Research Progress on the Role of Puerarin in the Prevention and Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that affects cognitive abilities in the elderly. Puerarin plays an important role in the prevention and treatment of AD. It exerts potential therapeutic effects in multiple aspects, including regulating the expression of amyloid β-protein (Aβ), inhibiting abnormal phosphorylation of microtubule-associated protein-τ (Tau), scavenging free radicals, resisting oxidation, regulating metal metabolism to maintain cholinergic system stability, improving mitochondrial dysfunction, and resisting inflammation. However, the specific mechanisms by which puerarin protects cortical neurons in the brain are not fully explored. Hypothetical therapeutic pathways still require further scientific verification.

 

MissingLinkText

Keywords

alzheimer's disease - puerarin - dementia - cortical neurons

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder closely related to the aging process, characterized by the gradual loss of cognitive function. This disease not only severely impacts the quality of life of elderly individuals but also brings a significant socioeconomic burden.[1] Despite substantial efforts by researchers, the pathogenesis of AD remains unclear. Current medications such as memantine and donepezil have unsatisfactory efficacy.[2] Therefore, in-depth research into the pathological mechanisms and therapeutic strategies of AD, identifying its fundamental causes, and developing effective treatments are key to solving this issue.[3] Presently, there are many challenges in finding new drugs that can effectively alleviate symptoms or prevent disease progression, making this an area of intense focus in the scientific community.

Pueraria, the dried root of the perennial leguminous vine Pueraria lobata (Willd.) Ohwi, is sweet, pungent and cool in nature, and it enters the spleen, stomach, and lung meridians. Pueraria was first recorded in Shennong's Classic of Materia Medica (Shen Nong Ben Cao Jing), which describes its effects: “It is mainly effective for thirst, severe fever of the body, vomiting, various pains, promoting yin energy and removing toxicity.” Pueraria has been found to have heat-clearing, detoxifying, antihypertensive, and antioxidant effects.[4] Research has found that pueraria contains various chemical components, primarily including puerarin, puerarin xyloglucoside, and soybean flavonoids, among others.[5] Among them, puerarin is an isoflavone monomer in pueraria, which has the function of improving blood circulation and protecting brain neurons.[6] Relevant studies suggest that puerarin may inhibit the occurrence and progression of AD.[7] This article aims to review the research progress on the role of puerarin in the prevention and treatment of AD and summarize its therapeutic mechanisms in preventing and treating AD, thus providing a reference for further exploration of puerarin's medicinal value.

 

MissingLinkText

Traditional Chinese Medicine's Understanding of Alzheimer's Disease

Traditional Chinese medicine (TCM) believes that the brain marrow plays a crucial role in regulating mental activities in the human body. The Danger Zone of Medicine (Yi Bian) states: “The brain is the sea of marrow, and marrow is derived from essence. When essence is insufficient, it should be replenished with flavors, which all ascend to the brain as the source of generation and transformation.” Zhang et al.[8] believe that brain marrow constitutes the material foundation for mental activities, and therefore, the deprived nourishment to the brain marrow is closely related to the onset of AD. In The Yellow Emperor's Inner Classic: Basic Questions (Huang Di Nei Jing Su Wen), it is stated: “At the age of forty, half of the yin qi in their body has already been consumed, early aging begins to appear in their daily activities; at the age of fifty, their body becomes heavy and their eyes and ears cannot see and hear well…” This describes the phenomenon of physical decline with age. Among the many influencing factors of AD, age is critically important, suggesting that aging is a key factor in the development of AD. Additionally, in Benshen: Basic State of Spirit (Ling Shu:Ben Shen), it states: “The kidney stores essence and essence houses understanding ability”; In The Yellow Emperor's Inner Classic: Basic Questions (Huang Di Nei Jing Su Wen), it states: “The kidney is the organ similar to an official with great power and is responsible for further digestion of skills,” which emphasizes the close connection between the kidney and brain function such as memory and intelligence.[9] In The Yellow Emperor's Inner Classic: Basic Questions (Huang Di Nei Jing Su Wen), it states: “If the kidney fails to produce marrow, bone marrow will become deficient.” This highlights the relationship between kidney qi and brain marrow, with the fundamental pathology of dementia mainly involving the depletion of kidney essence and the deficiency of brain marrow. Modern research further reveals that puerarin can stabilize cerebral vascular function, improve blood circulation in the brain, enhance oxygen and blood supply to the brain, and protect nerve cells in the central nervous system. Therefore, puerarin demonstrates significant medicinal potential in combating AD.

 

MissingLinkText

Mechanism of Puerarin in Alzheimer's Disease

The pathogenesis of AD is extremely complex, and a specific cause has not yet been discovered. However, several theories have partially explained the mechanisms underlying AD, mainly involving the related mechanisms of deposition of amyloid β-protein (Aβ), hyperphosphorylation of microtubule-associated protein-τ (Tau), metal ion imbalance, cholinergic system disorder, mitochondrial dysfunction, and neuroinflammation[10] (see [Fig. 1]).

