secondary metabolites have a significant impact on the research and development of novel medications against neurodegenerative disease. Plant-derived natural products are frequently regarded as safe and relatively safer substitutes for synthetic drugs. The present review deals with the elucidation of plant-derived secondary metabolites, namely alkaloids, flavonoids, and terpenoids, as anti-neurological therapeutics with special reference to various enzymatic targets, such as β-secretase, γ-secretase, α-Secretase, acetylcholinesterase, monoamine oxidase, and phosphodiesterase-4.

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2025-05-27
2025-09-02
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References

  1. Lamptey R.N.L. Chaulagain B. Trivedi R. Gothwal A. Layek B. Singh J. A review of the common neurodegenerative disorders: Current therapeutic approaches and the potential role of nanotherapeutics. Int. J. Mol. Sci. 2022 23 3 1851 10.3390/ijms23031851 35163773
    [Google Scholar]
  2. Merelli A. Czornyj L. Lazarowski A. Erythropoietin: A neuroprotective agent in cerebral hypoxia, neurodegeneration, and epilepsy. Curr. Pharm. Des. 2013 19 38 6791 6801 10.2174/1381612811319380011 23530506
    [Google Scholar]
  3. Hoover B.R. Reed M.N. Su J. Penrod R.D. Kotilinek L.A. Grant M.K. Pitstick R. Carlson G.A. Lanier L.M. Yuan L.L. Ashe K.H. Liao D. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010 68 6 1067 1081 10.1016/j.neuron.2010.11.030 21172610
    [Google Scholar]
  4. Milnerwood A.J. Raymond L.A. Early synaptic pathophysiology in neurodegeneration: Insights from Huntington’s disease. Trends Neurosci. 2010 33 11 513 523 10.1016/j.tins.2010.08.002 20850189
    [Google Scholar]
  5. Scott D.A. Tabarean I. Tang Y. Cartier A. Masliah E. Roy S. A pathologic cascade leading to synaptic dysfunction in α-synuclein-induced neurodegeneration. J. Neurosci. 2010 30 24 8083 8095 10.1523/JNEUROSCI.1091‑10.2010 20554859
    [Google Scholar]
  6. Kovacs G.G. Molecular pathology of neurodegenerative diseases: Principles and practice. J. Clin. Pathol. 2019 72 11 725 735 10.1136/jclinpath‑2019‑205952 31395625
    [Google Scholar]
  7. Muddapu V.R. Dharshini S.A.P. Chakravarthy V.S. Gromiha M.M. Neurodegenerative diseases–is metabolic deficiency the root cause? Front. Neurosci. 2020 14 213 10.3389/fnins.2020.00213 32296300
    [Google Scholar]
  8. Kiaei M. New hopes and challenges for treatment of neurodegenerative disorders: Great opportunities for young neuroscientists. Basic Clin. Neurosci. 2013 4 1 3 4 25337322
    [Google Scholar]
  9. Gan L. Cookson M.R. Petrucelli L. La Spada A.R. Converging pathways in neurodegeneration, from genetics to mechanisms. Nat. Neurosci. 2018 21 10 1300 1309 10.1038/s41593‑018‑0237‑7 30258237
    [Google Scholar]
  10. Awasthi M. Singh S. Pandey V.P. Dwivedi U.N. Alzheimer’s disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products. J. Neurol. Sci. 2016 361 256 271 10.1016/j.jns.2016.01.008 26810552
    [Google Scholar]
  11. Abubakar M.B. Sanusi K.O. Ugusman A. Mohamed W. Kamal H. Ibrahim N.H. Khoo C.S. Kumar J. Alzheimer’s disease: An update and insights into pathophysiology. Front. Aging Neurosci. 2022 14 742408 10.3389/fnagi.2022.742408 35431894
    [Google Scholar]
  12. Möller H.J. Graeber M.B. The case described by Alois Alzheimer in 1911. Eur. Arch. Psychiatry Clin. Neurosci. 1998 248 3 111 122 10.1007/s004060050027 9728729
    [Google Scholar]
  13. de Laureto P P. Polyphenols as Potential Therapeutic Drugs in Neurodegeneration. Neuroprotection - New Approaches and Prospects IntechOpen 2019
    [Google Scholar]
  14. Selkoe D.J. Alzheimer’s disease: Genes, proteins, and therapy. Physiol. Rev. 2001 81 2 741 766 10.1152/physrev.2001.81.2.741 11274343
    [Google Scholar]
  15. Vermunt L. Sikkes S.A.M. van den Hout A. Handels R. Bos I. van der Flier W.M. Kern S. Ousset P.J. Maruff P. Skoog I. Verhey F.R.J. Freund-Levi Y. Tsolaki M. Wallin Å.K. Olde Rikkert M. Soininen H. Spiru L. Zetterberg H. Blennow K. Scheltens P. Muniz-Terrera G. Visser P.J. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 2019 15 7 888 898 10.1016/j.jalz.2019.04.001 31164314
    [Google Scholar]
  16. Sperling R.A. Aisen P.S. Beckett L.A. Bennett D.A. Craft S. Fagan A.M. Iwatsubo T. Jack C.R. Jr Kaye J. Montine T.J. Park D.C. Reiman E.M. Rowe C.C. Siemers E. Stern Y. Yaffe K. Carrillo M.C. Thies B. Morrison-Bogorad M. Wagster M.V. Phelps C.H. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 7 3 280 292 10.1016/j.jalz.2011.03.003 21514248
    [Google Scholar]
  17. Albert M.S. DeKosky S.T. Dickson D. Dubois B. Feldman H.H. Fox N.C. Gamst A. Holtzman D.M. Jagust W.J. Petersen R.C. Snyder P.J. Carrillo M.C. Thies B. Phelps C.H. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 7 3 270 279 10.1016/j.jalz.2011.03.008 21514249
    [Google Scholar]
  18. McKhann G.M. Knopman D.S. Chertkow H. Hyman B.T. Jack C.R. Jr Kawas C.H. Klunk W.E. Koroshetz W.J. Manly J.J. Mayeux R. Mohs R.C. Morris J.C. Rossor M.N. Scheltens P. Carrillo M.C. Thies B. Weintraub S. Phelps C.H. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 7 3 263 269 10.1016/j.jalz.2011.03.005 21514250
    [Google Scholar]
  19. Blennow K. Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol 2003 2 10 605 613 10.1016/S1474‑4422(03)00530‑1 14505582
    [Google Scholar]
  20. Hampel H. Biomarkers for Alzheimer's disease: Academic, industry and regulatory perspectives. Nat Rev Drug Discov 2010 9 7 560 574 10.1038/nrd3115 20592748
    [Google Scholar]
  21. Lorenzi M. Donohue M. Paternicò D. Scarpazza C. Ostrowitzki S. Blin O. Irving E. Frisoni G.B. Enrichment through biomarkers in clinical trials of Alzheimer’s drugs in patients with mild cognitive impairment. Neurobiol. Aging 2010 31 8 1443 1451.e1 10.1016/j.neurobiolaging.2010.04.036 20541287
    [Google Scholar]
  22. Chopra K. Misra S. Kuhad A. Current perspectives on pharmacotherapy of Alzheimer’s disease. Expert Opin. Pharmacother. 2011 12 3 335 350 10.1517/14656566.2011.520702 21222549
    [Google Scholar]
  23. Grutzendler J. Morris J.C. Cholinesterase inhibitors for Alzheimer’s disease. Drugs 2001 61 1 41 52 10.2165/00003495‑200161010‑00005 11217870
    [Google Scholar]
