Naringin and Naringenin: Potential Multi-Target Agents for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is one of the most common forms of neurodegenerative dementia. The etiology of AD is multifactorial, and its complex pathophysiology involves tau and amyloid-β deposition, increased oxidative stress, neuroinflammation, metabolic disorders, and massive neuronal loss. Due to its complex pathology, no effective cure for AD has been found to date. Therefore, there is an unmet clinical need for the development of new drugs against AD. Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents. Naringin, a naturally occurring flavanone glycoside, is predominantly found in citrus fruits and Chinese medicinal herbs. Mounting evidence shows that naringin and its aglycone, naringenin, have direct neuroprotective effects on AD, such as anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, and anti-neuroinflammatory effects, as well as metal chelation. Furthermore, they are known to improve disordered glucose/lipid metabolism, which is a high risk factor for AD. In this review, we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology. Additionally, we provide an overview of the current clinical applications of naringin and naringenin. The novel delivery systems for naringin and naringenin, which can address their widespread pharmacokinetic limitations, are also discussed. The literature indicates that naringin and naringenin could be multilevel, multitargeted, and multifaceted for preventing and treating AD.

References

[1] 2023 Alzheimer’s disease facts and figures. Alzheimers Dement, 2023,19(4):1598–1695

[2] Forrest SL, Kovacs GG. Current concepts of mixed pathologies in neurodegenerative diseases. Can J Neurol Sci, 2023, 50(3): 329-345.

[3] Wimo A, Guerchet M, Ali GC, et al. . The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement, 2017, 13(1): 1-7.

[4] Ma C, Hong F, Yang S. Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions. Molecules, 2022, 27(4): 1210.

[5] Gao Y, Tan L, Yu JT, et al. . Tau in Alzheimer’s Disease: Mechanisms and Therapeutic Strategies. Curr Alzheimer Res, 2018, 15(3): 283-300.

[6] Bai R, Guo J, Ye XY, et al. . Oxidative stress: The core pathogenesis and mechanism of Alzheimer’s disease. Aging Res Rev, 2022, 77: 101619.

[7] Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?. Nat Rev Neurol, 2021, 17(3): 157-172.

[8] Song Y, Liu J, Zhao K, et al. . Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases. Cell Metab, 2021, 33(10): 1911-1925.

[9] Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol, 2018, 14(10): 591-604.

[10] Picone P, Di Carlo M, Nuzzo D. Obesity and Alzheimer’s disease: Molecular bases. Eur J Neurosci, 2020, 52(8): 3944-3950.

[11] Vinciguerra F, Graziano M, Hagnäs M, et al. . Influence of the mediterranean and ketogenic diets on cognitive status and decline: a narrative review. Nutrients, 2020, 12(4): 1019.

[12] Glynn-Servedio BE, Ranola TS. AChE Inhibitors and NMDA Receptor Antagonists in Advanced Alzheimer’s Disease. Consult Pharm, 2017, 32(9): 511-518.

[13] Terao I, Kodama W. Comparative efficacy, tolerability and acceptability of donanemab, lecanemab, aducanumab and lithium on cognitive function in mild cognitive impairment and Alzheimer’s disease: A systematic review and network metaanalysis. Aging Res Rev, 2024, 94: 102203.

[14] Kumar MS, Khan S. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr Neuropharmacol, 2020, 18(11): 1106-1125.

[15] Patel D, Shukla S, Gupta S. Apigenin and cancer chemoprevention: progress, potential and promise. Int J Oncol, 2007, 30(1): 233-245

[16] Miccadei S, Di Venere D, Cardinali A, et al. . Antioxidative and apoptotic properties of polyphenolic extracts from edible part of artichoke (Cynara scolymus L.) on cultured rat hepatocytes and on human hepatoma cells. Nutr Cancer, 2008, 60(2): 276-283.

[17] Madunić J, Madunić IV, Gajski G, et al. . Apigenin: A dietary flavonoid with diverse anticancer properties. Cancer Lett, 2018, 413: 11-22.

[18] Abenavoli L, Izzo AA, Milić N, et al. . Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res, 2018, 32(11): 2202-2213.

[19] Azzini E, Maiani G, Garaguso I, et al. . The potential health benefits of polyphenol-rich extracts from Cichorium intybus L. studied on Caco-2 cells model. Oxid Med Cell Longev, 2016, 2016: 1594616.

[20] Calderaro A, Patanè GT, Tellone E, et al. . The Neuroprotective Potentiality of Flavonoids on Alzheimer’s Disease. Int J Mol Sci, 2022, 23(23): 14835.

[21] Yin L, Cheng W, Qin Z, et al. . Effects of naringin on proliferation and osteogenic differentiation of human periodontal ligament stem cells in vitro and in vivo. Stem Cells Int, 2015, 2015: 758760.

