The Neuroprotective Effect of Flavonoids in Huntington’s Disease: a Systematic Review
DOI:
https://doi.org/10.36733/medicamento.v12i1.12361Keywords:
flavonoids, Huntington’s disease, neuroprotectionAbstract
Background: Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by progressive striatal and cortical neuronal loss, resulting in severe motor, cognitive, and psychiatric deficits for which no disease-modifying therapy currently exists. Flavonoids, abundant polyphenolic phytochemicals, are increasingly recognized for their potent neuroprotective properties, specifically acting as antioxidants, anti-inflammatory agents, and modulators of apoptosis and autophagy.
Objective: This systematic literature review was conducted to synthesize and critically evaluate contemporary preclinical evidence regarding the efficacy of flavonoids in animal models of HD.
Methods: A comprehensive search was executed across PubMed, ScienceDirect, and MEDLINE databases (2015–2025) using specific keyword combinations. Studies investigating flavonoid effects in HD animal models with full-text availability were included, whereas publications older than ten years and review studies were excluded. Methodological quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal tool. Twelve eligible animal studies were identified, demonstrating methodological quality ranging from good to very good.
Results: Consistent findings indicated that flavonoid administration significantly enhanced motor coordination and cognitive performance, attenuated oxidative stress and neuroinflammation, and preserved neuronal integrity. These protective outcomes were mediated through the modulation of multiple molecular pathways, encompassing antioxidant defense systems, inflammatory signaling cascades, and apoptosis-related mechanisms.
Conclusion: While current preclinical evidence is promising, underscoring the critical roles of flavonoids as multifaceted neuroprotective agents, further rigorously designed clinical trials are imperative to validate these findings and establish the therapeutic potential and clinical applicability of flavonoids for patients suffering from Huntington’s disease.
References
1. Caron NS, Dorsey ER, Hayden MR. Therapeutic approaches to huntington disease: From the bench to the clinic. Nat Rev Drug Discov. Nature Publishing Group. 2018;17(10):729-750. doi:10.1038/nrd.2018.133
2. Bayram-Weston Z, Jones L, Dunnett SB, Brooks SP. Comparison of mHTT antibodies in Huntington’s disease mouse models reveal specific binding profiles and steady-state ubiquitin levels with disease development. PLoS One. 2016;11(5). doi:10.1371/journal.pone.0155834
3. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting Huntingtin Expression in Patients with Huntington’s Disease. New England Journal of Medicine. 2019;380(24):2307-2316. doi:10.1056/NEJMoa1900907
4. Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. Journal of Clinical Investigation. 2015;125(5):1979-1986. doi:10.1172/JCI80743
5. Bhatia M, Phadte AS, Lakhina A, Monte Carlo AR, Barndt S, Pluciennik A. DNA extrusion size determines pathway choice during CAG repeat expansion. Preprint posted online May 15, 2025. doi:10.1101/2025.05.12.653571
6. Wang N, Gray M, Lu XH, et al. Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington’s disease. Nat Med. 2014;20(5):536-541. doi:10.1038/nm.3514
7. Li X, Tong H, Xu S, et al. Neuroinflammatory Proteins in Huntington’s Disease: Insights into Mechanisms, Diagnosis, and Therapeutic Implications. Int J Mol Sci. 2024;25(21):11787. doi:10.3390/ijms252111787