  24. O'Brien R.J. Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 2011 34 185 204
    [Google Scholar]
  25. Stelzmann R.A. Norman Schnitzlein H. Reed Murtagh F. Murtagh F.R. An english translation of Alzheimer’s 1907 paper, “über eine eigenartige erkankung der hirnrinde”. Clin. Anat. 1995 8 6 429 431 10.1002/ca.980080612 8713166
    [Google Scholar]
  26. Glenner G.G. Wong C.W. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 1984 120 3 885 890 10.1016/S0006‑291X(84)80190‑4 6375662
    [Google Scholar]
  27. Kinoshita A. Fukumoto H. Shah T. Whelan C.M. Irizarry M.C. Hyman B.T. Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes. J. Cell Sci. 2003 116 16 3339 3346 10.1242/jcs.00643 12829747
    [Google Scholar]
  28. Haass C. Hung A.Y. Selkoe D.J. Processing of beta-amyloid precursor protein in microglia and astrocytes favors an internal localization over constitutive secretion. J. Neurosci. 1991 11 12 3783 3793 10.1523/JNEUROSCI.11‑12‑03783.1991 1744690
    [Google Scholar]
  29. Burdick D. Kosmoski J. Knauer M.F. Glabe C.G. Preferential adsorption, internalization and resistance to degradation of the major isoform of the Alzheimer’s amyloid peptide, Aβ1–42, in differentiated PC12 cells. Brain Res. 1997 746 1-2 275 284 10.1016/S0006‑8993(96)01262‑0 9037507
    [Google Scholar]
  30. Mohamed A. Posse de Chaves E. Aβ internalization by neurons and glia. Int. J. Alzheimers Dis. 2011 2011 1 127984 10.4061/2011/127984 21350608
    [Google Scholar]
  31. Lai A.Y. McLaurin J. Mechanisms of amyloid-Beta Peptide uptake by neurons: The role of lipid rafts and lipid raft-associated proteins. Int. J. Alzheimers Dis. 2011 2011 1 548380 10.4061/2011/548380 21197446
    [Google Scholar]
  32. Deane R. Du Yan S. Submamaryan R.K. LaRue B. Jovanovic S. Hogg E. Welch D. Manness L. Lin C. Yu J. Zhu H. Ghiso J. Frangione B. Stern A. Schmidt A.M. Armstrong D.L. Arnold B. Liliensiek B. Nawroth P. Hofman F. Kindy M. Stern D. Zlokovic B. RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat. Med. 2003 9 7 907 913 10.1038/nm890 12808450
    [Google Scholar]
  33. Fukumori A. Okochi M. Tagami S. Jiang J. Itoh N. Nakayama T. Yanagida K. Ishizuka-Katsura Y. Morihara T. Kamino K. Tanaka T. Kudo T. Tanii H. Ikuta A. Haass C. Takeda M. Presenilin-dependent γ-secretase on plasma membrane and endosomes is functionally distinct. Biochemistry 2006 45 15 4907 4914 10.1021/bi052412w 16605258
    [Google Scholar]
  34. Masters C.L. Simms G. Weinman N.A. Multhaup G. McDonald B.L. Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 1985 82 12 4245 4249 10.1073/pnas.82.12.4245 3159021
    [Google Scholar]
  35. Mehta P.D. Pirttila T. Patrick B.A. Barshatzky M. Mehta S.P. Amyloid β protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci. Lett. 2001 304 1-2 102 106 10.1016/S0304‑3940(01)01754‑2 11335065
    [Google Scholar]
  36. Walsh D.M. Tseng B.P. Rydel R.E. Podlisny M.B. Selkoe D.J. The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 2000 39 35 10831 10839 10.1021/bi001048s 10978169
    [Google Scholar]
  37. DaRocha-Souto B. Scotton T.C. Coma M. Serrano-Pozo A. Hashimoto T. Serenó L. Rodríguez M. Sánchez B. Hyman B.T. Gómez-Isla T. Brain oligomeric β-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J. Neuropathol. Exp. Neurol. 2011 70 5 360 376 10.1097/NEN.0b013e318217a118 21487307
    [Google Scholar]
  38. Sunde M. Serpell L.C. Bartlam M. Fraser P.E. Pepys M.B. Blake C.C.F. Common core structure of amyloid fibrils by synchrotron X-ray diffraction 1 1Edited by F. E. Cohen. J. Mol. Biol. 1997 273 3 729 739 10.1006/jmbi.1997.1348 9356260
    [Google Scholar]
  39. Hardy J.A. Higgins G.A. Disease: Alzheimer’s cascade hypothesis amyloid. Sci. New Ser 1992 256 184 185 10.1126/science.1566067 1566067
    [Google Scholar]
  40. Hartley, D.; Blumenthal, T.; Carrillo, M.; DiPaolo, G.; Esralew, L.; Gardiner, K.; Granholm, A.C.; Iqbal, K.; Krams, M.; Lemere, C.; Lott, I.; Mobley, W.; Ness, S.; Nixon, R.; Potter, H.; Reeves, R.; Sabbagh, M.; Silverman, W.; Tycko, B.; Whitten, M.; Wisniewski, T. Down syndrome and Alzheimer's disease: Common pathways, common goals. Alzheimer's & dementia: The J. Alzheimer's Assoc., 2015, 11(6), 700-709. https://doi.org/10.1016/j.jalz.2014.10.007
  41. Mucke L. Selkoe D.J. Neurotoxicity of amyloid β-protein: Synaptic and network dysfunction. Cold Spring Harb. Perspect. Med. 2012 2 7 a006338 10.1101/cshperspect.a006338 22762015
    [Google Scholar]
  42. Ferreira S.T. Lourenco M.V. Oliveira M.M. De Felice F.G. Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease. Front. Cell. Neurosci. 2015 9 191 10.3389/fncel.2015.00191 26074767
    [Google Scholar]
  43. Kowalska A. The beta-amyloid cascade hypothesis: A sequence of events leading to neurodegeneration in Alzheimer’s disease. Neurol. Neurochir. Pol. 2004 38 5 405 411 15565529
    [Google Scholar]
  44. Hardy J. Duff K. Hardy K.G. Perez-Tur J. Hutton M. Genetic dissection of Alzheimer’s disease and related dementias: Amyloid and its relationship to tau. Nat. Neurosci. 1998 1 5 355 358 10.1038/1565 10196523
    [Google Scholar]
  45. Goetz C.G. The history of Parkinson’s disease: Early clinical descriptions and neurological therapies. Cold Spring Harb. Perspect. Med. 2011 1 1 a008862 10.1101/cshperspect.a008862 22229124
    [Google Scholar]
  46. Parkinson J. An essay on the shaking palsy. Whittingham and Rowland for Sherwood, Needly, and Jones London 1817 10.1176/jnp.14.2.223
    [Google Scholar]
  47. Charcot J-M. Lectures on diseases of the nervous system delivered at the Salpêtrière. New Sydenham Society London 1872 129 156
    [Google Scholar]
  48. Trétiakoff C. Contribution to the study of the anatomy of the locus nigerr. Rev. Neurol. 1921 37 592 608
    [Google Scholar]
  49. Brissaud E. Lessons on Nervous Diseases Legare Street Press 1899
    [Google Scholar]
  50. Foix M.C. The central gray nuclei and the mesencephalo-suboptic region. Masson Paris 1925
    [Google Scholar]
  51. Aasly J.O. Long-term outcomes of genetic Parkinson’s disease. J. Mov. Disord. 2020 13 2 81 96 10.14802/jmd.19080 32498494
    [Google Scholar]
