Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Author(s): Mahdi Khodadadi and Behjat Javadi*

DOI: 10.2174/0113895575306884240604065754

DownloadDownload PDF Flyer Cite As
A Review of the Protective Effects of Alkaloids against Alpha-synuclein Toxicity in Parkinson's Disease

Page: [112 - 127] Pages: 16

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Alpha-synuclein (α-syn) aggregation products may cause neural injury and several neurodegenerative disorders (NDs) known as α-synucleinopathies. Alkaloids are secondary metabolites present in a variety of plant species and may positively affect human health, particularly α-synucleinopathy-associated NDs.

Aim: To summarize the latest scientific data on the inhibitory properties of alkaloids in α- synucleinopathies, especially in Parkinson’s disease.

Methods: Literature search was performed using web-based databases including Web of Science, PubMed, and Scopus up to January 2024, in the English language.

Results: Harmala alkaloids, caffein, lycorine, piperin, acetylcorynoline, berberin, papaverine, squalamine, trodusquemine and nicotin have been found to be the most active natural alkaloids against synucleinopathy. The underlying mechanisms that contribute to this effect would be the inhibition of α-syn aggregation; elimination of formed aggregates; improvement in autophagy activation; promotion of the activity and expression of antioxidative enzymes; and prevention of oxidative injury and apoptosis in dopaminergic neurons.

Conclusion: The findings of the present study highlight the inhibitory activities of alkaloids against synucleinopathy. However, no clinical data supports the reported activities in humans, which calls attention to the need for conducting clinical trials to elucidate the efficacy, safety, proper dosage, unwanted effects and pharmacokinetics aspects of alkaloids in humans.

Keywords: Synuclein, Parkinson’s disease, neurodegeneration, alkaloids, plants, non-motor symptoms.

Graphical Abstract

[1]
Mhyre, T.R.; Boyd, J.T.; Hamill, R.W.; Zeiss, M.K.A. Parkinson’s disease. Subcell. Biochem., 2012, 65, 389-455.
[http://dx.doi.org/10.1007/978-94-007-5416-4_16] [PMID: 23225012]
[2]
Rizek, P.; Kumar, N.; Jog, M.S. An update on the diagnosis and treatment of Parkinson disease. CMAJ, 2016, 188(16), 1157-1165.
[http://dx.doi.org/10.1503/cmaj.151179] [PMID: 27221269]
[3]
Kouli, A.; Torsney, K.M.; Kuan, W-L. Parkinson’s disease: Etiology, neuropathology, and pathogenesis; Exon Publications: Brisbane (AU), 2018, pp. 3-26.
[4]
Ramazani, E. YazdFazeli, M.; Emami, S.A.; Mohtashami, L.; Javadi, B.; Asili, J.; Najaran, T.Z. Protective effects of Cinnamomum verum, Cinnamomum cassia and cinnamaldehyde against 6-OHDA-induced apoptosis in PC12 cells. Mol. Biol. Rep., 2020, 47(4), 2437-2445.
[http://dx.doi.org/10.1007/s11033-020-05284-y] [PMID: 32166553]
[5]
Alexoudi, A.; Alexoudi, I.; Gatzonis, S. Parkinson’s disease pathogenesis, evolution and alternative pathways: A review. Rev. Neurol., 2018, 174(10), 699-704.
[http://dx.doi.org/10.1016/j.neurol.2017.12.003] [PMID: 30131173]
[6]
Kabra, A.; Sharma, R.; Kabra, R.; Baghel, U.S. Emerging and alternative therapies for Parkinson disease: An updated review. Curr. Pharm. Des., 2018, 24(22), 2573-2582.
[http://dx.doi.org/10.2174/1381612824666180820150150] [PMID: 30124146]
[7]
Heim, B.; Krismer, F.; De Marzi, R.; Seppi, K. Magnetic resonance imaging for the diagnosis of Parkinson’s disease. J. Neural Transm., 2017, 124(8), 915-964.
[http://dx.doi.org/10.1007/s00702-017-1717-8] [PMID: 28378231]
[8]
Lee, T.K.; Yankee, E.L. A review on Parkinson’s disease treatment. Neuroimmunol. Neuroinflamm., 2022, 8, 222.
[http://dx.doi.org/10.20517/2347-8659.2020.58]
[9]
Ciga, B.S.; Fairen, D.M.; Kim, J.J.; Singleton, A.B. Genetics of Parkinson’s disease: An introspection of its journey towards precision medicine. Neurobiol. Dis., 2020, 137, 104782.
[http://dx.doi.org/10.1016/j.nbd.2020.104782] [PMID: 31991247]
[10]
Benito, G.M.; Granado, N.; Sanz, G.P.; Michel, A.; Dumoulin, M.; Moratalla, R. Modeling Parkinson’s disease with the alpha-synuclein protein. Front. Pharmacol., 2020, 11, 356.
[http://dx.doi.org/10.3389/fphar.2020.00356] [PMID: 32390826]
[11]
Ghaderi, M.A.; Emami, S.A.; Olia, B.M.D.; Javadi, B. The role of sesamin in targeting neurodegenerative disorders: A systematic review. Mini Rev. Med. Chem., 2023, 23(6), 756-770.