Fig. 1 Mechanism of Alzheimer's disease (AD). ACh, acetylcholine; AChE, acetylcholinesterase; BChE, butyrylcholinesterase; ChAT, choline acetyltransferase; ROS, reactive oxygen species.

Puerarin Reduces the Expression of Amyloid β-Protein in Alzheimer's Disease

Aβ is a protein fragment generated by the cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The deposition of Aβ is considered a hallmark of AD.[11] Aβ may exacerbate the progression of AD through various pathways, including activating glial cells to induce inflammation, increase oxidative stress, damage mitochondrial function, and activate specific signaling pathways that lead to abnormal phosphorylation of Tau protein.[12] Studies have shown that puerarin significantly reduces the levels of Aβ_40/42 in SH-SY5Y cells, demonstrating its significant role in maintaining the function of brain neurons.[13] Other studies have found that puerarin can reduce β-secretase activity and the mRNA level of β-secretase,[14] thereby reducing the expression of Aβ. Puerarin can also inhibit apoptosis of PC12 cells induced by Aβ_25–35, further confirming its protective effect on nerve cells.[15] In AD rat brain tissue, puerarin intervention led to a decrease in the expression of Aβ_1–40 and Bax,[16] as well as reduced levels of propylene glycol content and lactate dehydrogenase leakage, while superoxide dismutase (SOD) levels increased. Estrogen response element (ERE) reporter gene analysis showed that puerarin could preferentially upregulate androgen receptor expression without upregulating estrogen receptor expression, thus promoting Aβ degradation and enhancing neuroprotection.[17] These findings suggest that puerarin can treat AD by regulating Aβ expression. Puerarin regulates the phosphorylation level dependent on vascular growth factors by reducing the expression of protein kinase B and endothelial nitric oxide synthase, thereby improving Aβ₄₀-induced human endothelial cell function.[18]

 

MissingLinkText

Puerarin Inhibits the Hyperphosphorylation of Tau Protein

The phosphorylation state and the tertiary structure of Tau protein lead to an increase in its phosphorylation pattern. When Tau protein undergoes pathological hyperphosphorylation, it tends to aggregate into paired helical filaments, eventually leading to neurofibrillary tangles (NFTs), which is one of the main pathological features of AD.[19] Experiments have shown that puerarin can enhance memory function in rats, reduce Aβ levels, and inhibit the phosphorylation process of Tau protein.[20] Glycogen synthase kinase 3β (GSK-3β), a highly conserved serine/threonine kinase, plays a crucial role in the connection between Aβ and NFTs.[21] Puerarin can also activate the GSK-3β-Ser9 and Wnt/β-catenin signaling pathways, increasing β-catenin and Cyclin D1 expression in the G₁/S phase.[22] It can also regulate the level of FGF-2 to inhibit the overactivation of GSK-3,[23] thus alleviating Tau hyperphosphorylation and inhibiting Aβ-induced Tau hyperphosphorylation. Research by Yu et al.[24] found that puerarin regulates the level of Tau protein phosphorylation in AD model rats, and its mechanism is closely related to GSK-3β activity. Another study found that puerarin significantly reduces the phosphorylation level of Tau protein at the Ser199/202 site in the hippocampus of aged rats.[25] Furthermore, puerarin can inhibit Aβ-induced Tau protein phosphorylation at Ser396 and Thr231 in SH-SY5Y cells, as well as increase the number of Pser404 tau-positive cells in the rat hippocampus induced by Aβ, thereby alleviating Tau hyperphosphorylation. Other research indicates that various physiological stresses produced during exercise can enhance the expression of small molecular weight heat shock protein B5 (HSPB5), which increases the structural stability of Tau monomers and inhibits the aggregation of Tau monomers.[26]

 

MissingLinkText

The Effect of Puerarin on the Scavenging of Oxygen Free Radicals and Antioxidant Activity

Reactive oxygen species (ROS) are widely present in nature, and the generation and elimination of free radicals in the body generally maintain a dynamic balance, which is crucial for normal physiological functions.[27] Excessive oxidative stress in the brain leads to the generation of Aβ, and the imbalance between the production and elimination of oxygen free radicals can cause abnormal autophagy in hippocampal neurons, thereby exacerbating AD.[28] Puerarin can scavenge oxygen free radicals, inhibit erythrocyte hemolysis and lipid peroxidation processes, demonstrating its antioxidant properties and its ability to prevent free radical damage. Studies have shown that puerarin can reduce the levels of malondialdehyde (MDA) in the prefrontal cortex region and increase the activity of SOD.[29] Additionally, puerarin treatment in AD mice also elevated the activity of glutathione peroxidase (GPx),[30] effectively alleviating brain tissue damage caused by oxidative stress. Oral administration of puerarin can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) target gene heme oxygenase-1 in the hippocampus to reduce oxidative stress.[31] After puerarin treatment, the activities of GPx and SOD in the substantia nigra of injured rats increased, and MDA levels decreased, thereby enhancing antioxidant capacity.[32] Studies have shown that puerarin can reduce the accumulation of ROS in cells and, by regulating the Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) ratio, block the activation of c-Jun N-terminal kinase (JNK), P38 protein, and caspase-3, it inhibits cell apoptosis caused by oxidative stress.[33] MicroRNAs (miRNAs) have predictive value for the pathogenesis of AD.[34] Some miRNAs may participate in the occurrence of oxidative stress through pathways such as mitogen-activated protein kinase (MAPK), neurotrophic factor signal transduction, axonal guidance, hormone synthesis, and insulin signal transduction.[35] Puerarin can regulate miR-214 in neural stem cells to mitigate hypoxia-induced damage.[36]