  52. Polymeropoulos M.H. Lavedan C. Leroy E. Ide S.E. Dehejia A. Dutra A. Pike B. Root H. Rubenstein J. Boyer R. Stenroos E.S. Chandrasekharappa S. Athanassiadou A. Papapetropoulos T. Johnson W.G. Lazzarini A.M. Duvoisin R.C. Di Iorio G. Golbe L.I. Nussbaum R.L. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997 276 5321 2045 2047 10.1126/science.276.5321.2045 9197268
    [Google Scholar]
  53. Spillantini M.G. Schmidt M.L. Lee V.M.Y. Trojanowski J.Q. Jakes R. Goedert M. α-Synuclein in Lewy bodies. Nature 1997 388 6645 839 840 10.1038/42166 9278044
    [Google Scholar]
  54. Lunati A. Lesage S. Brice A. The genetic landscape of Parkinson’s disease. Rev. Neurol. 2018 174 9 628 643 10.1016/j.neurol.2018.08.004 30245141
    [Google Scholar]
  55. Paisán-Ruíz C. Jain S. Evans E.W. Gilks W.P. Simón J. van der Brug M. de Munain A.L. Aparicio S. Gil A.M. Khan N. Johnson J. Martinez J.R. Nicholl D. Carrera I.M. Peňa A.S. de Silva R. Lees A. Martí-Massó J.F. Pérez-Tur J. Wood N.W. Singleton A.B. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004 44 4 595 600 10.1016/j.neuron.2004.10.023 15541308
    [Google Scholar]
  56. Zimprich A. Biskup S. Leitner P. Lichtner P. Farrer M. Lincoln S. Kachergus J. Hulihan M. Uitti R.J. Calne D.B. Stoessl A.J. Pfeiffer R.F. Patenge N. Carbajal I.C. Vieregge P. Asmus F. Müller-Myhsok B. Dickson D.W. Meitinger T. Strom T.M. Wszolek Z.K. Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004 44 4 601 607 10.1016/j.neuron.2004.11.005 15541309
    [Google Scholar]
  57. Gordián-Vélez W.J. Chouhan D. España R.A. Chen H.I. Burdick J.A. Duda J.E. Cullen D.K. Restoring lost nigrostriatal fibers in Parkinson’s disease based on clinically-inspired design criteria. Brain Res. Bull. 2021 175 168 185 10.1016/j.brainresbull.2021.07.016 34332016
    [Google Scholar]
  58. DeMaagd G. Philip A. Parkinson’s disease and its management: Part 1: Disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P&T 2015 40 8 504 532 26236139
    [Google Scholar]
  59. Poewe W. Seppi K. Tanner C.M. Halliday G.M. Brundin P. Volkmann J. Schrag A.E. Lang A.E. Parkinson disease. Nat. Rev. Dis. Primers 2017 3 1 17013 10.1038/nrdp.2017.13 28332488
    [Google Scholar]
  60. Dorsey E.R. Constantinescu R. Thompson J.P. Biglan K.M. Holloway R.G. Kieburtz K. Marshall F.J. Ravina B.M. Schifitto G. Siderowf A. Tanner C.M. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 2007 68 5 384 386 10.1212/01.wnl.0000247740.47667.03 17082464
    [Google Scholar]
  61. Goyal V. Radhakrishnan D.M. Parkinson’s disease: A review. Neurol. India 2018 66 7 Suppl. 26 10.4103/0028‑3886.226451 29503325
    [Google Scholar]
  62. Jankovic J. Tan E.K. Parkinson’s disease: Etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 2020 91 8 795 808 10.1136/jnnp‑2019‑322338 32576618
    [Google Scholar]
  63. Feustel A.C. MacPherson A. Fergusson D.A. Kieburtz K. Kimmelman J. Risks and benefits of unapproved disease-modifying treatments for neurodegenerative disease. Neurology 2020 94 1 e1 e14 10.1212/WNL.0000000000008699 31792092
    [Google Scholar]
  64. Marek K. Chowdhury S. Siderowf A. Lasch S. Coffey C.S. Caspell-Garcia C. Simuni T. Jennings D. Tanner C.M. Trojanowski J.Q. Shaw L.M. Seibyl J. Schuff N. Singleton A. Kieburtz K. Toga A.W. Mollenhauer B. Galasko D. Chahine L.M. Weintraub D. Foroud T. Tosun-Turgut D. Poston K. Arnedo V. Frasier M. Sherer T. The Parkinson’s progression markers initiative (PPMI) – Establishing a PD biomarker cohort. Ann. Clin. Transl. Neurol. 2018 5 12 1460 1477 10.1002/acn3.644 30564614
    [Google Scholar]
  65. Jankovic J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov. Disord. 2019 34 1 41 44 10.1002/mds.27534 30484897
    [Google Scholar]
  66. Jankovic J. Goodman I. Safirstein B. Marmon T.K. Schenk D.B. Koller M. Zago W. Ness D.K. Griffith S.G. Grundman M. Soto J. Ostrowitzki S. Boess F.G. Martin-Facklam M. Quinn J.F. Isaacson S.H. Omidvar O. Ellenbogen A. Kinney G.G. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti–α-synuclein monoclonal antibody, in patients with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2018 75 10 1206 1214 10.1001/jamaneurol.2018.1487 29913017
    [Google Scholar]
  67. Brys M. Fanning L. Hung S. Ellenbogen A. Penner N. Yang M. Welch M. Koenig E. David E. Fox T. Makh S. Aldred J. Goodman I. Pepinsky B. Liu Y. Graham D. Weihofen A. Cedarbaum J.M. Randomized phase I clinical trial of anti–α-synuclein antibody BIIB054. Mov. Disord. 2019 34 8 1154 1163 10.1002/mds.27738 31211448
    [Google Scholar]
  68. Savitt D. Jankovic J. Targeting α-synuclein in Parkinson’s disease: Progress towards the development of disease-modifying therapeutics. Drugs 2019 79 8 797 810 10.1007/s40265‑019‑01104‑1 30982161
    [Google Scholar]
  69. Dickson D.W. Braak H. Duda J.E. Duyckaerts C. Gasser T. Halliday G.M. Hardy J. Leverenz J.B. Del Tredici K. Wszolek Z.K. Litvan I. Neuropathological assessment of Parkinson’s disease: Refining the diagnostic criteria. Lancet Neurol. 2009 8 12 1150 1157 10.1016/S1474‑4422(09)70238‑8 19909913
    [Google Scholar]
  70. Goedert M. Spillantini M.G. Del Tredici K. Braak H. 100 years of Lewy pathology. Nat. Rev. Neurol. 2013 9 1 13 24 10.1038/nrneurol.2012.242 23183883
    [Google Scholar]
  71. Giguère N. Burke Nanni S. Trudeau L.E. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front. Neurol. 2018 9 455 10.3389/fneur.2018.00455 29971039
    [Google Scholar]
  72. Dauer W. Przedborski S. Parkinson’s disease. Neuron 2003 39 6 889 909 10.1016/S0896‑6273(03)00568‑3 12971891
    [Google Scholar]
  73. Sian J. Dexter D.T. Lees A.J. Daniel S. Agid Y. Javoy-Agid F. Jenner P. Marsden C.D. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol. 1994 36 3 348 355 10.1002/ana.410360305 8080242
    [Google Scholar]
  74. Graham D.G. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol. Pharmacol. 1978 14 4 633 643 10.1016/S0026‑895X(25)13535‑9 98706
    [Google Scholar]
  75. Schapira A.H.V. Cooper J.M. Dexter D. Clark J.B. Jenner P. Marsden C.D. Mitochondrial complex I deficiency in Parkinson’s disease. J. Neurochem. 1990 54 3 823 827 10.1111/j.1471‑4159.1990.tb02325.x 2154550
    [Google Scholar]
  76. Greenamyre J.T. Sherer T.B. Betarbet R. Panov A.V. Complex I and Parkinson’s disease. IUBMB Life 2001 52 3-5 135 141 10.1080/15216540152845939 11798025
    [Google Scholar]