[22] Wong KC, Pang WY, Wang XL, et al. . Drynaria fortunei-derived total flavonoid fraction and isolated compounds exert oestrogen-like protective effects in bone. Br J Nutr, 2013, 110(3): 475-485.

[23] Lee S, Youn K, Lim G, et al. . In silico docking and in vitro approaches towards BACE1 and cholinesterases inhibitory effect of citrus flavanones. Molecules, 2018, 23(7): 1509.

[24] Garcez ML, Mina F, Bellettini-Santos T, et al. . The Involvement of NLRP3 on the Effects of Minocycline in an AD-Like Pathology Induced by β-Amyloid Oligomers Administered to Mice. Mol Neurobiol, 2018, 56(4): 2606-2617.

[25] Ahsan AU, Sharma VL, Wani A, et al. . Naringenin upregulates AMPK-mediated autophagy to rescue neuronal cells from β-amyloid (1–42) evoked neurotoxicity. Mol Neurobiol, 2020, 57(8): 3589-3602.

[26] Wang K, Chen Z, Huang L, et al. . Naringenin reduces oxidative stress and improves mitochondrial dysfunction via activation of the Nrf2/ARE signaling pathway in neurons. Int J Mol Med, 2017, 40(5): 1582-1590.

[27] Kumar A, Prakash A, Dogra S. Naringin alleviates cognitive impairment, mitochondrial dysfunction and oxidative stress induced by D-galactose in mice. Food Chem Toxicol, 2010, 48(2): 626-632.

[28] Sachdeva AK, Kuhad A, Chopra K. Naringin ameliorates memory deficits in experimental paradigm of Alzheimer’s disease by attenuating mitochondrial dysfunction. Pharmacol Biochem Behav, 2014, 127: 101-110.

[29] Zaidun NH, Thent ZC, Abd Latiff A. Combating oxidative stress disorders with citrus flavonoid: Naringenin. Life Sci, 2018, 208: 111-122.

[30] Heo HJ, Kim M-J, Lee J-M, et al. . Naringenin from Citrus junos has an inhibitory effect on acetylcholinesterase and a mitigating effect on amnesia. Dement Geriatr Cogn Disord, 2004, 17(3): 151-157.

[31] Umukoro S, Kalejaye HA, Ben-Azu B, et al. . Naringenin attenuates behavioral derangements induced by social defeat stress in mice via inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines. Biomed Pharmacother, 2018, 105: 714-723.

[32] Haider S, Liaquat L, Ahmad S, et al. . Naringenin protects AlCl3/D-galactose induced neurotoxicity in rat model of AD via attenuation of acetylcholinesterase levels and inhibition of oxidative stress. PLoS One, 2020, 15(1): e0227631.

[33] Wu LH, Lin C, Lin HY, et al. . Naringenin suppresses neuroinflammatory responses through inducing suppressor of cytokine signaling 3 expression. Mol Neurobiol, 2016, 53(2): 1080-1091.

[34] Khajevand-Khazaei MR, Ziaee P, Motevalizadeh SA, et al. . Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat. Eur J Pharmacol, 2018, 826: 114-122.

[35] Chen C, Wei YZ, He XM, et al. . Naringenin produces neuroprotection against LPS-induced dopamine neurotoxicity via the inhibition of microglial NLRP3 inflammasome activation. Front Immunol, 2019, 10: 936.

[36] Yang Z, Kuboyama T, Tohda C. Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression. Phytother Res, 2019, 33(4): 1114-1121.

[37] Jahanshahi M, Khalili M, Margedari A. Naringin chelates excessive iron and prevents the formation of amyloid-beta plaques in the hippocampus of iron-overloaded mice. Front Pharmacol, 2021, 12: 651156.

[38] Guo LX, Sun B. N, N′-1, 10-Bis (Naringin) Triethylenetetraamine, Synthesis and as a Cu (II) Chelator for Alzheimer’s Disease Therapy. Biol Pharm Bull, 2021, 44(1): 51-56.

[39] Jagetia GC, Reddy TK, Venkatesha V, et al. . Influence of naringin on ferric iron induced oxidative damage in vitro. Clin Chim Acta, 2004, 347(1–2): 189-197.

[40] Yang Y, Trevethan M, Wang S, et al. . Beneficial effects of citrus flavanones naringin and naringenin and their food sources on lipid metabolism: An update on bioavailability, pharmacokinetics, and mechanisms. J Nutr Biochem, 2022, 104: 108967.

[41] Nyane NA, Tlaila TB, Malefane TG, et al. . Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: Molecular and pharmacological insights. Eur J Pharmacol, 2017, 803: 103-111.

[42] Stevens Y, Rymenant EV, Grootaert C, et al. . The Intestinal Fate of Citrus Flavanones and Their Effects on Gastrointestinal Health. Nutrients, 2019, 11(7): 1464.