[http://dx.doi.org/10.2174/1389557522666220523112027] [PMID: 35616667]
[12]
Goedert, M.; Jakes, R.; Spillantini, M.G. The synucleinopathies: Twenty years on. J. Parkinsons Dis., 2017, 7(s1), S51-S69.
[http://dx.doi.org/10.3233/JPD-179005] [PMID: 28282814]
[13]
Wong, Y.C.; Krainc, D. α-synuclein toxicity in neurodegeneration: Mechanism and therapeutic strategies. Nat. Med., 2017, 23(2), 1-13.
[http://dx.doi.org/10.1038/nm.4269] [PMID: 28170377]
[14]
Burré, J. The synaptic function of α-synuclein. J. Parkinsons Dis., 2015, 5(4), 699-713.
[http://dx.doi.org/10.3233/JPD-150642] [PMID: 26407041]
[15]
Popova, B.; Galka, D. Häffner, N.; Wang, D.; Schmitt, K.; Valerius, O. α-Synuclein decreases the abundance of proteasome subunits and alters ubiquitin conjugates in yeast. Cells, 2021, 10(9), 2229.
[16]
Lin, K.J.; Lin, K.L.; Chen, S.D.; Liou, C.W.; Chuang, Y.C.; Lin, H.Y. The overcrowded crossroads: Mitochondria, alpha-synuclein, and the endo-lysosomal system interaction in Parkinson’s disease. Int. J. Mo.l Sci., 2019, 20(21), 5312.
[17]
Devi, L.; Raghavendran, V.; Prabhu, B.M.; Avadhani, N.G.; Anandatheerthavarada, H.K. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem., 2008, 283(14), 9089-9100.
[http://dx.doi.org/10.1074/jbc.M710012200] [PMID: 18245082]
[18]
Risiglione, P.; Zinghirino, F.; Di Rosa, M.C.; Magrì, A.; Messina, A. Alpha-synuclein and mitochondrial dysfunction in parkinson’s disease: The emerging role of VDAC. Biomolecules, 2021, 11(5), 718.
[19]
Tsunemi, T.; Ishiguro, Y.; Yoroisaka, A.; Valdez, C.; Miyamoto, K.; Ishikawa, K.; Saiki, S.; Akamatsu, W.; Hattori, N.; Krainc, D. Astrocytes protect human dopaminergic neurons from α-synuclein accumulation and propagation. J. Neurosci., 2020, 40(45), 8618-8628.
[http://dx.doi.org/10.1523/JNEUROSCI.0954-20.2020] [PMID: 33046546]
[20]
Lashuel, H.A.; Overk, C.R.; Oueslati, A.; Masliah, E. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nat. Rev. Neurosci., 2013, 14(1), 38-48.
[http://dx.doi.org/10.1038/nrn3406] [PMID: 23254192]
[21]
Manske, R.H.F.; Holmes, H.L. The alkaloids: Chemistry and physiology; Elsevier, 2014.
[22]
Ng, Y.P.; Or, T.C.T.; Ip, N.Y. Plant alkaloids as drug leads for Alzheimer’s disease. Neurochem. Int., 2015, 89, 260-270.
[http://dx.doi.org/10.1016/j.neuint.2015.07.018] [PMID: 26220901]
[23]
Chen, J.F.; Schwarzschild, M.A. Do caffeine and more selective adenosine A(2A) receptor antagonists protect against dopaminergic neurodegeneration in Parkinson’s disease? Parkinson. Relat Disord., 2020, 80(S1), S45-S53.
[24]
Stefanis, L. α-Synuclein in Parkinson’s disease. Cold Spring Harb. Perspect. Med., 2012, 2(2), a009399.
[http://dx.doi.org/10.1101/cshperspect.a009399] [PMID: 22355802]
[25]
Mor, D.E.; Ugras, S.E.; Daniels, M.J.; Ischiropoulos, H. Dynamic structural flexibility of α-synuclein. Neurobiol. Dis., 2016, 88, 66-74.
[http://dx.doi.org/10.1016/j.nbd.2015.12.018] [PMID: 26747212]
[26]
Bisaglia, M.; Trolio, A.; Bellanda, M.; Bergantino, E.; Bubacco, L.; Mammi, S. Structure and topology of the non‐amyloid‐β component fragment of human α‐synuclein bound to micelles: Implications for the aggregation process. Protein Sci., 2006, 15(6), 1408-1416.
[http://dx.doi.org/10.1110/ps.052048706] [PMID: 16731975]
[27]
Singh, A.; Maharana, S.K.; Shukla, R.; Kesharwani, P. Nanotherapeutics approaches for targeting alpha synuclien protein in the management of Parkinson disease. Process Biochem., 2021, 110, 181-194.
[http://dx.doi.org/10.1016/j.procbio.2021.08.008]
[28]
Emamzadeh, F. Alpha-synuclein structure, functions, and interactions. J. Res. Med. Sci., 2016, 21(1), 29.
[http://dx.doi.org/10.4103/1735-1995.181989] [PMID: 27904575]
[29]
Srinivasan, E.; Chandrasekhar, G.; Chandrasekar, P.; Anbarasu, K.; Vickram, A.S.; Karunakaran, R.; Rajasekaran, R.; Srikumar, P.S. Alpha-synuclein aggregation in Parkinson’s disease. Front. Med., 2021, 8, 736978.
