Taxifolin: From Racemic Ambiguity to Stereospecific Pharmacological Precision: A Systematic Review of Isomeric Efficacy
DOI:
https://doi.org/10.55544/jrasb.5.4.3Keywords:
Taxifolin, Neuroprotection, Stereochemistry, Traumatic Brain Injury, Oxidative Stress, Neuroinflammation, NanomedicineAbstract
Taxifolin (dihydroquercetin), a naturally occurring flavanonol, has attracted increasing scientific interest because of its broad neuroprotective, antioxidant, and anti-inflammatory properties. Despite extensive experimental evidence supporting its therapeutic potential, the pharmacological translation of taxifolin remains limited by poor bioavailability, rapid metabolism, and the widespread use of undefined racemic mixtures in research. The saturated C2–C3 bond in Taxifolin creates multiple stereoisomers, yet most published studies fail to evaluate stereospecific pharmacodynamic and pharmacokinetic differences, leading to inconsistent biological outcomes. This systematic review summarizes current evidence regarding the stereochemical, pharmacological, and translational aspects of Taxifolin in neurodegenerative disorders and traumatic brain injury (TBI). Experimental findings from in vitro and in vivo studies demonstrate that Taxifolin exerts neuroprotective effects through modulation of oxidative stress, neuroinflammation, mitochondrial dysfunction, and apoptotic signaling. The compound activates antioxidant pathways, including Nrf2/HO-1 and PI3K/Akt, while suppressing inflammatory mediators such as NF-κB, JAK/STAT3, MAPKs, and the NLRP3 inflammasome. Taxifolin also reduces amyloid-β aggregation, preserves synaptic integrity, and improves cognitive performance in experimental models. Pharmacokinetic investigations indicate stereoselective differences between isomers, with the (2R,3R)-isomer showing superior tissue retention and therapeutic activity compared to other stereoisomeric forms. Recent advances in nanomedicine-based delivery systems, including nanoparticles and phospholipid complexes, have demonstrated improved brain targeting and enhanced bioavailability. This review highlights the importance of stereochemical precision, targeted drug delivery, and mechanistic multi-pathway modulation in advancing Taxifolin from a nutraceutical compound toward a clinically relevant neuroprotective therapy.
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[1] Sunil C, Xu B. An insight into the health-promoting effects of taxifolin (dihydroquercetin). Phytochemistry. 2019;166:112066.
[2] Weidmann AE. Dihydroquercetin: More than just an impurity? Eur J Pharmacol. 2012;684(1–3):19–26.
[3] Topal F, Nar M, Gocer H, et al. Antioxidant activity of taxifolin: an activity–structure relationship. J Enzyme Inhib Med Chem. 2016;31(4):674–683.
[4] Liu Y, Shi X, Tian Y, et al. An insight into novel therapeutic potentials of taxifolin. Front Pharmacol. 2023;14.
[5] Wang Y-H, Wang W-Y, Chang C-C, et al. Taxifolin ameliorates cerebral ischemia-reperfusion injury in rats through its anti-oxidative effect and modulation of NF-kappa B activation. J Biomed Sci. 2006;13(1):127–141.
[6] Turck D, Bresson J, Burlingame B, et al. Scientific Opinion on taxifolin‐rich extract from Dahurian Larch (Larix gmelinii). EFSA J. 2017;15(2).
[7] Administration UF and D. GRAS Notice No. GRN 000916: Dihydroquercetin (Taxifolin). Silver Spring, MD; 2020.
[8] Qian H-L, Xu S-T, Yan X-P. Recent Advances in Separation and Analysis of Chiral Compounds. Anal Chem. 2023;95(1):304–318.
[9] Baranowska I, Hejniak J, Magiera S. LC-ESI-MS/MS method for the enantioseparation of six flavanones. Anal Methods. 2017;9(6):1018–1030.
[10] Vega‐Villa KR, Remsberg CM, Takemoto JK, et al. Stereospecific pharmacokinetics of racemic homoeriodictyol, isosakuranetin, and taxifolin in rats and their disposition in fruit. Chirality. 2011;23(4):339–348.
[11] Terekhov RP, Melnikov ES, Nikitin ID, et al. Diastereomers of Spheroidal Form and Commercially Available Taxifolin Samples. Sci Pharm. 2024;92(1):5.
[12] Terekhov RP, Savina AD, Pankov DI, et al. Insights into the stereoisomerism of dihydroquercetin: analytical and pharmacological aspects. Front Chem. 2024;12.
[13] Pinto C, Cidade H, Pinto M, et al. Chiral Flavonoids as Antitumor Agents. Pharmaceuticals. 2021;14(12):1267.
[14] Chuong P-H, Nguyen LA, He H. Chiral Drugs. An Overview. Int J Biomed Sci. 2006;2(2):85–100.