[43] Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci, 2016, 5: e47.

[44] Kay CD. The future of flavonoid research. Br J Nutr, 2010, 104(S3): S91-S95.

[45] Kasote DM, Katyare SS, Hegde MV, et al. . Significance of antioxidant potential of plants and its relevance to therapeutic applications. Int J Biol Sci, 2015, 11(8): 982-991.

[46] Manchope MF, Casagrande R, Verri WA Jr. Naringenin: an analgesic and anti-inflammatory citrus flavanone. Oncotarget, 2017, 8(3): 3766-3767.

[47] Memariani Z, Abbas SQ, Ul Hassan SS, et al. . Naringin and naringenin as anticancer agents and adjuvants in cancer combination therapy: Efficacy and molecular mechanisms of action, a comprehensive narrative review. Pharmacol Res, 2021, 171: 105264.

[48] Barreca D, Gattuso G, Bellocco E, et al. . Flavanones: Citrus phytochemical with health-promoting properties. Biofactors, 2017, 43(4): 495-506.

[49] Di Majo D, Giammanco M, La Guardia M, et al. . Flavanones in Citrus fruit: Structure-antioxidant activity relationships. Food Res Int, 2005, 38(10): 1161-1166.

[50] Hsiu SL, Huang TY, Hou YC, et al. . Comparison of metabolic pharmacokinetics of naringin and naringenin in rabbits. Life Sci, 2002, 70(13): 1481-1489.

[51] Liu M, Zou W, Yang C, et al. . Metabolism and excretion studies of oral administered naringin, a putative antitussive, in rats and dogs. Biopharm Drug Dispos, 2012, 33(3): 123-134.

[52] Orrego-Lagarón N, Martínez-Huélamo M, Vallverdú-Queralt A, et al. . High gastrointestinal permeability and local metabolism of naringenin: influence of antibiotic treatment on absorption and metabolism. Br J Nutr, 2015, 114(2): 169-180.

[53] Zeng X, Bai Y, Peng W, et al. . Identification of naringin metabolites in human urine and feces. Eur J Drug Metab Pharmacokinet, 2017, 42: 647-656.

[54] Li SQ, Dong S, Su ZH, et al. . Comparative pharmacokinetics of naringin in rat after oral administration of chaihu-shugan-san aqueous extract and naringin alone. Metabolites, 2013, 3(4): 867-880.

[55] Zeng X, Yao H, Zheng Y, et al. . Tissue distribution of naringin and derived metabolites in rats after a single oral administration. J Chromatogr B Analyt Technol Biomed Life Sci, 2020, 1136: 121846.

[56] Manach C, Williamson G, Morand C, et al. . Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr, 2005, 81(1): 230S-242S.

[57] Zou W, Luo Y, Liu M, et al. . Human intestinal microbial metabolism of naringin. Eur J Drug Metab Pharmacokinet, 2015, 40: 363-367.

[58] Joshi R, Kulkarni YA, Wairkar S. Pharmacokinetic, pharmacodynamic and formulations aspects of Naringenin: An update. Life Sci, 2018, 215: 43-56.

[59] Rebello CJ, Beyl RA, Lertora JJ, et al. . Safety and pharmacokinetics of naringenin: A randomized, controlled, single-ascending-dose clinical trial. Diabetes Obes Metab, 2020, 22(1): 91-98.

[60] Zeng X, Su W, Zheng Y, et al. . Pharmacokinetics, tissue distribution, metabolism, and excretion of naringin in aged rats. Front Pharmacol, 2019, 10: 34.

[61] Zou W, Yang C, Liu M, et al. . Tissue distribution study of naringin in rats by liquid chromatography-tandem mass spectrometry. Arzneimittelforschung, 2012, 62(4): 181-186.

[62] Khan MB, Khan MM, Khan A, et al. . Naringenin ameliorates Alzheimer’s disease (AD)-type neurodegeneration with cognitive impairment (AD-TNDCI) caused by the intracerebroventricular-streptozotocin in rat model. Neurochem Int, 2012, 61(7): 1081-1093.

[63] Kay CD, Pereira-Caro G, Ludwig IA, et al. . Anthocyanins and flavanones are more bioavailable than previously perceived: A review of recent evidence. Annu Rev Food Sci Technol, 2017, 8: 155-180.

[64] Zhang J, Brodbelt JS. Screening flavonoid metabolites of naringin and narirutin in urine after human consumption of grapefruit juice by LC-MS and LC-MS/MS. Analyst, 2004, 129(12): 1227-1233.

[65] Pereira-Caro G, Ludwig IA, Polyviou T, et al. . Identification of plasma and urinary metabolites and catabolites derived from orange juice (poly) phenols: analysis by high-performance liquid chromatography-high-resolution mass spectrometry. J Agric Food Chem, 2016, 64(28): 5724-5735.