  77. Struzyna L.A. Browne K.D. Brodnik Z.D. Burrell J.C. Harris J.P. Chen H.I. Wolf J.A. Panzer K.V. Lim J. Duda J.E. España R.A. Cullen D.K. Tissue engineered nigrostriatal pathway for treatment of Parkinson’s disease. J. Tissue Eng. Regen. Med. 2018 12 7 1702 1716 10.1002/term.2698 29766664
    [Google Scholar]
  78. Yan R. Bienkowski M.J. Shuck M.E. Miao H. Tory M.C. Pauley A.M. Brashler J.R. Stratman N.C. Mathews W.R. Buhl A.E. Carter D.B. Tomasselli A.G. Parodi L.A. Heinrikson R.L. Gurney M.E. Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature 1999 402 6761 533 537 10.1038/990107 10591213
    [Google Scholar]
  79. Ohno M. Sametsky E.A. Younkin L.H. Oakley H. Younkin S.G. Citron M. Vassar R. Disterhoft J.F. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 2004 41 1 27 33 10.1016/S0896‑6273(03)00810‑9 14715132
    [Google Scholar]
  80. Luo Y. Bolon B. Kahn S. Bennett B.D. Babu-Khan S. Denis P. Fan W. Kha H. Zhang J. Gong Y. Martin L. Louis J.C. Yan Q. Richards W.G. Citron M. Vassar R. Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci. 2001 4 3 231 232 10.1038/85059 11224535
    [Google Scholar]
  81. Kobayashi D. Zeller M. Cole T. Buttini M. McConlogue L. Sinha S. Freedman S. Morris R.G.M. Chen K.S. BACE1 gene deletion: Impact on behavioral function in a model of Alzheimer’s disease. Neurobiol. Aging 2008 29 6 861 873 10.1016/j.neurobiolaging.2007.01.002 17331621
    [Google Scholar]
  82. Willem M. Garratt A.N. Novak B. Citron M. Kaufmann S. Rittger A. DeStrooper B. Saftig P. Birchmeier C. Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 2006 314 5799 664 666 10.1126/science.1132341 16990514
    [Google Scholar]
  83. Haass C. Schlossmacher M.G. Hung A.Y. Vigo-Pelfrey C. Mellon A. Ostaszewski B.L. Lieberburg I. Koo E.H. Schenk D. Teplow D.B. Selkoe D.J. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 1992 359 6393 322 325 10.1038/359322a0 1383826
    [Google Scholar]
  84. Henley D.B. May P.C. Dean R.A. Siemers E.R. Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin. Pharmacother. 2009 10 10 1657 1664 10.1517/14656560903044982 19527190
    [Google Scholar]
  85. Weggen S. Eriksen J.L. Das P. Sagi S.A. Wang R. Pietrzik C.U. Findlay K.A. Smith T.E. Murphy M.P. Bulter T. Kang D.E. Marquez-Sterling N. Golde T.E. Koo E.H. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 2001 414 6860 212 216 10.1038/35102591 11700559
    [Google Scholar]
  86. Van Marum R.J. Current and future therapy in Alzheimer’s disease. Fundam. Clin. Pharmacol. 2008 22 3 265 274 10.1111/j.1472‑8206.2008.00578.x 18485144
    [Google Scholar]
  87. Saify Z.S. Sultana N. Role of acetylcholinesterase inhibitors and Alzheimer Disease. Drug design and discovery in Alzheimer’s disease. Elsevier 2014 387 425 10.1016/B978‑0‑12‑803959‑5.50007‑6
    [Google Scholar]
  88. Rees T. M. Brimijoin S. The role of acetylcholinesterase in the pathogenesis of Alzheimer's disease. Drugs Today 2003 39 1 75 83 10.1358/dot.2003.39.1.740206
    [Google Scholar]
  89. Wang S. Kong X. Chen Z. Wang G. Zhang J. Wang J. Role of natural compounds and target enzymes in the treatment of Alzheimer’s disease. Molecules 2022 27 13 4175 10.3390/molecules27134175 35807418
    [Google Scholar]
  90. Bhat A. Ray B. Mahalakshmi A.M. Tuladhar S. Nandakumar D.N. Srinivasan M. Essa M.M. Chidambaram S.B. Guillemin G.J. Sakharkar M.K. Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders. Pharmacol. Res. 2020 160 105078 10.1016/j.phrs.2020.105078 32673703
    [Google Scholar]
  91. Bortolato M. Chen K. Shih J.C. Monoamine oxidase inactivation: From pathophysiology to therapeutics. Adv. Drug Deliv. Rev. 2008 60 13-14 1527 1533 10.1016/j.addr.2008.06.002 18652859
    [Google Scholar]
  92. Shih J.C. Monoamine oxidase isoenzymes: Genes, functions and targets for behavior and cancer therapy. J. Neural Transm. 2018 125 11 1553 1566 10.1007/s00702‑018‑1927‑8 30259128
    [Google Scholar]
  93. Carradori S. Secci D. Petzer J.P. MAO inhibitors and their wider applications: A patent review. Expert Opin. Ther. Pat. 2018 28 3 211 226 10.1080/13543776.2018.1427735 29324067
    [Google Scholar]
  94. Stocchi F. Fossati C. Torti M. Rasagiline for the treatment of Parkinson’s disease: An update. Expert Opin. Pharmacother. 2015 16 14 2231 2241 10.1517/14656566.2015.1086748 26364897
    [Google Scholar]
  95. Chen J.J. Swope D.M. Clinical pharmacology of rasagiline: A novel, second-generation propargylamine for the treatment of Parkinson disease. J. Clin. Pharmacol. 2005 45 8 878 894 10.1177/0091270005277935 16027398
    [Google Scholar]
  96. Bainbridge J.L. Lee Page R. Ruscin J.M. Elucidating the mechanism of action and potential interactions of MAO-B inhibitors. Neurol. Clin. 2008 26 Suppl. 3 85 96 10.1016/j.ncl.2008.05.002 18774444
    [Google Scholar]
  97. Carradori S. D’Ascenzio M. Chimenti P. Secci D. Bolasco A. Selective MAO-B inhibitors: A lesson from natural products. Mol. Divers. 2014 18 1 219 243 10.1007/s11030‑013‑9490‑6 24218136
    [Google Scholar]
  98. Xu H. Yang F. The interplay of dopamine metabolism abnormalities and mitochondrial defects in the pathogenesis of Schizophrenia. Transl. Psychiatry 2022 12 1 464 10.1038/s41398‑022‑02233‑0 36344514
    [Google Scholar]
  99. Rodrigues T. Reker D. Schneider P. Schneider G. Counting on natural products for drug design. Nat. Chem. 2016 8 6 531 541 10.1038/nchem.2479 27219696
    [Google Scholar]
  100. Kuboyama T. Tohda C. Komatsu K. Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases. Biol. Pharm. Bull. 2014 37 6 892 897 10.1248/bpb.b14‑00022 24882401
    [Google Scholar]
  101. Corona J.C. Natural compounds for the management of Parkinson’s disease and attention-deficit/hyperactivity disorder. BioMed Res. Int. 2018 2018 1 12 10.1155/2018/4067597 30596091
    [Google Scholar]
  102. Girdhar S. Girdhar A. Verma S.K. Lather V. Pandita D. Plant derived alkaloids in major neurodegenerative diseases: From animal models to clinical trials. J. Ayurv. Herb. Med. 2015 1 3 91 100 10.31254/jahm.2015.1307
    [Google Scholar]
  103. McCaleb R. Nature’s medicine for memory loss. HerbalGram 1990 23 15
    [Google Scholar]
  104. Orhan G. Orhan I. Subutay-Oztekin N. Ak F. Sener B. Contemporary anticholinesterase pharmaceuticals of natural origin and their synthetic analogues for the treatment of Alzheimer’s disease. Recent Patents CNS Drug Discov. 2009 4 1 43 51 10.2174/157488909787002582 19149713