[http://dx.doi.org/10.3389/fmed.2021.736978] [PMID: 34733860]
[30]
Ulmer, T.S.; Bax, A.; Cole, N.B.; Nussbaum, R.L. Structure and dynamics of micelle-bound human α-synuclein. J. Biol. Chem., 2005, 280(10), 9595-9603.
[http://dx.doi.org/10.1074/jbc.M411805200] [PMID: 15615727]
[31]
Breydo, L.; Wu, J.W.; Uversky, V.N. α-Synuclein misfolding and Parkinson’s disease. Biochim. Biophys. Acta Mol. Basis Dis., 2012, 1822(2), 261-285.
[http://dx.doi.org/10.1016/j.bbadis.2011.10.002]
[32]
Nuber, S.; Rajsombath, M.; Minakaki, G.; Winkler, J.; Müller, C.P.; Ericsson, M. Abrogating native α-synuclein tetramers in mice causes a L-DOPA-responsive motor syndrome closely resembling Parkinson’s disease. Neuron, 2018, 100(1), 75-90. e5
[http://dx.doi.org/10.1016/j.neuron.2018.09.014]
[33]
Wang, L.; Das, U.; Scott, D.A.; Tang, Y.; McLean, P.J.; Roy, S. α-synuclein multimers cluster synaptic vesicles and attenuate recycling. Curr. Biol., 2014, 24(19), 2319-2326.
[http://dx.doi.org/10.1016/j.cub.2014.08.027] [PMID: 25264250]
[34]
Baba, M.; Nakajo, S.; Tu, P.H.; Tomita, T.; Nakaya, K.; Lee, V.M.; Trojanowski, J.Q.; Iwatsubo, T. Aggregation of alpha-synuclein in lewy bodies of sporadic Parkinson’s disease and dementia with lewy bodies. Am. J. Pathol., 1998, 152(4), 879-884.
[PMID: 9546347]
[35]
Alam, P.; Bousset, L.; Melki, R.; Otzen, D.E. α‐synuclein oligomers and fibrils: A spectrum of species, a spectrum of toxicities. J. Neurochem., 2019, 150(5), 522-534.
[http://dx.doi.org/10.1111/jnc.14808] [PMID: 31254394]
[36]
Harati, M.; Najaran, T.Z.; Javadi, B. Dietary flavonoids: Promising compounds for targeting α-synucleinopathy in Parkinson’s disease. PharmaNutrition, 2023, 24, 100334.
[http://dx.doi.org/10.1016/j.phanu.2023.100334]
[37]
Conde, B.L.D.; Acevedo, R.R. Hernández, R.M.A.; Olvera, B.A.J.; Moreno, M.I.D.; Sánchez, A.R.; Schüle, B.; Crespo, G.M. Alpha-synuclein physiology and pathology: A perspective on cellular structures and organelles. Front. Neurosci., 2020, 13, 1399.
[http://dx.doi.org/10.3389/fnins.2019.01399] [PMID: 32038126]
[38]
Conway, K.A.; Rochet, J.C.; Bieganski, R.M.; Lansbury, P.T., Jr Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct. Science, 2001, 294(5545), 1346-1349.
[http://dx.doi.org/10.1126/science.1063522] [PMID: 11701929]
[39]
Schulz-Schaeffer, W.J. The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol., 2010, 120(2), 131-143.
[http://dx.doi.org/10.1007/s00401-010-0711-0] [PMID: 20563819]
[40]
Jankovic, J.; Tan, E.K. Parkinson’s disease: Etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry, 2020, 91(8), 795-808.
[http://dx.doi.org/10.1136/jnnp-2019-322338] [PMID: 32576618]
[41]
Calo, L.; Wegrzynowicz, M.; Perez, S.J.; Spillantini, G.M. Synaptic failure and α‐synuclein. Mov. Disord., 2016, 31(2), 169-177.
[http://dx.doi.org/10.1002/mds.26479] [PMID: 26790375]
[42]
Iranshahy, M.; Javadi, B.; Sahebkar, A. Protective effects of functional foods against Parkinson’s disease: A narrative review on pharmacology, phytochemistry, and molecular mechanisms. Phytother. Res., 2022, 36(5), 1952-1989.
[http://dx.doi.org/10.1002/ptr.7425] [PMID: 35244296]
[43]
Alecu, I.; Bennett, S.A.L. Dysregulated lipid metabolism and its role in α-synucleinopathy in Parkinson’s disease. Front. Neurosci., 2019, 13, 328.
[http://dx.doi.org/10.3389/fnins.2019.00328] [PMID: 31031582]
[44]
Zhang, G.; Xia, Y.; Wan, F.; Ma, K.; Guo, X.; Kou, L.; Yin, S.; Han, C.; Liu, L.; Huang, J.; Xiong, N.; Wang, T. New perspectives on roles of alpha-synuclein in Parkinson’s disease. Front. Aging Neurosci., 2018, 10, 370.
[http://dx.doi.org/10.3389/fnagi.2018.00370] [PMID: 30524265]
[45]
Melland, H.; Arvell, E.H.; Gordon, S.L. Disorders of synaptic vesicle fusion machinery. J. Neurochem., 2021, 157(2), 130-164.
[http://dx.doi.org/10.1111/jnc.15181] [PMID: 32916768]
[46]
De Miranda, B.R.; Rocha, E.M.; Castro, S.L.; Greenamyre, J.T. Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20. NPJ Parkinsons Dis., 2020, 6(1), 1-10.