[66] Additives EPo Feed PoSuiA. Scientific Opinion on the safety and efficacy of naringin when used as a sensory additive for all animal species. EFSA J, 2011, 9(11): 2416

[67] Bacanli M, Başaran AA, Başaran N. The major flavonoid of grapefruit: naringin. Polyphenols: prevention and treatment of human disease, 2018 37-44.

[68] Li P, Wang S, Guan X, et al. . Acute and 13 weeks subchronic toxicological evaluation of naringin in Sprague-Dawley rats. Food Chem Toxicol, 2013, 60: 1-9.

[69] Li D, Lu L, Zhang J, et al. . Mitigating the effects of Xuebijing injection on hematopoietic cell injury induced by total body irradiation with γ rays by decreasing reactive oxygen species levels. Int J Mol Sci, 2014, 15(6): 10541-10553.

[70] Fuhr U, Kummert AL. The fate of naringin in humans: a key to grapefruit juice-drug interactions?. Clin Pharmacol Ther, 1995, 58(4): 365-373.

[71] Tiwari MK, Kepp KP. β-Amyloid pathogenesis: Chemical properties versus cellular levels. Alzheimers Dement, 2016, 12(2): 184-194.

[72] Hardy J, Higgins G. Disease: Alzheimer’s cascade hypothesis amyloid. Science, 1992, 256: 184-185.

[73] Hardy J, Selkoe DJ. The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics. Science, 2002, 297(5580): 353-356.

[74] Zhou T, Liu L, Wang Q, et al. . Naringenin alleviates cognition deficits in high-fat diet-fed SAMP8 mice. J Food Biochem, 2020, 44(9): e13375.

[75] Meng X, Fu M, Wang S, et al. . Naringin ameliorates memory deficits and exerts neuroprotective effects in a mouse model of Alzheimer’s disease by regulating multiple metabolic pathways. Mol Med Rep, 2021, 23(5): 332.

[76] Adewole KE, Ishola AA. BACE1 and cholinesterase inhibitory activities of compounds from Cajanus cajan and Citrus reticulata: an in silico study. LIn Silico Pharmacol, 2021, 9(1): 14.

[77] Zhang N, Hu Z, Zhang Z, et al. . Protective Role Of Naringenin Against Aβ(25–35)-Caused Damage via ER and PI3K/Akt-Mediated Pathways. Cell Mol Neurobiol, 2018, 38(2): 549-557.

[78] Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell, 2017, 66(6): 789-800.

[79] Ghofrani S, Joghataei MT, Mohseni S, et al. . Naringenin improves learning and memory in an Alzheimer’s disease rat model: Insights into the underlying mechanisms. Eur J Pharmacol, 2015, 764: 195-201.

[80] Choi GY, Kim HB, Hwang ES, et al. . Naringin enhances long-term potentiation and recovers learning and memory deficits of amyloid-beta induced Alzheimer’s disease-like behavioral rat model. Neurotoxicology, 2023, 95: 35-45.

[81] Onyango IG. Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer’s disease. Neural Regen Res, 2018, 13(1): 19-25.

[82] Varshney V, Garabadu D. Naringin Exhibits Mas Receptor–Mediated Neuroprotection Against Amyloid Beta–Induced Cognitive Deficits and Mitochondrial Toxicity in Rat Brain. Neurotox Res, 2021, 39(4): 1023-1043.

[83] Wang DM, Yang YJ, Zhang L, et al. . Naringin Enhances CaMKII Activity and Improves Long-Term Memory in a Mouse Model of Alzheimer’s Disease. Int J Mol Sci, 2013, 14(3): 5576-86.

[84] Lei P, Ayton S, Bush AI. The essential elements of Alzheimer’s disease. J Biol Chem, 2021, 296: 100105.

[85] Chen LL, Fan YG, Zhao LX, et al. . The metal ion hypothesis of Alzheimer’s disease and the anti-neuroinflammatory effect of metal chelators. Bioorg Chem, 2023, 131: 106301.

[86] Ban XX, Wan H, Wan XX, et al. . Copper Metabolism and Cuproptosis: Molecular Mechanisms and Therapeutic Perspectives in Neurodegenerative Diseases. Curr Med Sci, 2024, 44(1): 28-50.

[87] Eleutherio ECA, Silva Magalhães RS, de Araújo Brasil A, et al. . SOD1, more than just an antioxidant. Arch Biochem Biophys, 2021, 697: 108701.

[88] Rios M, Habecker B, Sasaoka T, et al. . Catecholamine synthesis is mediated by tyrosinase in the absence of tyrosine hydroxylase. J Neurosci, 1999, 19(9): 3519-3526.