    [Google Scholar]
  105. Howes M.J.R. Perry N.S.L. Houghton P.J. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother. Res. 2003 17 1 1 18 10.1002/ptr.1280 12557240
    [Google Scholar]
  106. Singh A. Duggal S. Kaur N. Singh J. Berberine: Alkaloid with a wide spectrum of pharmacological activities. J. Nat. Prod. 2010 3 64 75
    [Google Scholar]
  107. Asai M. Iwata N. Yoshikawa A. Aizaki Y. Ishiura S. Saido T.C. Maruyama K. Berberine alters the processing of Alzheimer’s amyloid precursor protein to decrease Aβ secretion. Biochem. Biophys. Res. Commun. 2007 352 2 498 502 10.1016/j.bbrc.2006.11.043 17125739
    [Google Scholar]
  108. Bhullar K.S. Rupasinghe H.P.V. Polyphenols: Multipotent therapeutic agents in neurodegenerative diseases. Oxid. Med. Cell. Longev. 2013 2013 1 18 10.1155/2013/891748 23840922
    [Google Scholar]
  109. Okello E.J. Leylabi R. McDougall G.J. Inhibition of acetylcholinesterase by green and white tea and their simulated intestinal metabolites. Food Funct. 2012 3 6 651 661 10.1039/c2fo10174b 22418730
    [Google Scholar]
  110. Tufekci K.U. Meuwissen R. Genc S. Genc K. Inflammation in Parkinson’s disease. Adv. Protein Chem. Struct. Biol. 2012 88 69 132 10.1016/B978‑0‑12‑398314‑5.00004‑0 22814707
    [Google Scholar]
  111. Pandey K.B. Rizvi S.I. Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cell. Longev. 2009 2 5 270 278 10.4161/oxim.2.5.9498 20716914
    [Google Scholar]
  112. Han X. Shen T. Lou H. Dietary polyphenols and their biological significance. Int. J. Mol. Sci. 2007 8 9 950 988 10.3390/i8090950
    [Google Scholar]
  113. Qin X.Y. Cheng Y. Yu L.C. Potential protection of green tea polyphenols against intracellular amyloid beta-induced toxicity on primary cultured prefrontal cortical neurons of rats. Neurosci. Lett. 2012 513 2 170 173 10.1016/j.neulet.2012.02.029 22381400
    [Google Scholar]
  114. Liu P. Kemper L.J. Wang J. Zahs K.R. Ashe K.H. Pasinetti G.M. Grape seed polyphenolic extract specifically decreases aβ*56 in the brains of Tg2576 mice. J. Alzheimers Dis. 2011 26 4 657 666 10.3233/JAD‑2011‑110383 21743132
    [Google Scholar]
  115. Ksiezak-Reding H. Ho L. Santa-Maria I. Diaz-Ruiz C. Wang J. Pasinetti G.M. Ultrastructural alterations of Alzheimer’s disease paired helical filaments by grape seed-derived polyphenols. Neurobiol. Aging 2012 33 7 1427 1439 10.1016/j.neurobiolaging.2010.11.006 21196065
    [Google Scholar]
  116. Wang Y.H. Du G.H. Ginsenoside Rg1 inhibits β-secretase activity in vitro and protects against Aβ-induced cytotoxicity in PC12 cells. J. Asian Nat. Prod. Res. 2009 11 7 604 612 10.1080/10286020902843152 20183297
    [Google Scholar]
  117. Thomas P. Wang Y.J. Zhong J.H. Kosaraju S. O’Callaghan N.J. Zhou X.F. Fenech M. Grape seed polyphenols and curcumin reduce genomic instability events in a transgenic mouse model for Alzheimer’s disease. Mutat. Res. 2009 661 1-2 25 34 10.1016/j.mrfmmm.2008.10.016 19027755
    [Google Scholar]
  118. Feng Y. Wang X. Yang S. Wang Y. Zhang X. Du X. Sun X. Zhao M. Huang L. Liu R. Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. Neurotoxicology 2009 30 6 986 995 10.1016/j.neuro.2009.08.013 19744518
    [Google Scholar]
  119. Huang T.C. Lu K.T. Wo Y.Y.P. Wu Y.J. Yang Y.L. Resveratrol protects rats from Aβ-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoS One 2011 6 12 e29102 10.1371/journal.pone.0029102 22220203
    [Google Scholar]
  120. Gong E.J. Park H.R. Kim M.E. Piao S. Lee E. Jo D.G. Chung H.Y. Ha N.C. Mattson M.P. Lee J. Morin attenuates tau hyperphosphorylation by inhibiting GSK3β. Neurobiol. Dis. 2011 44 2 223 230 10.1016/j.nbd.2011.07.005 21782947
    [Google Scholar]
  121. Mori T. Rezai-Zadeh K. Koyama N. Arendash G.W. Yamaguchi H. Kakuda N. Horikoshi-Sakuraba Y. Tan J. Town T. Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J. Biol. Chem. 2012 287 9 6912 6927 10.1074/jbc.M111.294025 22219198
    [Google Scholar]
  122. Devi L. Ohno M. 7,8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 2012 37 2 434 444 10.1038/npp.2011.191 21900882
    [Google Scholar]
  123. Jiménez-Aliaga K. Bermejo-Bescós P. Benedí J. Martín-Aragón S. Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci. 2011 89 25-26 939 945 10.1016/j.lfs.2011.09.023 22008478
    [Google Scholar]
  124. Khan M.M. Ahmad A. Ishrat T. Khan M.B. Hoda M.N. Khuwaja G. Raza S.S. Khan A. Javed H. Vaibhav K. Islam F. Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’s disease. Brain Res. 2010 1328 139 151 10.1016/j.brainres.2010.02.031 20167206
    [Google Scholar]
  125. Bournival J. Plouffe M. Renaud J. Provencher C. Martinoli M.G. Quercetin and sesamin protect dopaminergic cells from MPP+-induced neuroinflammation in a microglial (N9)-neuronal (PC12) coculture system. Oxid. Med. Cell. Longev. 2012 2012 1 11 10.1155/2012/921941 22919443
    [Google Scholar]
  126. Lv C. Hong T. Yang Z. Zhang Y. Wang L. Dong M. Zhao J. Mu J. Meng Y. Effect of quercetin in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Evid. Based Complement. Alternat. Med. 2012 2012 1 6 10.1155/2012/928643 22454690
    [Google Scholar]
  127. Mony T.J. Elahi F. Choi J.W. Park S.J. Neuropharmacological effects of terpenoids on preclinical animal models of psychiatric disorders: A review. Antioxidants 2022 11 9 1834 10.3390/antiox11091834 36139909
    [Google Scholar]
  128. Yoo K.Y. Park S.Y. Terpenoids as potential anti-Alzheimer’s disease therapeutics. Molecules 2012 17 3 3524 3538 10.3390/molecules17033524 22430119
    [Google Scholar]
  129. Liu Z.Q. Luo X.Y. Liu G.Z. Chen Y.P. Wang Z.C. Sun Y.X. In vitro study of the relationship between the structure of ginsenoside and its antioxidative or prooxidative activity in free radical induced hemolysis of human erythrocytes. J. Agric. Food Chem. 2003 51 9 2555 2558 10.1021/jf026228i 12696936
    [Google Scholar]
  130. Chen F. Eckman E.A. Eckman C.B. Chen F. Eckman E.A. Eckman C.B. Reductions in levels of the Alzheimer’s amyloid β peptide after oral administration of ginsenosides. FASEB J. 2006 20 8 1269 1271 10.1096/fj.05‑5530fje 16636099
    [Google Scholar]