[47]
Di Maio, R.; Barrett, P.J.; Hoffman, E.K.; Barrett, C.W.; Zharikov, A.; Borah, A. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci. Translat. Med., 2016, 8(342), 342ra78-342ra78.
[48]
Fields, C.R.; Bengoa-Vergniory, N.; Wade-Martins, R. Targeting alpha-synuclein as a therapy for Parkinson’s disease. Front. Mol. Neurosci., 2019, 12, 299.
[http://dx.doi.org/10.3389/fnmol.2019.00299] [PMID: 31866823]
[49]
Dehay, B.; Vila, M.; Bezard, E.; Brundin, P.; Kordower, J.H. Alpha‐synuclein propagation: New insights from animal models. Mov. Disord., 2016, 31(2), 161-168.
[http://dx.doi.org/10.1002/mds.26370] [PMID: 26347034]
[50]
Fatima, A. Rahul; Siddique, Y.H. Role of tangeritin against cognitive impairments in transgenic Drosophila model of Parkinson’s disease. Neurosci. Lett., 2019, 705, 112-117.
[http://dx.doi.org/10.1016/j.neulet.2019.04.047] [PMID: 31039425]
[51]
Cuadrado, F.A.; Sanchez, S.D.; Moriano, M.A.; Cenjor, L.E.; Olmo, L.V.; Marcos, M.A. Astrogliosis and sexually dimorphic neurodegeneration and microgliosis in the olfactory bulb in Parkinson’s disease. NPJ Parkinsons Dis., 2021, 7(1), 1-13.
[52]
Lin, K.J.; Lin, K.L.; Chen, S.D.; Liou, C.W.; Chuang, Y.C.; Lin, H.Y.; Lin, T.K. The overcrowded crossroads: Mitochondria, alpha-synuclein, and the endo-lysosomal system interaction in Parkinson’s disease. Int. J. Mol. Sci., 2019, 20(21), 5312.
[http://dx.doi.org/10.3390/ijms20215312] [PMID: 31731450]
[53]
Dzamko, N.; Gysbers, A.; Perera, G.; Bahar, A.; Shankar, A.; Gao, J.; Fu, Y.; Halliday, G.M. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol., 2017, 133(2), 303-319.
[http://dx.doi.org/10.1007/s00401-016-1648-8] [PMID: 27888296]
[54]
Koob, A.O.; Paulino, A.D.; Masliah, E. GFAP reactivity, apolipoprotein E redistribution and cholesterol reduction in human astrocytes treated with α-synuclein. Neurosci. Lett., 2010, 469(1), 11-14.
[http://dx.doi.org/10.1016/j.neulet.2009.11.034] [PMID: 19932737]
[55]
Alkaloids - Their importance in nature and for human life. In: Joanna, K., Ed.; Alkaloids; IntechOpen: Rijeka, 2019.
[56]
Heinrich, M.; Mah, J.; Amirkia, V. Alkaloids used as medicines: Structural phytochemistry meets biodiversity-An update and forward look. Molecules, 2021, 26(7), 1836.
[57]
Johannsen, K.K.L.; Kayser, O. Tropane alkaloids: Chemistry, pharmacology, biosynthesis and production. Molecules, 2019, 24(4), 796.
[58]
Uzor, P.F. Alkaloids from plants with antimalarial activity: A review of recent studies. Evid. Based Complement. Alternat. Med., 2020, 2020, 1-17.
[http://dx.doi.org/10.1155/2020/8749083] [PMID: 32104196]
[59]
Vitali Serdoz, L.; Rittger, H.; Furlanello, F.; Bastian, D. Quinidine—A legacy within the modern era of antiarrhythmic therapy. Pharmacol. Res., 2019, 144, 257-263.
[http://dx.doi.org/10.1016/j.phrs.2019.04.028] [PMID: 31026503]
[60]
Martino, E.; Casamassima, G.; Castiglione, S.; Cellupica, E.; Pantalone, S.; Papagni, F.; Rui, M.; Siciliano, A.M.; Collina, S. Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead. Bioorg. Med. Chem. Lett., 2018, 28(17), 2816-2826.
[http://dx.doi.org/10.1016/j.bmcl.2018.06.044] [PMID: 30122223]
[61]
Thawabteh, A.; Juma, S.; Bader, M.; Karaman, D.; Scrano, L.; Bufo, S.A. The biological activity of natural alkaloids against herbivores, cancerous cells and pathogens. Toxins, 2019, 11(11), 656.
[62]
Song, C.; Ma, J.; Li, G.; Pan, H.; Zhu, Y.; Jin, Q.; Cai, Y.; Han, B. Natural composition and biosynthetic pathways of alkaloids in medicinal Dendrobium species. Front. Plant Sci., 2022, 13, 850949.
[http://dx.doi.org/10.3389/fpls.2022.850949] [PMID: 35599884]
[63]
Tzin, V.; Galili, G. The biosynthetic pathways for shikimate and aromatic amino acids in Arabidopsis thaliana. Arabidopsis Book, 2010, 8, e0132.
[http://dx.doi.org/10.1199/tab.0132] [PMID: 22303258]
[64]
Perez de Souza, L.; Garbowicz, K.; Brotman, Y.; Tohge, T.; Fernie, A.R. The acetate pathway supports flavonoid and lipid biosynthesis in arabidopsis. Plant Physiol., 2020, 182(2), 857-869.