8. Uddin MdS, Hossain MdF, Mamun A Al, et al. Exploring the multimodal role of phytochemicals in the modulation of cellular signaling pathways to combat age-related neurodegeneration. Science of The Total Environment. 2020;725:138313. doi:10.1016/j.scitotenv.2020.138313
9. Barreca MM, Alessandro R, Corrado C. Effects of Flavonoids on Cancer, Cardiovascular and Neurodegenerative Diseases: Role of NF-κB Signaling Pathway. Int J Mol Sci. 2023;24(11):9236. doi:10.3390/ijms24119236
10. Bellavite P. Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action. Antioxidants. MDPI. 2023;12(2). doi:10.3390/antiox12020280
11. Utpal BK, Sutradhar B, Zehravi M, et al. Cellular stress response and neuroprotection of flavonoids in neurodegenerative diseases: Clinical insights into targeted therapy and molecular signaling pathways. Brain Res. 2025;1847:149310. doi:https://doi.org/10.1016/j.brainres.2024.149310
12. Rębas E. Role of Flavonoids in Protecting Against Neurodegenerative Diseases—Possible Mechanisms of Action. Int J Mol Sci. Multidisciplinary Digital Publishing Institute (MDPI). 2025;26(10). doi:10.3390/ijms26104763
13. Szulc A, Wiśniewska K, Żabińska M, et al. Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases. Foods. Multidisciplinary Digital Publishing Institute (MDPI). 2024;13(12). doi:10.3390/foods13121931
14. Barker TH, Habibi N, Aromataris E, et al. The revised JBI critical appraisal tool for the assessment of risk of bias for quasi-experimental studies. JBI Evid Synth. 2024;22(3):378-388. doi:10.11124/JBIES-23-00268
15. Pierzynowska K, Podlacha M, Gaffke L, et al. Correction of symptoms of Huntington disease by genistein through FOXO3-mediated autophagy stimulation. Autophagy. 2024;20(5):1159-1182. doi:10.1080/15548627.2023.2286116
16. Mohammed A, Ramadan A, Elnour AA, et al. Luteolin as potential treatment for Huntington’s disease: Insights from a transgenic mouse model. CNS Neurosci Ther. 2024;30(9). doi:10.1111/cns.70025
17. Etukuri NB, Avula PR. Hesperetin attenuates neuroprotective effect against 3-Nitropropionic acid induced Huntington’s disease-like behavioral symptoms in rats. Journal of Drug Delivery and Therapeutics. 2024;14(11):31-38. doi:10.22270/jddt.v14i11.6823
18. Mahdi WA, AlGhamdi SA, Alghamdi AM, et al. Neuroprotectant Effects of Hibiscetin in 3-Nitropropionic Acid-Induced Huntington’s Disease via Subsiding Oxidative Stress and Modulating Monoamine Neurotransmitters in Rats Brain. Molecules. 2023;28(3). doi:10.3390/molecules28031402
19. Salman M, Sharma P, Alam MI, Tabassum H, Parvez S. Naringenin mitigates behavioral alterations and provides neuroprotection against 3-nitropropinoic acid-induced Huntington’s disease like symptoms in rats. Nutr Neurosci. 2022;25(9):1898-1908. doi:10.1080/1028415X.2021.1913319
20. Purushothaman B, Sumathi T. 5,6,7 trihydroxy flavone armoured neurodegeneration caused by Quinolinic acid induced huntington’s like disease in rat striatum - reinstating the level of brain neurotrophins with special reference to cognitive-socio behaviour, biochemical and histopathological aspects. Neurosci Res. 2022;174:25-35. doi:10.1016/j.neures.2021.08.003
21. Moghaddam MH, Bayat AH, Eskandari N, et al. Elderberry diet ameliorates motor function and prevents oxidative stress-induced cell death in rat models of Huntington disease. Brain Res. 2021;1762. doi:10.1016/j.brainres.2021.147444
22. Barriga GGD, Giralt A, Anglada-Huguet M, et al. 7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington’s disease mouse model through specific activation of the PLCγ1 pathway. Hum Mol Genet. 2017;26(16):3144-3160. doi:10.1093/hmg/ddx198