[15] Li Y, Su H, Yin Z-P, et al. Metabolism, tissue distribution and excretion of taxifolin in rat. Biomed Pharmacother. 2022;150:112959.
[16] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;n71.
[17] Bramer WM, Rethlefsen ML, Kleijnen J, et al. Optimal database combinations for literature searches in systematic reviews: a prospective exploratory study. Syst Rev. 2017;6(1):245.
[18] Greenhalgh T, Peacock R. Effectiveness and efficiency of search methods in systematic reviews of complex evidence: audit of primary sources. BMJ. 2005;331(7524):1064–1065.
[19] Santos CM da C, Pimenta CA de M, Nobre MRC. The PICO strategy for the research question construction and evidence search. Rev Lat Am Enfermagem. 2007;15(3):508–511.
[20] Ouzzani M, Hammady H, Fedorowicz Z, et al. Rayyan—a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210.
[21] Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions. Higgins JPT, Thomas J, Chandler J, et al., editors. Chichester, uk: Wiley; 2019.
[22] Hooijmans CR, Rovers MM, de Vries RB, et al. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14(1):43.
[23] Schneider K, Schwarz M, Burkholder I, et al. “ToxRTool”, a new tool to assess the reliability of toxicological data. Toxicol Lett. 2009;189(2):138–144.
[24] Yang C-J, Wang Z-B, Mi Y-Y, et al. UHPLC-MS/MS Determination, Pharmacokinetic, and Bioavailability Study of Taxifolin in Rat Plasma after Oral Administration of its Nanodispersion. Molecules. 2016;21(4):494.
[25] Zhang Y, Yu J, Dong X-D, et al. Research on Characteristics, Antioxidant and Antitumor Activities of Dihydroquercetin and Its Complexes. Molecules. 2017;23(1):20.
[26] Li Y, Su H, Wang W, et al. Fabrication of taxifolin loaded zein-caseinate nanoparticles and its bioavailability in rat. Food Sci Hum Wellness. 2023;12(6):2306–2313.
[27] Vega‐Villa KR, Remsberg CM, Ohgami Y, et al. Stereospecific high‐performance liquid chromatography of taxifolin, applications in pharmacokinetics, and determination in tu fu ling ( Rhizoma smilacis glabrae ) and apple ( Malus × domestica ). Biomed Chromatogr. 2009;23(6):638–646.
[28] Pozharitskaya ON, Karlina M V., Shikov AN, et al. Determination and pharmacokinetic study of taxifolin in rabbit plasma by high-performance liquid chromatography. Phytomedicine. 2009;16(2–3):244–251.
[29] Jasenovec T, Radosinska D, Kollarova M, et al. Effects of Taxifolin in Spontaneously Hypertensive Rats with a Focus on Erythrocyte Quality. Life. 2022;12(12):2045.
[30] Yang P, Xu F, Li H-F, et al. Detection of 191 Taxifolin Metabolites and Their Distribution in Rats Using HPLC-ESI-IT-TOF-MSn. Molecules. 2016;21(9):1209.
[31] Turovskaya MV, Gaidin SG, Mal’tseva VN, et al. Taxifolin protects neurons against ischemic injury in vitro via the activation of antioxidant systems and signal transduction pathways of GABAergic neurons. Mol Cell Neurosci. 2019;96:10–24.
[32] Petrillo S, D’Amico J, Nicita F, et al. Antioxidant Response in Human X-Linked Adrenoleukodystrophy Fibroblasts. Antioxidants. 2022;11(11):2125.
[33] Yang R, Yang X, Zhang F. New Perspectives of Taxifolin in Neurodegenerative Diseases. Curr Neuropharmacol. 2023;21(10):2097–2109.
[34] Wang Y, Wang Q, Bao X, et al. Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A2/prostaglandin E2 content. Metab Brain Dis. 2018;33(4):1069–1079.
[35] Saito S, Yamamoto Y, Maki T, et al. Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy. Acta Neuropathol Commun. 2017;5(1):26.
[36] Inoue T, Saito S, Tanaka M, et al. Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy. Proc Natl Acad Sci. 2019;116(20):10031–10038.
[37] Gunesch S, Hoffmann M, Kiermeier C, et al. 7-O-Esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo. Redox Biol. 2020;29:101378.
[38] Liu X-L, Zu S, Yue H, et al. Taxifolin ameliorates the D-galactose-induced aging of mouse hippocampal neurons HT-22 cells through modulating SIRT1/p53 and PI3K/AKT signaling pathways. J Asian Nat Prod Res. 2025;27(4):615–631.
[39] Obeidat HM, Abukhalil MH, Althunibat OY, et al. Taxifolin attenuates gentamicin-induced hepatotoxicity via modulation of oxidative stress, inflammation, and apoptosis in mice: potential involvement of Nrf2/HO-1 signaling. Egypt J Basic Appl Sci. 2025;12(1):151–166.