[http://dx.doi.org/10.1104/pp.19.00683] [PMID: 31719153]
[65]
Lu, J.H.; Tan, J.Q.; Durairajan, S.S.K.; Liu, L.F.; Zhang, Z.H.; Ma, L.; Shen, H.M.; Chan, H.Y.E.; Li, M. Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy. Autophagy, 2012, 8(1), 98-108.
[http://dx.doi.org/10.4161/auto.8.1.18313] [PMID: 22113202]
[66]
Ghanem, S.S.; Fayed, H.S.; Zhu, Q.; Lu, J.H.; Vaikath, N.N.; Ponraj, J. Natural alkaloid compounds as inhibitors for alpha-synuclein seeded fibril formation and toxicity. Molecules, 2021, 26(12), 3736.
[http://dx.doi.org/10.3390/molecules26123736]
[67]
Devi, S.; Kumar, V.; Singh, S.K.; Dubey, A.K.; Kim, J.J. Flavonoids: Potential candidates for the treatment of neurodegenerative disorders. Biomedicines, 2021, 9(2), 99.
[http://dx.doi.org/10.3390/biomedicines9020099] [PMID: 33498503]
[68]
Limbocker, R.; Staats, R.; Chia, S.; Ruggeri, F.S.; Mannini, B.; Xu, C.K.; Perni, M.; Cascella, R.; Bigi, A.; Sasser, L.R.; Block, N.R.; Wright, A.K.; Kreiser, R.P.; Custy, E.T.; Meisl, G.; Errico, S.; Habchi, J.; Flagmeier, P.; Kartanas, T.; Hollows, J.E.; Nguyen, L.T.; LeForte, K.; Barbut, D.; Kumita, J.R.; Cecchi, C.; Zasloff, M.; Knowles, T.P.J.; Dobson, C.M.; Chiti, F.; Vendruscolo, M. Squalamine and its derivatives modulate the aggregation of amyloid-β and α-synuclein and suppress the toxicity of their oligomers. Front. Neurosci., 2021, 15, 680026.
[http://dx.doi.org/10.3389/fnins.2021.680026] [PMID: 34220435]
[69]
Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M.B.D.; Challa, P.K.; Kirkegaard, J.B.; Flagmeier, P.; Cohen, S.I.A.; Cascella, R.; Chen, S.W.; Limbocker, R.; Sormanni, P.; Heller, G.T.; Aprile, F.A.; Cremades, N.; Cecchi, C.; Chiti, F.; Nollen, E.A.A.; Knowles, T.P.J.; Vendruscolo, M.; Bax, A.; Zasloff, M.; Dobson, C.M. A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. Proc. Natl. Acad. Sci., 2017, 114(6), E1009-E1017.
[http://dx.doi.org/10.1073/pnas.1610586114] [PMID: 28096355]
[70]
Perni, M.; Flagmeier, P.; Limbocker, R.; Cascella, R.; Aprile, F.A.; Galvagnion, C.; Heller, G.T.; Meisl, G.; Chen, S.W.; Kumita, J.R.; Challa, P.K.; Kirkegaard, J.B.; Cohen, S.I.A.; Mannini, B.; Barbut, D.; Nollen, E.A.A.; Cecchi, C.; Cremades, N.; Knowles, T.P.J.; Chiti, F.; Zasloff, M.; Vendruscolo, M.; Dobson, C.M. Multistep inhibition of α-synuclein aggregation and toxicity in vitro and in vivo by trodusquemine. ACS Chem. Biol., 2018, 13(8), 2308-2319.
[http://dx.doi.org/10.1021/acschembio.8b00466] [PMID: 29953201]
[71]
Manson, A.J.; Turner, K.; Lees, A.J. Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson’s disease: Long‐term follow‐up study of 64 patients. Mov. Disord., 2002, 17(6), 1235-1241.
[http://dx.doi.org/10.1002/mds.10281] [PMID: 12465062]
[72]
Heurtaux, T.; Kirchmeyer, M.; Koncina, E.; Felten, P.; Richart, L.; Huarte, U.O.; Schohn, H.; Mittelbronn, M. Apomorphine reduces A53T α-synuclein-induced microglial reactivity through activation of NRF2 signalling pathway. Cell. Mol. Neurobiol., 2022, 42(8), 2673-2695.
[http://dx.doi.org/10.1007/s10571-021-01131-1] [PMID: 34415465]
[73]
Subramaniam, S.R.; Federoff, H.J. Targeting microglial activation states as a therapeutic avenue in Parkinson’s disease. Front. Aging Neurosci., 2017, 9, 176.
[http://dx.doi.org/10.3389/fnagi.2017.00176] [PMID: 28642697]
[74]
Kirchweger, B.; Klein-Junior, L.C.; Pretsch, D.; Chen, Y.; Cretton, S.; Gasper, A.L.; Heyden, Y.V.; Christen, P.; Kirchmair, J.; Henriques, A.T.; Rollinger, J.M. Azepine-indole alkaloids from Psychotria nemorosa Modulate 5-HT2A receptors and prevent in vivo protein toxicity in transgenic Caenorhabditis elegans. Front. Neurosci., 2022, 16, 826289.