[89] Squitti R. Copper dysfunction in Alzheimer’s disease: from meta-analysis of biochemical studies to new insight into genetics. J Trace Elem Med Biol, 2012, 26(2–3): 93-96.

[90] Rembach A, Hare DJ, Lind M, et al. . Decreased copper in Alzheimer’s disease brain is predominantly in the soluble extractable fraction. Int J Alzheimers Dis, 2013, 2013: 623241.

[91] Bayer TA, Schafer S, Simons A, et al. . Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci U S A, 2003, 100(24): 14187-14192.

[92] Matheou CJ, Younan ND, Viles JH. Cu2+ accentuates distinct misfolding of Aβ (1–40) and Aβ (1–42) peptides, and potentiates membrane disruption. Biochem J, 2015, 466(2): 233-242.

[93] Guilloreau L, Combalbert S, Sournia-Saquet A, et al. . Redox chemistry of copper-amyloid-β: The generation of hydroxyl radical in the presence of ascorbate is linked to redox-potentials and aggregation state. Chembiochem, 2007, 8(11): 1317-1325.

[94] Multhaup G, Schlicksupp A, Hesse L, et al. . The amyloid precursor protein of Alzheimer’s disease in the reduction of copper (II) to copper (I). Science, 1996, 271(5254): 1406-1409.

[95] Fernandez MT, Mira ML, Florêncio MH, et al. . Iron and copper chelation by flavonoids: an electrospray mass spectrometry study. J Inorg Biochem, 2002, 92(2): 105-111.

[96] Celiz G, Suarez SA, Arias A, et al. . Synthesis, structural elucidation and antiradical activity of a copper (II) naringenin complex. Biometals, 2019, 32(4): 595-610.

[97] Tarkowski E, Andreasen N, Tarkowski A, et al. . Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry, 2003, 74(9): 1200-1205.

[98] Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest, 2012, 122(4): 1164-1171.

[99] Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol, 2016, 173(4): 649-665.

[100] Cao J, Hou J, Ping J, et al. . Advances in developing novel therapeutic strategies for Alzheimer’s disease. Mol Neurodegener, 2018, 13(1): 1-20.

[101] Subhramanyam CS, Wang C, Hu Q, et al. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol: Elsevier, 2019,112–120.

[102] Xu Y, Gao W, Sun Y, et al. . New insight on microglia activation in neurodegenerative diseases and therapeutics. Front Neurosci, 2023, 17: 1308345.

[103] Cai Z, Hussain MD, Yan LJ. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci, 2014, 124(5): 307-321.

[104] Vepsäläinen S, Helisalmi S, Mannermaa A, et al. . Combined risk effects of IDE and NEP gene variants on Alzheimer disease. J Neurol Neurosurg Psychiatry, 2009, 80(11): 1268-1270.

[105] Park HY, Kim GY, Choi YH. Naringenin attenuates the release of pro-inflammatory mediators from lipopolysaccharide-stimulated BV2 microglia by inactivating nuclear factor-κB and inhibiting mitogen-activated protein kinases. Int J Mol Med, 2012, 30(1): 204-210

[106] Zhang B, Wei YZ, Wang GQ, et al. . Targeting MAPK pathways by naringenin modulates microglia M1/M2 polarization in lipopolysaccharide-stimulated cultures. Front Cell Neurosci, 2019, 12: 531.

[107] Bai J, Li S, Wu G, et al. . Naringin inhibits lipopolysaccharide-induced activation of microglia cells. Cell Mol Biol (Noisy-le-grand), 2019, 65(5): 38-42.

[108] Qin H, Roberts KL, Niyongere SA, et al. . Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. J Immunol, 2007, 179(9): 5966-5976.

[109] Ahmed NY, Knowles R, Dehorter N. New Insights Into Cholinergic Neuron Diversity. Front Mol Neurosci, 2019, 12: 204.

[110] Darvesh S, Hopkins DA, Geula C. Neurobiology of butyrylcholinesterase. Nat Rev Neurosci, 2003, 4(2): 131-138.

[111] Hampel H, Mesulam MM, Cuello AC, et al. . The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 2018, 141(7): 1917-1933.

[112] Goyal A, Verma A, Dubey N, et al. . Naringenin: A prospective therapeutic agent for Alzheimer’s and Parkinson’s disease. J Food Biochem, 2022, 46(12): e14415.

[113] Al-Rajhi AMH, Qanash H, Almashjary MN, et al. . Anti-Helicobacter pylori, Antioxidant, Antidiabetic, and Anti-Alzheimer’s Activities of Laurel Leaf Extract Treated by Moist Heat and Molecular Docking of Its Flavonoid Constituent, Naringenin, against Acetylcholinesterase and Butyrylcholinesterase. Life (Basel), 2023, 13(7): 1512

[114] Remya C, Dileep KV, Tintu I, et al. . Flavanone glycosides as acetylcholinesterase inhibitors: computational and experimental evidence. Indian J Pharm Sci, 2014, 76(6): 567-570.