[40] Xia M, Liu D, Tang X, et al. Dihydroartemisinin inhibits the proliferation of IgAN mesangial cells through the mTOR signaling pathway. Int Immunopharmacol. 2020;80:106125.
[41] Shen M, Lin B, Qian F, et al. Taxifolin ameliorates sepsis-induced lung capillary leak through inhibiting the JAK/STAT3 pathway. Allergol Immunopathol (Madr). 2022;50(2):7–15.
[42] Hou J, Hu M, Zhang L, et al. Dietary Taxifolin Protects Against Dextran Sulfate Sodium-Induced Colitis via NF-κB Signaling, Enhancing Intestinal Barrier and Modulating Gut Microbiota. Front Immunol. 2021;11.
[43] Chilosi M, Doglioni C, Ravaglia C, et al. Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia. Biomedicines. 2022;10(6):1332.
[44] Zhang X, Lian X, Li H, et al. Taxifolin attenuates inflammation via suppressing MAPK signal pathway in vitro and in silico analysis. Chinese Herb Med. 2022;14(4):554–562.
[45] Das A, Baidya R, Chakraborty T, et al. Pharmacological basis and new insights of taxifolin: A comprehensive review. Biomed Pharmacother. 2021;142:112004.
[46] Alanezi AA, Almuqati AF, Alfwuaires MA, et al. Taxifolin Prevents Cisplatin Nephrotoxicity by Modulating Nrf2/HO-1 Pathway and Mitigating Oxidative Stress and Inflammation in Mice. Pharmaceuticals. 2022;15(11):1310.
[47] Schauss AG, Tselyico SS, Kuznetsova VA, et al. Toxicological and Genotoxicity Assessment of a Dihydroquercetin-Rich Dahurian Larch Tree ( Larix gmelinii Rupr) Extract (Lavitol). Int J Toxicol. 2015;34(2):162–181.
[48] Zhanataev AK, Kulakova A V., Nasonova V V., et al. In vivo study of dihydroquercetin genotoxicity. Bull Exp Biol Med. 2008;145(3):338–340.
[49] Serra H, Mendes T, Bronze MR, et al. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg Med Chem. 2008;16(7):4009–4018.
[50] Harwood M, Danielewska-Nikiel B, Borzelleca JF, et al. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 2007;45(11):2179–2205.
[51] H. Brooks W, C. Guida W, G. Daniel K. The Significance of Chirality in Drug Design and Development. Curr Top Med Chem. 2011;11(7):760–770.
[52] Hutt AG, O’Grady J. Drug chirality: a consideration of the significance of the stereochemistry of antimicrobial agents. J Antimicrob Chemother. 1996;37(1):7–32.
[53] McConathy J, Owens MJ. Stereochemistry in Drug Action. Prim Care Companion CNS Disord. 2003;5(2).
[54] Yáñez JA, Remsberg CM, Miranda ND, et al. Pharmacokinetics of selected chiral flavonoids: hesperetin, naringenin and eriodictyol in rats and their content in fruit juices. Biopharm Drug Dispos. 2008;29(2):63–82.
[55] Brand W, van der Wel PAI, Rein MJ, et al. Metabolism and Transport of the Citrus Flavonoid Hesperetin in Caco-2 Cell Monolayers. Drug Metab Dispos. 2008;36(9):1794–1802.
[56] Agranat I, Caner H, Caldwell J. Putting chirality to work: the strategy of chiral switches. Nat Rev Drug Discov. 2002;1(10):753–768.
[57] Abou Baker DH. An ethnopharmacological review on the therapeutical properties of flavonoids and their mechanisms of actions: A comprehensive review based on up to date knowledge. Toxicol Reports. 2022;9:445–469.
[58] Chen X, Yin OQP, Zuo Z, et al. Pharmacokinetics and Modeling of Quercetin and Metabolites. Pharm Res. 2005;22(6):892–901.
[59] Youdim KA, Qaiser MZ, Begley DJ, et al. Flavonoid permeability across an in situ model of the blood–brain barrier. Free Radic Biol Med. 2004;36(5):592–604.
[60] Vieira D, Gamarra L. Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier. Int J Nanomedicine. 2016;Volume 11:5381–5414.
[61] Saraiva C, Praça C, Ferreira R, et al. Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases. J Control Release. 2016;235:34–47.
[62] Teleanu DM, Chircov C, Grumezescu AM, et al. Blood-Brain Delivery Methods Using Nanotechnology. Pharmaceutics. 2018;10(4):269.
[63] Zhou Y, Peng Z, Seven ES, et al. Crossing the blood-brain barrier with nanoparticles. J Control Release. 2018;270:290–303.