[http://dx.doi.org/10.3389/fnins.2022.826289] [PMID: 35360162]
[75]
Fu, R.H.; Wang, Y.C.; Chen, C.S.; Tsai, R.T.; Liu, S.P.; Chang, W.L.; Lin, H.L.; Lu, C.H.; Wei, J.R.; Wang, Z.W.; Shyu, W.C.; Lin, S.Z. Acetylcorynoline attenuates dopaminergic neuron degeneration and α-synuclein aggregation in animal models of Parkinson’s disease. Neuropharmacology, 2014, 82, 108-120.
[http://dx.doi.org/10.1016/j.neuropharm.2013.08.007] [PMID: 23973292]
[76]
Leem, Y.H.; Park, J.S.; Park, J.E.; Kim, D.Y.; Kang, J.L.; Kim, H.S. Papaverine inhibits α-synuclein aggregation by modulating neuroinflammation and matrix metalloproteinase-3 expression in the subacute MPTP/P mouse model of Parkinson’s disease. Biomed. Pharmacother., 2020, 130, 110576.
[http://dx.doi.org/10.1016/j.biopha.2020.110576] [PMID: 32768884]
[77]
Leem, Y.H.; Park, J.S.; Park, J.E.; Kim, D.Y.; Kim, H.S. Papaverine exerts neuroprotective effect by inhibiting NLRP3 inflammasome activation in an MPTP-induced microglial priming mouse model challenged with LPS. Biomol. Ther., 2021, 29(3), 295-302.
[http://dx.doi.org/10.4062/biomolther.2021.039] [PMID: 33911050]
[78]
Ding, K.; Liu, L.; Cheng, X.; Wang, C.; Wang, Z. Investigation on representation methods of dissolubility property of total alkaloid extract from Peganum harmala. Zhongguo Zhongyao Zazhi, 2010, 35(17), 2250-2253.
[PMID: 21137330]
[79]
Zhang, L.; Li, D.; Yu, S. Pharmacological effects of harmine and its derivatives: A review. Arch. Pharm. Res., 2020, 43(12), 1259-1275.
[http://dx.doi.org/10.1007/s12272-020-01283-6] [PMID: 33206346]
[80]
Djamshidian, A.; Reif, B.S.; Poewe, W.; Lees, A.J. Banisteriopsis caapi, a forgotten potential therapy for Parkinson’s disease? Mov. Disord. Clin. Pract., 2016, 3(1), 19-26.
[http://dx.doi.org/10.1002/mdc3.12242] [PMID: 30713897]
[81]
Cai, C.Z.; Zhou, H.F.; Yuan, N.N.; Wu, M.Y.; Lee, S.M.Y.; Ren, J.Y.; Su, H.X.; Lu, J.J.; Chen, X.P.; Li, M.; Tan, J.Q.; Lu, J.H. Natural alkaloid harmine promotes degradation of alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation. Phytomedicine, 2019, 61, 152842.
[http://dx.doi.org/10.1016/j.phymed.2019.152842] [PMID: 31048127]
[82]
Zhu, Q.; Zhuang, X.; Chen, J.; Yuan, N.; Chen, Y.; Cai, C.; Tan, J.; Su, H.; Lu, J. Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson’s disease models. Phytomedicine, 2021, 87, 153578.
[http://dx.doi.org/10.1016/j.phymed.2021.153578] [PMID: 34038839]
[83]
Xu, J.; Ao, Y.L.; Huang, C.; Song, X.; Zhang, G.; Cui, W.; Wang, Y.; Zhang, X-Q.; Zhang, Z. Harmol promotes α-synuclein degradation and improves motor impairment in Parkinson’s models via regulating autophagy-lysosome pathway. NPJ Parkinsons Dis., 2022, 8(1), 100.
[http://dx.doi.org/10.1038/s41531-022-00361-4]
[84]
Abulimiti, G.; Zeng, J.; Aimaiti, M.; Lei, X.; Mi, N. Harmol hydrochloride dihydrate induces autophagy in neuro cells and promotes the degradation of α‐Syn by Atg5/Atg12‐dependent pathway. Food Sci. Nutr., 2022, 10(12), 4371-4379.
[http://dx.doi.org/10.1002/fsn3.3031] [PMID: 36514773]
[85]
Deng, H.; Ma, Z. Protective effects of berberine against MPTP-induced dopaminergic neuron injury through promoting autophagy in mice. Food Funct., 2021, 12(18), 8366-8375.
[http://dx.doi.org/10.1039/D1FO01360B] [PMID: 34342315]
[86]
Yu, L.; Hu, X.; Xu, R.; Zhao, Y.; Xiong, L.; Ai, J.; Wang, X.; Chen, X.; Ba, Y.; Xing, Z.; Guo, C.; Mi, S.; Wu, X. Piperine promotes PI3K/AKT/mTOR-mediated gut-brain autophagy to degrade α-Synuclein in Parkinson’s disease rats. J. Ethnopharmacol., 2024, 322, 117628.
[http://dx.doi.org/10.1016/j.jep.2023.117628] [PMID: 38158101]
[87]
Huang, L.; Zhong, X.; Zhou, Z.; Cai, Y.; Deng, M. Piperine increases striatal levels of DA and TH and decreases α-syn and Aβ42 deposition in PDD mice by regulting autophagy: Downexpression Beclin-1 and LC3B and upexpression p62. Appl. Biol. Chem., 2022, 65(1), 42.