[115] Zaki HF, Abd-El-Fattah MA, Attia AS. Naringenin protects against scopolamine-induced dementia in rats. Bulletin of Faculty of Pharmacy, Cairo University, 2014, 52(1): 15-25.

[116] Mahdavinia M, Ahangarpour A, Zeidooni L, et al. . Protective effect of naringin on bisphenol A-induced cognitive dysfunction and oxidative damage in rats. Int J Mol Cell Med, 2019, 8(2): 141-153.

[117] Sachdeva AK, Chopra K. Naringin mitigate okadaic acid-induced cognitive impairment in an experimental paradigm of Alzheimer’s disease. J Funct Foods, 2015, 19: 110-125.

[118] Ionescu-Tucker A, Cotman CW. Emerging roles of oxidative stress in brain aging and Alzheimer’s disease. Neurobiol Aging, 2021, 107: 86-95.

[119] Sies H, Berndt C, Jones DP. Oxidative Stress. Annu Rev Biochem, 2017, 86(1): 715-748.

[120] Andersen JK. Oxidative stress in neurodegeneration: cause or consequence?. Nat Med, 2004, 10(Suppl7): S18-S25.

[121] Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev, 2013, 2013: 316523.

[122] Chen R, Qi QL, Wang MT, et al. . Therapeutic potential of naringin: an overview. Pharm Biol, 2016, 54(12): 3203-3210.

[123] Rajadurai M, Prince PS. Preventive effect of naringin on isoproterenol-induced cardiotoxicity in Wistar rats: an in vivo and in vitro study. Toxicology, 2007, 232(3): 216-225.

[124] Cavia-Saiz M, Busto MD, Pilar-Izquierdo MC, et al. . Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J Sci Food Agric, 2010, 90(7): 1238-1244.

[125] Muthaiah VP, Venkitasamy L, Michael FM, et al. . Neuroprotective role of naringenin on carbaryl induced neurotoxicity in mouse neuroblastoma cells. Pharmacol Pharmacother, 2013, 4(3): 192-197.

[126] de Oliveira MR, Custódio de Souza IC, Fürstenau CR. Promotion of mitochondrial protection by naringenin in methylglyoxal-treated SH-SY5Y cells: Involvement of the Nrf2/GSH axis. Chem Biol Interact, 2019, 310: 108728.

[127] de Oliveira MR, Brasil FB, Andrade CMB. Naringenin Attenuates H2O2-Induced Mitochondrial Dysfunction by an Nrf2-Dependent Mechanism in SH-SY5Y Cells. Neurochem Res, 2017, 42(11): 3341-3350.

[128] Kumar A, Dogra C, Prakash A. Protective Effect of Naringin, a Citrus Flavonoid, Against Colchicine-Induced Cognitive Dysfunction and Oxidative Damage in Rats. J Med Food, 2010, 13(4): 976-984.

[129] Hassan HM, Elnagar MR, Abdelrazik E, et al. . Neuroprotective effect of naringin against cerebellar changes in Alzheimer’s disease through modulation of autophagy, oxidative stress and tau expression: An experimental study. Front Neuroanat, 2022, 16: 1012422.

[130] Anstey KJ, Ashby-Mitchell K, Peters R. Updating the Evidence on the Association between Serum Cholesterol and Risk of Late-Life Dementia: Review and Meta-Analysis. Alzheimers Dis, 2017, 56(1): 215-228.

[131] Popp J, Meichsner S, Kölsch H, et al. . Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer’s disease. Biochem Pharmacol, 2013, 86(1): 37-42.

[132] Souza JPF, Povala G, Brum WS, et al. . Hypercholesterolemia accelerates aβ deposition in regions associated with early amyloidosis: Neuroimaging/optimal neuroimaging measures for tracking disease progression. Alzheimers Dement, 2020, 16: e044114.

[133] Raulin AC, Doss SV, Trottier ZA, et al. . ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegener, 2022, 17(1): 72.

[134] Nabizadeh F, Valizadeh P, Balabandian M. Does statin use affect amyloid beta deposition and brain metabolism?. CNS Neurosci Ther, 2023, 29(5): 1434-1443.

[135] Chen JM, Chang CW, Chang TH, et al. . Effects of statins on incident dementia in patients with type 2 DM: a population-based retrospective cohort study in Taiwan. PLoS One, 2014, 9(2): e88434.

[136] Taghibiglou C, Martin HG, Lai TW, et al. . Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat Med, 2009, 15(12): 1399-1406.