[64] Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood–brain barrier by nanoparticles. J Control Release. 2012;161(2):264–273.
[65] Corps KN, Roth TL, McGavern DB. Inflammation and Neuroprotection in Traumatic Brain Injury. JAMA Neurol. 2015;72(3):355.
[66] Karve IP, Taylor JM, Crack PJ. The contribution of astrocytes and microglia to traumatic brain injury. Br J Pharmacol. 2016;173(4):692–702.
[67] Simon DW, McGeachy MJ, Bayır H, et al. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol. 2017;13(3):171–191.
[68] Hiebert JB, Shen Q, Thimmesch AR, et al. Traumatic Brain Injury and Mitochondrial Dysfunction. Am J Med Sci. 2015;350(2):132–138.
[69] Cheng G, Kong R, Zhang L, et al. Mitochondria in traumatic brain injury and mitochondrial‐targeted multipotential therapeutic strategies. Br J Pharmacol. 2012;167(4):699–719.
[70] Washington PM, Villapol S, Burns MP. Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy? Exp Neurol. 2016;275:381–388.
[71] Johnson VE, Stewart W, Smith DH. Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease? Nat Rev Neurosci. 2010;11(5):361–370.
[72] Gruenbaum SE, Zlotnik A, Gruenbaum BF, et al. Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury: A Systematic Review of the Clinical Literature. CNS Drugs. 2016;30(9):791–806.
[73] Reagan‐Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659–661.
[74] Mondello S, Schmid K, Berger RP, et al. The Challenge of Mild Traumatic Brain Injury: Role of Biochemical Markers in Diagnosis of Brain Damage. Med Res Rev. 2014;34(3):503–531.
[75] Cook AM, Michas M, Robbins B. Update on Neuroprotection after Traumatic Brain Injury. CNS Drugs. 2025;39(5):473–484.
[76] Stein DG. Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015;29(11):1259–1272.
[77] Mir M, Khan A, Khan A. Pharmacological investigation of taxifolin for its therapeutic potential in depression. Heliyon. 2024;10(9):e30467.
[78] Cornelius C, Crupi R, Calabrese V, et al. Traumatic Brain Injury: Oxidative Stress and Neuroprotection. Antioxid Redox Signal. 2013;19(8):836–853.
[79] Lambert JD, Sang S, Yang CS. Biotransformation of Green Tea Polyphenols and the Biological Activities of Those Metabolites. Mol Pharm. 2007;4(6):819–825.
[80] Senkuttuvan N, Komarasamy B, Krishnamoorthy R, et al. The significance of chirality in contemporary drug discovery-a mini review. RSC Adv. 2024;14(45):33429–33448.
[81] Smith SW. Chiral Toxicology: It’s the Same Thing…Only Different. Toxicol Sci. 2009;110(1):4–30.
[82] FDA’S policy statement for the development of new stereoisomeric drugs. Chirality. 1992;4(5):338–340.
[83] Agranat I, Caner H. Intellectual property and chirality of drugs. Drug Discov Today. 1999;4(7):313–321.
[84] Faria A, Mateus N, Calhau C. Flavonoid transport across blood-brain barrier: Implication for their direct neuroprotective actions. Nutr Aging. 2012;1(2):89–97.
[85] Agrawal M, Saraf S, Saraf S, et al. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J Control Release. 2018;281:139–177.
[86] Luo Q, Yang J, Yang M, et al. Utilization of nanotechnology to surmount the blood-brain barrier in disorders of the central nervous system. Mater Today Bio. 2025;31:101457.
[87] Atanasov AG, Zotchev SB, Dirsch VM, et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov. 2021;20(3):200–216.
[88] Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol. 2013;9(4):211–221.
[89] Ramos-Cejudo J, Wisniewski T, Marmar C, et al. Traumatic Brain Injury and Alzheimer’s Disease: The Cerebrovascular Link. EBioMedicine. 2018;28:21–30.
[90] Percie du Sert N, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. Boutron I, editor. PLOS Biol. 2020;18(7):e3000410.
[91] Singh J. The national centre for the replacement, refinement, and reduction of animals in research. J Pharmacol Pharmacother. 2012;3(1):87–89.
[92] Wilkinson MD, Dumontier M, Aalbersberg IjJ, et al. The FAIR Guiding Principles for scientific data management and stewardship. Sci Data. 2016;3(1):160018.
[93] Rethlefsen ML, Kirtley S, Waffenschmidt S, et al. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst Rev. 2021;10(1):39.
[94] Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1.
[95] Editors IC of MJ. Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals.
[96] Authorship and AI tools. 2024.
[97] Zielinski C, Winker MA, Aggarwal R, et al. Chatbots, generative AI, and scholarly manuscripts. Colomb Med. 2023;54(3):e1015868.
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