[http://dx.doi.org/10.1186/s13765-022-00710-0]
[88]
Li, R.; Lu, Y.; Zhang, Q.; Liu, W.; Yang, R.; Jiao, J.; Liu, J.; Gao, G.; Yang, H. Piperine promotes autophagy flux by P2RX4 activation in SNCA/α-synuclein-induced Parkinson disease model. Autophagy, 2022, 18(3), 559-575.
[http://dx.doi.org/10.1080/15548627.2021.1937897] [PMID: 34092198]
[89]
Kardani, J.; Roy, I. Understanding caffeine’s role in attenuating the toxicity of α-synuclein aggregates: Implications for risk of Parkinson’s disease. ACS Chem. Neurosci., 2015, 6(9), 1613-1625.
[http://dx.doi.org/10.1021/acschemneuro.5b00158] [PMID: 26167732]
[90]
Luan, Y.; Ren, X.; Zheng, W.; Zeng, Z.; Guo, Y.; Hou, Z.; Guo, W.; Chen, X.; Li, F.; Chen, J.F. Chronic caffeine treatment protects against α-synucleinopathy by reestablishing autophagy activity in the mouse striatum. Front. Neurosci., 2018, 12, 301.
[http://dx.doi.org/10.3389/fnins.2018.00301] [PMID: 29770111]
[91]
Zhang, Y.; Wu, Q.; Zhang, L.; Wang, Q.; Yang, Z.; Liu, J.; Feng, L. Caffeic acid reduces A53T α-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson’s disease. Pharmacol. Res., 2019, 150, 104538.
[http://dx.doi.org/10.1016/j.phrs.2019.104538] [PMID: 31707034]
[92]
Yan, R.; Zhang, J.; Park, H.J.; Park, E.S.; Oh, S.; Zheng, H.; Junn, E.; Voronkov, M.; Stock, J.B.; Mouradian, M.M. Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB. Proc. Natl. Acad. Sci., 2018, 115(51), E12053-E12062.
[http://dx.doi.org/10.1073/pnas.1813365115] [PMID: 30509990]
[93]
Benowitz, N.L.; Hukkanen, J.; Jacob, P. III Nicotine chemistry, metabolism, kinetics and biomarkers. Handb. Exp. Pharmacol., 2009, 2009(192), 29-60.
[94]
Olsen, A.L.; Clemens, S.G.; Feany, M.B. Nicotine‐mediated rescue of α‐synuclein toxicity requires synaptic vesicle glycoprotein 2 in Drosophila. Mov. Disord., 2023, 38(2), 244-255.
[http://dx.doi.org/10.1002/mds.29283] [PMID: 36416213]
[95]
Bono, F.; Mutti, V.; Savoia, P.; Barbon, A.; Bellucci, A.; Missale, C.; Fiorentini, C. Nicotine prevents alpha-synuclein accumulation in mouse and human iPSC-derived dopaminergic neurons through activation of the dopamine D3- acetylcholine nicotinic receptor heteromer. Neurobiol. Dis., 2019, 129, 1-12.
[http://dx.doi.org/10.1016/j.nbd.2019.04.017] [PMID: 31051233]
[96]
Subramaniam, S.R.; Magen, I.; Bove, N.; Zhu, C.; Lemesre, V.; Dutta, G.; Elias, C.J.; Lester, H.A.; Chesselet, M.F. Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein. Neurobiol. Dis., 2018, 117, 170-180.
[http://dx.doi.org/10.1016/j.nbd.2018.05.018] [PMID: 29859873]
[97]
Kardani, J.; Sethi, R.; Roy, I. Nicotine slows down oligomerisation of α-synuclein and ameliorates cytotoxicity in a yeast model of Parkinson’s disease. Biochim. Biophys. Acta Mol. Basis Dis., 2017, 1863(6), 1454-1463.
[http://dx.doi.org/10.1016/j.bbadis.2017.02.002] [PMID: 28167231]
[98]
Lai, J.I.C.; Porcu, A.; Romoli, B.; Keisler, M.; Manfredsson, F.P.; Powell, S.B.; Dulcis, D. Nicotine-mediated recruitment of GABAergic neurons to a dopaminergic phenotype attenuates motor deficits in an alpha-synuclein Parkinson’s model. Int. J. Mol. Sci., 2023, 24(4), 4204.
[http://dx.doi.org/10.3390/ijms24044204] [PMID: 36835612]
[99]
Huang, C.Y.; Sivalingam, K.; Shibu, M.A.; Liao, P.H.; Ho, T.J.; Kuo, W.W.; Chen, R.J.; Day, C.H.; Viswanadha, V.P.; Ju, D.T. Induction of autophagy by vasicinone protects neural cells from mitochondrial dysfunction and attenuates paraquat-mediated Parkinson’s disease associated α-synuclein levels. Nutrients, 2020, 12(6), 1707.
[http://dx.doi.org/10.3390/nu12061707] [PMID: 32517337]
[100]
Jing, H.; Maodong, W.; Zhenjie, S.; Aimin, L. Protective effect of aloperine on dopamine neurons of Parkinson’s disease by activating autophagy. J. Biomater. Tissue Eng., 2020, 10(5), 602-608.