  131. Yang L. Hao J. Zhang J. Xia W. Dong X. Hu X. Kong F. Cui X. Ginsenoside Rg3 promotes beta-amyloid peptide degradation by enhancing gene expression of neprilysin. J. Pharm. Pharmacol. 2009 61 3 375 380 10.1211/jpp.61.03.0013 19222911
    [Google Scholar]
  132. Liang W. Ge S. Yang L. Yang M. Ye Z. Yan M. Du J. Luo Z. Ginsenosides Rb1 and Rg1 promote proliferation and expression of neurotrophic factors in primary Schwann cell cultures. Brain Res. 2010 1357 19 25 10.1016/j.brainres.2010.07.091 20682297
    [Google Scholar]
  133. Chen L. Lin Z. Zhu Y. Lin N. Zhang J. Pan X. Chen X. Ginsenoside Rg1 attenuates β-amyloid generation via suppressing PPARγ-regulated BACE1 activity in N2a-APP695 cells. Eur. J. Pharmacol. 2012 675 1-3 15 21 10.1016/j.ejphar.2011.11.039 22166376
    [Google Scholar]
  134. Lahlou M. The success of natural products in drug discovery Pharmacol. Pharmacol. & Pharm. 2013 4 17 31 10.4236/pp.2013.43A003
    [Google Scholar]
  135. Nisar B. Sultan A. Rubab S.L. Comparison of medicinally important natural products versus synthetic drugs-a short commentary. Nat. Prod. Chem. Res. 2018 6 2 308 10.4172/2329‑6836.1000308
    [Google Scholar]
  136. Menze E.T. Tadros M.G. Abdel-Tawab A.M. Khalifa A.E. Potential neuroprotective effects of hesperidin on 3-nitropropionic acid-induced neurotoxicity in rats. Neurotoxicology 2012 33 5 1265 1275 10.1016/j.neuro.2012.07.007 22850463
    [Google Scholar]
  137. Chakraborty S. Bandyopadhyay J. Chakraborty S. Basu S. Multi-target screening mines hesperidin as a multi-potent inhibitor: Implication in Alzheimer’s disease therapeutics. Eur. J. Med. Chem. 2016 121 810 822 10.1016/j.ejmech.2016.03.057 27068363
    [Google Scholar]
  138. Parhiz H. Roohbakhsh A. Soltani F. Rezaee R. Iranshahi M. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: An updated review of their molecular mechanisms and experimental models. Phytother. Res. 2015 29 3 323 331 10.1002/ptr.5256 25394264
    [Google Scholar]
  139. Ahmad S.S. Akhtar S. Danish Rizvi S.M. Kamal M.A. Sayeed U. Khan M.K.A. Siddiqui M.H. Arif J.M. Screening and elucidation of selected natural compounds for anti-Alzheimer’s potential targeting BACE-1 enzyme: A case computational study. Curr. Computeraided Drug Des. 2017 13 4 311 318 10.2174/1573409913666170414123825 28413992
    [Google Scholar]
  140. Ansari M.A. Abdul H.M. Joshi G. Opii W.O. Butterfield D.A. Protective effect of quercetin in primary neurons against Aβ(1–42): Relevance to Alzheimer’s disease. J. Nutr. Biochem. 2009 20 4 269 275 10.1016/j.jnutbio.2008.03.002 18602817
    [Google Scholar]
  141. Shi C. Zheng D. Wu F. Liu J. Xu J. The phosphatidyl inositol 3 kinase-glycogen synthase kinase 3β pathway mediates bilobalide-induced reduction in amyloid β-peptide. Neurochem. Res. 2012 37 2 298 306 10.1007/s11064‑011‑0612‑1 21952928
    [Google Scholar]
  142. Li R. Huang Y.G. Fang D. Le W.D. (−)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J. Neurosci. Res. 2004 78 5 723 731 10.1002/jnr.20315 15478178
    [Google Scholar]
  143. Lee Y.J. Choi D.Y. Yun Y.P. Han S.B. Oh K.W. Hong J.T. Epigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties. J. Nutr. Biochem. 2013 24 1 298 310 10.1016/j.jnutbio.2012.06.011 22959056
    [Google Scholar]
  144. Matsumura S. Murata K. Yoshioka Y. Matsuda H. Search for β-Secretase inhibitors from natural spices. Nat Prod Commun 2016 11 4 507 510 10.1177/1934578X1601100423
    [Google Scholar]
  145. Ullah M.A. Johora F.T. Sarkar B. Araf Y. Ahmed N. Nahar A.N. Akter T. Computer-assisted evaluation of plant-derived β-secretase inhibitors in Alzheimer’s disease. Egypt. J. Med. Hum. Genet. 2021 22 1 26 10.1186/s43042‑021‑00150‑3
    [Google Scholar]
  146. Sasaki H. Miki K. Kinoshita K. Koyama K. Juliawaty L.D. Achmad S.A. Hakim E.H. Kaneda M. Takahashi K. β-Secretase (BACE-1) inhibitory effect of biflavonoids. Bioorg. Med. Chem. Lett. 2010 20 15 4558 4560 10.1016/j.bmcl.2010.06.021 20598535
    [Google Scholar]
  147. Jung H.A. Min B.S. Yokozawa T. Lee J.H. Kim Y.S. Choi J.S. Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol. Pharm. Bull. 2009 32 8 1433 1438 10.1248/bpb.32.1433 19652386
    [Google Scholar]
  148. Jeon S.Y. Bae K. Seong Y.H. Song K.S. Green tea catechins as a BACE1 (β-Secretase) inhibitor. Bioorg. Med. Chem. Lett. 2003 13 22 3905 3908 10.1016/j.bmcl.2003.09.018 14592472
    [Google Scholar]
  149. Marumoto S. Miyazawa M. Structure–activity relationships for naturally occurring coumarins as β-secretase inhibitor. Bioorg. Med. Chem. 2012 20 2 784 788 10.1016/j.bmc.2011.12.002 22222157
    [Google Scholar]
  150. Karpagam V. Identification of BACE1 inhibitors from Panax ginseng saponins—An in silico approach. Comput Biol Med 2013 43 8 1037 1044 10.1016/j.compbiomed.2013.05.009
    [Google Scholar]
  151. Wang X. Kim J.R. Lee S.B. Kim Y.J. Jung M.Y. Kwon H.W. Ahn Y.J. Effects of curcuminoids identified in rhizomes of Curcuma longa on BACE-1 inhibitory and behavioral activity and lifespan of Alzheimer’s disease Drosophila models. BMC Complement. Altern. Med. 2014 14 1 88 10.1186/1472‑6882‑14‑88 24597901
    [Google Scholar]
  152. Jun M.R. Lee S.H Choi S.H. Bae K.H. Plant phenolics as β-secretase (BACE1) inhibitors. Food Sci. Biotechnology 2006 15 4 617 624
    [Google Scholar]
  153. Ganesh R. Kannan I. Molecular docking study of certain plant alkaloid derivatives as inhibitors of various drug targets of Alzheimer’s disease. Biomed. Pharmacol. J. 2017 10 3 1489 1494 10.13005/bpj/1257
    [Google Scholar]
  154. Murata K. Chemical diversity of β-secretase inhibitors from natural resources. Nat. Prod. Commun. 2019 14 12 1934578X1989481 10.1177/1934578X19894819
    [Google Scholar]
  155. Jeon S.Y. Kwon S.H. Seong Y.H. Bae K. Hur J.M. Lee Y.Y. Suh D.Y. Song K.S. β-secretase (BACE1)-inhibiting stilbenoids from Smilax Rhizoma. Phytomedicine 2007 14 6 403 408 10.1016/j.phymed.2006.09.003 17084604
    [Google Scholar]
  156. Park I.H. Jeon S.Y. Lee H.J. Kim S.I. Song K.S. A β-secretase (BACE1) inhibitor hispidin from the mycelial cultures of Phellinus linteus. Planta Med. 2004 70 2 143 146 10.1055/s‑2004‑815491 14994192
    [Google Scholar]
  157. Kwak W.J. Han C.K. Son K.H. Chang H.W. Kang S.S. Park B.K. Kim H.P. Effects of Ginkgetin from Ginkgo biloba Leaves on cyclooxygenases and in vivo skin inflammation. Planta Med. 2002 68 4 316 321 10.1055/s‑2002‑26742 11988854