[137] Yu X, Meng X, Yan Y, et al. . Extraction of Naringin from Pomelo and Its Therapeutic Potentials against Hyperlipidemia. Molecules, 2022, 27(24): 9033.

[138] Cai X, Wang S, Wang H, et al. . Naringenin inhibits lipid accumulation by activating the AMPK pathway in vivo and vitro. Food Sci Hum Wellness, 2023, 12(4): 1174-1183.

[139] Allister EM, Mulvihill EE, Barrett PH, et al. . Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor. J Lipid Res, 2008, 49(10): 2218-2229.

[140] Sui G, Xiao H, Lu X, et al. . Naringin Activates AMPK Resulting in Altered Expression of SREBPs, PCSK9, and LDLR To Reduce Body Weight in Obese C57BL/6J Mice. J Agric Food Chem, 2018, 66(34): 8983-8990.

[141] Choi H, Kim HJ, Yang J, et al. . Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models. Aging Cell, 2020, 19(1): e13081.

[142] Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci, 2016, 17(1): 22-35.

[143] Qiu Q, Lei X, Wang Y, et al. . Naringin Protects against Tau Hyperphosphorylation in Aβ (25–35)-Injured PC12 Cells through Modulation of ER, PI3K/AKT, and GSK-3β Signaling Pathways. Behav Neurol, 2023, 2023: 1857330.

[144] Md S, Gan SY, Haw YH, et al. . in vitro neuroprotective effects of naringenin nanoemulsion against β-amyloid toxicity through the regulation of amyloidogenesis and tau phosphorylation. Int J Biol Macromol, 2018, 118: 1211-1219. Pt A

[145] Kuji M, Becer E, Vatansever HS, et al. . Neuroprotective Effects of Hesperidin and Naringin in SK-N-AS Cell as an In Vitro Model for Alzheimer’s Disease. J Am Nutr Assoc, 2023, 42(4): 418-426

[146] Jia YR, Guo ZQ, Guo Q, et al. . Glycogen Synthase Kinase-3β, NLRP3 Inflammasome, and Alzheimer’s Disease. Curr Med Sci, 2023, 43(5): 847-854.

[147] Jope RS, Yuskaitis CJ, Beurel E. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res, 2007, 32: 577-595.

[148] Iwaloye O, Elekofehinti OO, Oluwarotimi EA, et al. . Insight into glycogen synthase kinase-3β inhibitory activity of phytoconstituents from Melissa officinalis: in silico studies. In Silico Pharmacol, 2020, 8(1): 2.

[149] Abd-Elmawla MA, Essam RM, Ahmed KA, et al. . Implication of Wnt/GSK-3β/β-Catenin Signaling in the Pathogenesis of Mood Disturbances Associated with Hyperthyroidism in Rats: Potential Therapeutic Effect of Naringin. ACS Chem Neurosci, 2023, 14(11): 2035-2048.

[150] Guo X, Ji Q, Wu M, et al. . Naringin attenuates acute myocardial ischemia-reperfusion injury via miR-126/GSK-3β/β-catenin signaling pathway. Acta Cir Bras, 2022, 37(1): e370102.

[151] Huang XT, Liu X, Ye CY, et al. . Iron-induced energy supply deficiency and mitochondrial fragmentation in neurons. J Neurochem, 2018, 147(6): 816-830.

[152] Hare D, Ayton S, Bush A, et al. . A delicate balance: Iron metabolism and diseases of the brain. Front Aging Neurosci, 2013, 5: 34.

[153] Levi S, Finazzi D. Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms. Front Pharmacol, 2014, 5: 99.

[154] Gleason A, Bush AI. Iron and Ferroptosis as Therapeutic Targets in Alzheimer’s Disease. Neurotherapeutics, 2021, 18(1): 252-264.

[155] Shamsi A, Shahwan M, Khan MS, et al. . Elucidating the interaction of human ferritin with quercetin and naringenin: Implication of natural products in neurodegenerative diseases: Molecular docking and dynamics simulation insight. ACS omega, 2021, 6(11): 7922-7930.

[156] Chtourou Y, Fetoui H, Gdoura R. Protective effects of naringenin on iron-overload-induced cerebral cortex neurotoxicity correlated with oxidative stress. Biol Trace Elem Res, 2014, 158(3): 376-383.

[157] Talbot K. Brain insulin resistance in Alzheimer’s disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag, 2014, 4(1): 31-40.

[158] Ashton NJ, Leuzy A, Karikari TK, et al. . The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers. Eur J Nucl Med Mol Imaging, 2021, 48(7): 2140-2156.

[159] Talbot K, Wang HY, Kazi H, et al. . Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest, 2012, 122(4): 1316-1338.

[160] Rivera EJ, Goldin A, Fulmer N, et al. . Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis, 2005, 8(3): 247-268.