[http://dx.doi.org/10.1166/jbt.2020.2367]
[101]
Outeiro, T.F.; Koss, D.J.; Erskine, D.; Walker, L.; Akanbi, K.M.; Burn, D.; Donaghy, P.; Morris, C.; Taylor, J.P.; Thomas, A.; Attems, J.; McKeith, I. Dementia with Lewy bodies: An update and outlook. Mol. Neurodegener., 2019, 14(1), 5.
[http://dx.doi.org/10.1186/s13024-019-0306-8] [PMID: 30665447]
[102]
Alam, S.; Sarker, M.M.R.; Afrin, S.; Richi, F.T.; Zhao, C.; Zhou, J.R.; Mohamed, I.N. Traditional herbal medicines, bioactive metabolites, and plant products against COVID-19: Update on clinical trials and mechanism of actions. Front. Pharmacol., 2021, 12, 671498.
[http://dx.doi.org/10.3389/fphar.2021.671498] [PMID: 34122096]
[103]
Hussain, G.; Rasul, A.; Anwar, H.; Aziz, N.; Razzaq, A.; Wei, W.; Ali, M.; Li, J.; Li, X. Role of plant derived alkaloids and their mechanism in neurodegenerative disorders. Int. J. Biol. Sci., 2018, 14(3), 341-357.
[http://dx.doi.org/10.7150/ijbs.23247] [PMID: 29559851]
[104]
Bali, Z.K.; Bruszt, N.; Kőszegi, Z.; Nagy, L.V.; Atlasz, T.; Kovács, P. Aconitum alkaloid songorine exerts potent gamma-aminobutyric acid-A receptor agonist action in vivo and effectively decreases anxiety without adverse sedative or psychomotor effects in the rat. Pharmaceutics, 2022, 14(10), 2067.
[http://dx.doi.org/10.3390/pharmaceutics14102067]
[105]
Aryal, B.; Raut, B.K.; Bhattarai, S.; Bhandari, S.; Tandan, P.; Gyawali, K.; Sharma, K.; Ranabhat, D.; Thapa, R.; Aryal, D.; Ojha, A.; Devkota, H.P.; Parajuli, N. Potential therapeutic applications of plant-derived alkaloids against inflammatory and neurodegenerative diseases. Evid. Based Complement. Alternat. Med., 2022, 2022, 1-18.
[http://dx.doi.org/10.1155/2022/7299778] [PMID: 35310033]
[106]
Khaafi, M.; Najaran, T.Z.; Javadi, B. Cinnamaldehyde as a promising dietary phytochemical against metabolic syndrome: A systematic review. Mini Rev. Med. Chem., 2024, 24(3), 355-369.
[http://dx.doi.org/10.2174/1389557523666230725113446] [PMID: 37489782]
[107]
Li, S.; Cheng, X.; Wang, C. A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum. J. Ethnopharmacol., 2017, 203, 127-162.
[http://dx.doi.org/10.1016/j.jep.2017.03.049] [PMID: 28359849]
[108]
Mahmoudian, M.; Salehian, P.; Jalilpour, H. Toxicity of peganum harmala: Review and a case report. Iran J. Pharmacol. Therap, 2002, 1, 1-4.
[109]
Ziegenhagen, R.; Heimberg, K.; Lampen, A.; Ernst, H.K.I. Safety aspects of the use of isolated piperine ingested as a bolus. Foods, 2021, 10(9), 2121.
[http://dx.doi.org/10.3390/foods10092121] [PMID: 34574230]
[110]
Ashrafi, S.; Alam, S.; Sultana, A.; Raj, A.; Emon, N.U.; Richi, F.T.; Sharmin, T.; Moon, M.; Park, M.N.; Kim, B. Papaverine: A miraculous alkaloid from opium and its multimedicinal application. Molecules, 2023, 28(7), 3149.
[http://dx.doi.org/10.3390/molecules28073149] [PMID: 37049912]
[111]
Kesarwani, K.; Gupta, R.; Mukerjee, A. Bioavailability enhancers of herbal origin: An overview. Asian Pac. J. Trop. Biomed., 2013, 3(4), 253-266.
[http://dx.doi.org/10.1016/S2221-1691(13)60060-X] [PMID: 23620848]
[112]
Khaafi, F.; Javadi, B. Molecular targets underlying the neuroprotective effects of boswellic acid: A systematic review. Mini Rev. Med. Chem., 2023, 23(19), 1912-1925.
[http://dx.doi.org/10.2174/1389557523666230330113611] [PMID: 36998129]
[113]
Mu, L.H.; Wang, B.; Ren, H.Y.; Liu, P.; Guo, D.H.; Wang, F.M.; Bai, L.; Guo, Y.S. Synthesis and inhibitory effect of piperine derivates on monoamine oxidase. Bioorg. Med. Chem. Lett., 2012, 22(9), 3343-3348.
[http://dx.doi.org/10.1016/j.bmcl.2012.02.090] [PMID: 22475561]
[114]
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.
[http://dx.doi.org/10.1016/j.jep.2004.01.013] [PMID: 15120460]
[115]
Huang, C.Y.; Sivalingam, K.; Shibu, M.A.; Liao, P.H.; Ho, T.J.; Kuo, W.W. Induction of autophagy by vasicinone protects neural cells from mitochondrial dysfunction and attenuates paraquat-mediated parkinson’s disease associated α-synuclein levels. Nutrients, 2020, 12(6), 1707.
[http://dx.doi.org/10.3390/nu12061707]