23. Suganya SN, Sumathi T. Effect of rutin against a mitochondrial toxin, 3-nitropropionicacid induced biochemical, behavioral and histological alterations-a pilot study on Huntington’s disease model in rats. Metab Brain Dis. 2017;32(2):471-481. doi:10.1007/s11011-016-9929-4
24. Menze ET, Esmat A, Tadros MG, Khalifa AE, Abdel-Naim AB. Genistein improves sensorimotor gating: Mechanisms related to its neuroprotective effects on the striatum. Neuropharmacology. Elsevier Ltd. 2016;105:35-46. doi:10.1016/j.neuropharm.2016.01.007
25. Kreilaus F, Spiro AS, Hannan AJ, Garner B, Jenner AM. Therapeutic Effects of Anthocyanins and Environmental Enrichment in R6/1 Huntington’s Disease Mice. J Huntingtons Dis. 2016;5(3):285-296. doi:10.3233/JHD-160204
26. Møllersen L, Moldestad O, Rowe AD, et al. Effects of anthocyanins on CAG repeat instability and behaviour in huntington’s disease R6/1 mice. PLoS Curr. 2016;8(HuntingtonDisease). doi:10.1371/currents.hd.58d04209ab6d5de0844db7ef5628ff67
27. Jaiswal N, Akhtar J, Singh SP, Ahsan F. An Overview on Genistein and its Various Formulations. Drug Res. 2019;69(06):305-313. doi:10.1055/a-0797-3657
28. Yao C, Dai S, Wang C, et al. Luteolin as a potential hepatoprotective drug: Molecular mechanisms and treatment strategies. Biomedicine & Pharmacotherapy. 2023;167:115464. doi:10.1016/j.biopha.2023.115464
29. Evans JA, Mendonca P, Soliman KFA. Neuroprotective Effects and Therapeutic Potential of the Citrus Flavonoid Hesperetin in Neurodegenerative Diseases. Nutrients. 2022;14(11):2228. doi:10.3390/nu14112228
30. Ragi C, Muraleedharan K. Hydrogen bonding interactions between Hibiscetin and ethanol/water: DFT studies on structure and topologies. Chemical Physics Impact. 2024;8:100416. doi:10.1016/j.chphi.2023.100416
31. Liu X, Wang N, Fan S, et al. The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway. Sci Rep. 2016;6(1):39735. doi:10.1038/srep39735
32. Dacrema M, Ullah H, Uniyal P, et al. Baicalein as a potential bioactive flavonoid: a concise overview. PHYTONutrients. Published online July 9, 2024:23-35. doi:10.62368/pn.v3i.24
33. Qi W, Qi W, Xiong D, Long M. Quercetin: Its Antioxidant Mechanism, Antibacterial Properties and Potential Application in Prevention and Control of Toxipathy. Molecules. 2022;27(19):6545. doi:10.3390/molecules27196545
34. Mohankumar T, Chandramohan V, Lalithamba HS, et al. Design and Molecular dynamic Investigations of 7,8-Dihydroxyflavone Derivatives as Potential Neuroprotective Agents Against Alpha-synuclein. Sci Rep. 2020;10(1):599. doi:10.1038/s41598-020-57417-9
35. Dogrukol-Ak D, Kirimer N, Tunçel M, Aboul-Enein HY. Determination of Rutin in Hypericum Perforatum Extract by Capillary Electrophoresis. Anal Lett. 2001;34(2):185-191. doi:10.1081/AL-100001569
36. Qi Q, Chu M, Yu X, et al. Anthocyanins and Proanthocyanidins: Chemical Structures, Food Sources, Bioactivities, and Product Development. Food Reviews International. 2023;39(7):4581-4609. doi:10.1080/87559129.2022.2029479
37. Hussain G, Zhang L, Rasul A, et al. Role of Plant-Derived Flavonoids and Their Mechanism in Attenuation of Alzheimer’s and Parkinson’s Diseases: An Update of Recent Data. Molecules. 2018;23(4):814. doi:10.3390/molecules23040814
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Copyright (c) 2026 Sang Ayu Arta Suryantari, Anak Agung Intan Pramesti, I Made Suma Wirawan, I Gusti Ngurah Mambal Wirajangsa, I Wayan Yudha Wedantha, Ni Putu Elisya Nathania Fidela
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