[161] Wang D, Yan J, Chen J, et al. . Naringin Improves Neuronal Insulin Signaling, Brain Mitochondrial Function, and Cognitive Function in High-Fat Diet-Induced Obese Mice. Cell Mol Neurobiol, 2015, 35(7): 1061-1071.

[162] Wang D, Gao K, Li X, et al. . Long-term naringin consumption reverses a glucose uptake defect and improves cognitive deficits in a mouse model of Alzheimer’s disease. Pharmacol Biochem Behav, 2012, 102(1): 13-20.

[163] Yang W, Ma J, Liu Z, et al. . Effect of naringenin on brain insulin signaling and cognitive functions in ICV-STZ induced dementia model of rats. Neurol Sci, 2014, 35(5): 741-751.

[164] Variya BC, Bakrania AK, Patel SS. Antidiabetic potential of gallic acid from Emblica officinalis: Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling. Phytomedicine, 2020, 73: 152906.

[165] Liu X, Liu M, Mo Y, et al. . Naringin ameliorates cognitive deficits in streptozotocin-induced diabetic rats. Iran J Basic Med Sci, 2016, 19(4): 417-422.

[166] Amawi H, Ashby CR Jr, Tiwari AK. Cancer chemoprevention through dietary flavonoids: what’s limiting?. Chin J Cancer, 2017, 36(1): 50.

[167] Salehi B, Fokou PVT, Sharifi-Rad M, et al. . The Therapeutic Potential of Naringenin: A Review of Clinical Trials. Pharmaceuticals, 2019, 12(1): 11.

[168] Barajas-Vega JL, Raffoul-Orozco AK, Hernandez-Molina D, et al. . Naringin reduces body weight, plasma lipids and increases adiponectin levels in patients with dyslipidemia. Int J Vitam Nutr Res, 2022, 92(3–4): 292-298.

[169] Jung UJ, Kim HJ, Lee JS, et al. . Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin Nutr, 2003, 22(6): 561-268.

[170] Nouri Z, Fakhri S, El-Senduny FF, et al. . On the Neuroprotective Effects of Naringenin: Pharmacological Targets, Signaling Pathways, Molecular Mechanisms, and Clinical Perspective. Biomolecules, 2019, 9(11): 690.

[171] Bhandari R, Paliwal JK, Kuhad A. Enhanced Bioavailability and Higher Uptake of Brain-Targeted Surface Engineered Delivery System of Naringenin developed as a Therapeutic for Autism Spectrum Disorder. Curr Drug Deliv, 2023, 20(2): 158-182.

[172] Hanna DMF, Youshia J, Fahmy SF, et al. Nose to brain delivery of naringin-loaded chitosan nanoparticles for potential use in oxaliplatin-induced chemobrain in rats: impact on oxidative stress, cGAS/STING and HMGB1/RAGE/TLR2/MYD88 inflammatory axes. Expert Opin Drug Deliv, 2023,1–15

[173] Yan C, Gu J, Yin S, et al. . Design and preparation of naringenin loaded functional biomimetic nano-drug delivery system for Alzheimer’s disease. J Drug Target, 2024, 32(1): 80-92.

[174] Shi X, Ma R, Lu Y, et al. . iRGD and TGN co-modified PAMAM for multi-targeted delivery of ATO to gliomas. Biochem Biophys Res Commun, 2020, 527(1): 117-123.

[175] Gandhi S, Shastri DH, Shah J, et al. . Nasal Delivery to the Brain: Harnessing Nanoparticles for Effective Drug Transport. Pharmaceutics, 2024, 16(4): 481.

[176] Gaba B, Khan T, Haider MF, et al. . Vitamin E Loaded Naringenin Nanoemulsion via Intranasal Delivery for the Management of Oxidative Stress in a 6-OHDA Parkinson’s Disease Model. Biomed Res Int, 2019, 2019: 2382563.

[177] Nagaraja S, Basavarajappa GM, Karnati RK, et al. . Ion-Triggered In Situ Gelling Nanoemulgel as a Platform for Nose-to-Brain Delivery of Small Lipophilic Molecules. Pharmaceutics, 2021, 13(8): 1216.

[178] Cunha S, Costa CP, Loureiro JA, et al. . Double Optimization of Rivastigmine-Loaded Nanostructured Lipid Carriers (NLC) for Nose-to-Brain Delivery Using the Quality by Design (QbD) Approach: Formulation Variables and Instrumental Parameters. Pharmaceutics, 2020, 12(7): 599.

[179] Qizilbash FF, Ashhar MU, Zafar A, et al. . Thymoquinone-Enriched Naringenin-Loaded Nanostructured Lipid Carrier for Brain Delivery via Nasal Route: In Vitro Prospect and In Vivo Therapeutic Efficacy for the Treatment of Depression. Pharmaceutics, 2022, 14(3): 656.