    [Google Scholar]
  158. Kumari R. Chaudhary A. Mani A. Casuarictin: A new herbal drug molecule for Alzheimer’s disease as inhibitor of presenilin stabilization factor like protein. Heliyon 2020 6 11 e05546 10.1016/j.heliyon.2020.e05546 33294689
    [Google Scholar]
  159. Rezai-Zadeh K. Douglas Shytle R. Bai Y. Tian J. Hou H. Mori T. Zeng J. Obregon D. Town T. Tan J. Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer’s disease β-amyloid production. J. Cell. Mol. Med. 2009 13 3 574 588 10.1111/j.1582‑4934.2008.00344.x 18410522
    [Google Scholar]
  160. Santos T.C. Gomes T.M. Pinto B.A.S. Camara A.L. Paes A.M.A. Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer’s disease therapy. Front. Pharmacol. 2018 9 1192 10.3389/fphar.2018.01192 30405413
    [Google Scholar]
  161. Choi S.Y. Piao Z.H. Jin L. Kim J.H. Kim G.R. Ryu Y. Lin M.Q. Kim H.S. Kee H.J. Jeong M.H. Piceatannol attenuates renal fibrosis induced by unilateral ureteral obstruction via downregulation of Histone Deacetylase 4/5 or p38-MAPK signaling. PLoS One 2016 11 11 e0167340 10.1371/journal.pone.0167340 27902771
    [Google Scholar]
  162. Narasingapa R.B. Jargaval M.R. Pullabhatla S. Htoo H.H. Rao J.K.S. Hernandez J.F. Govitrapong P. Vincent B. Activation of α-secretase by curcumin-aminoacid conjugates. Biochem. Biophys. Res. Commun. 2012 424 4 691 696 10.1016/j.bbrc.2012.07.010 22796219
    [Google Scholar]
  163. Obregon D.F. Rezai-Zadeh K. Bai Y. Sun N. Hou H. Ehrhart J. Zeng J. Mori T. Arendash G.W. Shytle D. Town T. Tan J. ADAM10 activation is required for green tea (-)-epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 2006 281 24 16419 16427 10.1074/jbc.M600617200 16624814
    [Google Scholar]
  164. Kaufmann D. Kaur Dogra A. Tahrani A. Herrmann F. Wink M. Extracts from traditional Chinese medicinal plants inhibit acetylcholinesterase, a known Alzheimer’s disease target. Molecules 2016 21 9 1161 10.3390/molecules21091161 27589716
    [Google Scholar]
  165. Singh A.K. Singh S.K. Nandi M.K. Mishra G. Maurya A. Rai A. Rai G.K. Awasthi R. Sharma B. Kulkarni G.T. Berberine: A plant-derived alkaloid with therapeutic potential to combat Alzheimer’s disease. Cent. Nerv. Syst. Agents Med. Chem. 2019 19 3 154 170 10.2174/1871524919666190820160053 31429696
    [Google Scholar]
  166. Howes M.J.R. Simmonds M.S.J. The role of phytochemicals as micronutrients in health and disease. Curr. Opin. Clin. Nutr. Metab. Care 2014 17 6 558 566 10.1097/MCO.0000000000000115 25252018
    [Google Scholar]
  167. Remya C. Dileep K.V. Tintu I. Variyar E.J. Sadasivan C. Design of potent inhibitors of acetylcholinesterase using morin as the starting compound. Front. Life Sci. 2012 6 3-4 107 117 10.1080/21553769.2013.815137
    [Google Scholar]
  168. López S. Bastida J. Viladomat F. Codina C. Acetylcholinesterase inhibitory activity of some Amaryllidaceae alkaloids and Narcissus extracts. Life Sci. 2002 71 21 2521 2529 10.1016/S0024‑3205(02)02034‑9 12270757
    [Google Scholar]
  169. Rollinger J.M. Schuster D. Baier E. Ellmerer E.P. Langer T. Stuppner H. Taspine: Bioactivity-guided isolation and molecular ligand-target insight of a potent acetylcholinesterase inhibitor from Magnolia x soulangiana. J. Nat. Prod. 2006 69 9 1341 1346 10.1021/np060268p 16989531
    [Google Scholar]
  170. Qi T. Li H. Li S. Indirubin improves antioxidant and anti-inflammatory functions in lipopolysaccharide-challenged mice. Oncotarget 2017 8 22 36658 36663 10.18632/oncotarget.17560 28525368
    [Google Scholar]
  171. Tang G.H. Dong Z. Guo Y.Q. Cheng Z.B. Zhou C.J. Yin S. Psiguajadials A–K: Unusual Psidium meroterpenoids as phosphodiesterase-4 inhibitors from the leaves of Psidium guajava. Sci. Rep. 2017 7 1 1047 10.1038/s41598‑017‑01028‑4 28432317
    [Google Scholar]
  172. Wojtunik-Kulesza K.A. Targowska-Duda K. Klimek K. Ginalska G. Jóźwiak K. Waksmundzka-Hajnos M. Cieśla Ł. Volatile terpenoids as potential drug leads in Alzheimer’s disease. Open Chem. 2017 15 1 332 343 10.1515/chem‑2017‑0040
    [Google Scholar]
  173. Wu M. Liu M. Wang F. Cai J. Luo Q. Li S. Zhu J. Tang Z. Fang Z. Wang C. Chen H. The inhibition mechanism of polyphenols from Phyllanthus emblica Linn. fruit on acetylcholinesterase: A interaction, kinetic, spectroscopic, and molecular simulation study. Food Res. Int. 2022 158 111497 10.1016/j.foodres.2022.111497 35840206
    [Google Scholar]
  174. Gulcan H. Orhan I. Sener B. Chemical and molecular aspects on interactions of galanthamine and its derivatives with cholinesterases. Curr. Pharm. Biotechnol. 2015 16 3 252 258 10.2174/1389201015666141202105105 25483718
    [Google Scholar]
  175. Qian Z.M. Ke Y. Huperzine A: Is it an effective disease-modifying drug for Alzheimer’s disease? Front. Aging Neurosci. 2014 6 216 10.3389/fnagi.2014.00216 25191267
    [Google Scholar]
  176. Conforti F. Rigano D. Formisano C. Bruno M. Loizzo M.R. Menichini F. Senatore F. Metabolite profile and in vitro activities of Phagnalon saxatile (L.) Cass. relevant to treatment of Alzheimer’s disease. J. Enzyme Inhib. Med. Chem. 2010 25 1 97 104 10.3109/14756360903018260 20030514
    [Google Scholar]
  177. Oleszek W. Jurzysta M. Ploszynski M. Colquhoun I.J. Price K.R. Fenwick G.R. Zahnic acid tridesmoside and other dominant saponins from alfalfa (Medicago sativa L.) aerial parts. J. Agric. Food Chem. 1992 40 2 191 196 10.1021/jf00014a005
    [Google Scholar]
  178. Cherdshewasart W. Nimsakul N. Clinical trial of Butea superba, an alternative herbal treatment for erectile dysfunction. Asian J. Androl. 2003 5 3 243 246 12937809
    [Google Scholar]
  179. Hwang T.L. Leu Y.L. Kao S.H. Tang M.C. Chang H.L. Viscolin, a new chalcone from Viscum coloratum, inhibits human neutrophil superoxide anion and elastase release via a cAMP-dependent pathway. Free Radic. Biol. Med. 2006 41 9 1433 1441 10.1016/j.freeradbiomed.2006.08.001 17023270
    [Google Scholar]
  180. Nishibe S. Mitsui-Saitoh K. Sakai J. Fujikawa T. The biological effects of forsythia leaves containing the Cyclic AMP Phosphodiesterase 4 inhibitor Phillyrin. Molecules 2021 26 8 2362 10.3390/molecules26082362 33921630
    [Google Scholar]
  181. Tang M. Taghibiglou C. The mechanisms of action of curcumin in Alzheimer’s disease. J. Alzheimers Dis. 2017 58 4 1003 1016 10.3233/JAD‑170188 28527218
    [Google Scholar]
  182. Hnatyszyn O. Moscatelli V. Garcia J. Rondina R. Costa M. Arranz C. Balaszczuk A. Ferraro G. Coussio J.D. Argentinian plant extracts with relaxant effect on the smooth muscle of the corpus cavernosum of Guinea pig. Phytomedicine 2003 10 8 669 674 10.1078/0944‑7113‑00261 14692728
    [Google Scholar]
  183. Macovschi O. Prigent A.F. Nemoz G. Pacheco H. Effects of an extract of Ginkgo biloba on the 3′,5′-cyclic AMP phosphodiesterase activity of the brain of normal and triethyltin-intoxicated rats. J. Neurochem. 1987 49 1 107 114 10.1111/j.1471‑4159.1987.tb03401.x 3035090
    [Google Scholar]
  184. Nikaido T. Ohmoto T. Kinoshita T. Sankawa U. Nishibe S. Hisada S. Inhibition of cyclic AMP phosphodiesterase by lignans. Chem. Pharm. Bull. 1981 29 12 3586 3592 10.1248/cpb.29.3586 6280885
    [Google Scholar]
  185. Abdelwaly A. Salama I. Gomaa M.S. Helal M.A. Discovery of tetrahydro-ß-carboline derivatives as a new class of phosphodiesterase 4 inhibitors. Med. Chem. Res. 2017 26 12 3173 3187 10.1007/s00044‑017‑2011‑x
    [Google Scholar]
  186. Ji H. Zhang H. Multipotent natural agents to combat Alzheimer’s disease. Functional spectrum and structural features. Acta Pharmacol. Sin. 2008 29 2 143 151 10.1111/j.1745‑7254.2008.00752.x 18215342
    [Google Scholar]
  187. Juvekar A.R. Khatri D.K. Kinetics of inhibition of monoamine oxidase using curcumin and ellagic acid. Pharmacogn. Mag. 2016 12 46 Suppl. 2 116 10.4103/0973‑1296.182168 27279695
    [Google Scholar]
  188. Baek S.C. Ryu H.W. Kang M.G. Lee H. Park D. Cho M.L. Oh S.R. Kim H. Selective inhibition of monoamine oxidase A by chelerythrine, an isoquinoline alkaloid. Bioorg. Med. Chem. Lett. 2018 28 14 2403 2407 10.1016/j.bmcl.2018.06.023 29925480
    [Google Scholar]
  189. Kukula-Koch W. Koch W. Czernicka L. Głowniak K. Asakawa Y. Umeyama A. Marzec Z. Kuzuhara T. MAO-A inhibitory potential of terpene constituents from ginger rhizomes—A bioactivity guided fractionation. Molecules 2018 23 6 1301 10.3390/molecules23061301 29844252
    [Google Scholar]
  190. Kong L.D. Cheng C.H.K. Tan R.X. Inhibition of MAO A and B by some plant-derived alkaloids, phenols and anthraquinones. J. Ethnopharmacol. 2004 91 2-3 351 355 10.1016/j.jep.2004.01.013 15120460
    [Google Scholar]
  191. Larit F. Elokely K.M. Chaurasiya N.D. Benyahia S. Nael M.A. León F. Abu-Darwish M.S. Efferth T. Wang Y.H. Belouahem-Abed D. Benayache S. Tekwani B.L. Cutler S.J. Inhibition of human monoamine oxidase A and B by flavonoids isolated from two Algerian medicinal plants. Phytomedicine 2018 40 27 36 10.1016/j.phymed.2017.12.032 29496172
    [Google Scholar]
  192. Ali T. Michael B.O. Ogbesejana A.B. Flavonoids with monoamine oxidase A and B inhibitory and anti-inflammatory effects from Vitex Grandifolia. Malays. J. Anal. Sci. 2020 24 6 1035 1044
    [Google Scholar]
  193. (a) Ilana B. Egger K. Cumming P. Monoamine Oxidase Inhibition by Plant-Derived β-Carbolines; Implications for the Psychopharmacology of Tobacco and Imbimbo, B. P. (2008). Therapeutic potential of γ-secretase inhibitors and modulators. Curr. Top. Med. Chem. 2022 8 1 54 61 10.3389/fphar.2022.886408
    [Google Scholar]
  194. (b) Imbimbo B.P. Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem 2008 8 1 54 61 10.3389/fphar.2022.886408
    [Google Scholar]
  195. Ray B. Maloney B. Sambamurti K. Karnati H.K. Nelson P.T. Greig N.H. Lahiri D.K. Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease. Transl. Psychiatry 2020 10 1 47 10.1038/s41398‑020‑0709‑x 32066688
    [Google Scholar]
  196. Rosita J. Cardiac toxicology. Heart Physiology and Pathophysiology Academic Press Cambridge, Massachusetts 2001 1211 1224
    [Google Scholar]
  197. Li H. Zuo J. Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front. Pharmacol. 2018 9 1048 10.3389/fphar.2018.01048 30386231
    [Google Scholar]
  198. Phillips J.E. Inhaled phosphodiesterase 4 (PDE4) inhibitors for inflammatory respiratory diseases. Front. Pharmacol. 2020 11 259 10.3389/fphar.2020.00259 32226383
    [Google Scholar]
  199. Sub Laban T. Saadabadi A. Monoamine Oxidase Inhibitors (MAOI). StatPearls StatPearls Publishing Treasure Island (FL) 2022
    [Google Scholar]
  200. Ye X. Wang H. Cheng S. Xia L. Xu X. Li X. Network pharmacology-based strategy to investigate the pharmacologic mechanisms of coptidis rhizoma for the treatment of Alzheimer’s disease. Front. Aging Neurosci. 2022 14 890046 10.3389/fnagi.2022.890046 35795239
    [Google Scholar]
  201. Zhang M. Zheng H. He J. Zhang M. Network pharmacology and in vivo studies reveal the neuroprotective effects of paeoniflorin on Alzheimer’s disease. Heliyon 2023 9 11 e21800 10.1016/j.heliyon.2023.e21800 38027768
    [Google Scholar]
  202. Wang Q. Pang Y. Yang H. Zhang X. Nie W. Zhou J. Chen R. Investigating the mechanism of Fuling-Banxia-Dafupi in the treatment of diabetic kidney disease using network pharmacology and molecular docking. Nat. Prod. Res. 2024 1 6 10.1080/14786419.2024.2370043 39001776
    [Google Scholar]
  203. Soleimani Zakeri N.S. Pashazadeh S. MotieGhader H. Drug repurposing for Alzheimer’s disease based on protein-protein interaction network. BioMed Res. Int. 2021 2021 1 1280237 10.1155/2021/1280237 34692825
    [Google Scholar]
  204. Zhu J. Liang Q. He S. Wang C. Lin X. Wu D. Lin G. Wang Z. Research trends and hotspots of neurodegenerative diseases employing network pharmacology: A bibliometric analysis. Front. Pharmacol. 2023 13 1109400 10.3389/fphar.2022.1109400 36712694
    [Google Scholar]
  205. Chen Q. Chen G. Wang Q. Application of network pharmacology in the treatment of neurodegenerative diseases with traditional chinese medicine. Planta Med. 2025 8. 10.1055/a‑2512‑8928 39778593
    [Google Scholar]
  206. Zhang Z. Gao J. Wang J. Mi Z. Li H. Dai Z. Pan Y. Dong J. Chen S. Lu S. Tan X. Chen H. Mechanism of Zhishi Xiebai Guizhi decoction to treat atherosclerosis: Insights into experiments, network pharmacology and molecular docking. J. Ethnopharmacol. 2024 333 118466 10.1016/j.jep.2024.118466 38885915
    [Google Scholar]
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