 

MissingLinkText

The Role of Puerarin in Regulating Metal Ion Metabolism Disorders

The imbalance of metal ions is closely related to the occurrence and development of AD. Studies have found that metal ions can participate in various mechanisms, such as Aβ deposition, NFTs, oxidative stress, and neuroinflammation, thereby contributing to the pathogenesis of AD.[37] The imbalance of intracellular iron homeostasis can lead to the generation of excessive ROS through the Fenton reaction, which causes severe damage to cells and results in ferroptosis, a form of iron-dependent cell death.[38] The end product of ferroptosis, 4-hydroxy-2,3-trans-nonenal (4-HNE), promotes the formation of Aβ fibrils and NFTs in AD, thereby exacerbating the inflammatory response.[39] In APP/PS1 mice treated with puerarin, the levels of iron and MDA significantly decreased, while the activities of SOD and GPx increased, and the levels of interleukin (IL)-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) significantly decreased.[37] Puerarin also promoted the action of relevant lipolysis carriers and GPx 4, and inhibited the expression of long-chain acyl-CoA synthetase 4 and lysophosphatidylcholine acyltransferase 3.[40] Additionally, puerarin downregulated the expression of divalent metal ion transporter 1 (DMT1) in the cerebral cortex of AD mice and upregulated the expression of ferroportin 1 (FPN1),[41] thereby alleviating neurodegeneration caused by iron overload and reducing endothelial cell damage caused by iron overload.[42] These results indicate that puerarin can inhibit ferroptosis and oxidative stress to improve cognitive function in AD. Aluminum has been confirmed to have certain neurotoxic effects in AD.[43] Experiments have shown that puerarin can regulate neurotransmitter homeostasis and concentration levels, as well as increase the concentrations of metal ions such as iron, magnesium, and zinc, thereby achieving metal ion homeostasis and normal function of the central nervous system.[44] At the same time, puerarin also significantly improves damage to the brain tissue and serum antioxidant systems in aluminum-poisoned rats.[45] Aβ can disrupt calcium ion homeostasis, which in turn affects signaling pathways in various mechanisms, and exacerbates cognitive dysfunction.[46] Puerarin can maintain calcium ion concentration homeostasis while upregulating brain-derived neurotrophic factors, thus protecting hippocampal neurons in rats and alleviating neuronal damage caused by calcium overload.[47] In addition to regulating calcium ion concentrations, puerarin can influence calcium ion dependence and the activity of calcium ion channels by enhancing calcium release,[48] and it can reduce the activity of calmodulin-dependent protein kinase II, thereby inhibiting calcium ion influx and providing neuroprotective effects.[49]

 

MissingLinkText

Puerarin Maintains the Stability of the Cholinergic System

Cholinergic signaling is crucial for memory formation, learning processes, attention, and higher cognitive functions. Defects in the cholinergic system can impair the learning and memory abilities of AD patients, thereby exacerbating disease progression.[50] Several studies have shown that puerarin can enhance learning and memory abilities in mice by increasing the levels of choline acetyltransferase (ChAT) and acetylcholine (ACh), and by reducing the activity of acetylcholinesterase (AChE).[51] Research also suggests that puerarin can improve nerve damage by reducing the activity of butyrylcholinesterase (BChE).[52] Additionally, puerarin can regulate the levels of the monoamine neurotransmitter serotonin, thereby restoring normal hippocampal function.[53] Some other studies indicate that puerarin can reduce the activity of dopamine and norepinephrine, among other monoamine neurotransmitters, in animal models induced by actinomycin,[54] and also lower the levels of 5-hydroxyindoleacetic acid in the rat brain,[55] thereby maintaining the normal operation of the cholinergic system. Research by Mei and others[56] found that puerarin activates the cholinergic anti-inflammatory pathway (CAP), inhibits proinflammatory factors, enhances immune cell activity, promotes the production of the anti-inflammatory cytokine IL-10, and thus regulates immune responses and inflammation.

 

MissingLinkText

Puerarin Improves Mitochondrial Dysfunction

Mitochondria, as important dynamic organelles within cells, primarily meet the majority of cellular adenine nucleoside triphosphate (ATP) demands through oxidative phosphorylation.[57] Mitochondrial dysfunction is closely related to aging and neurodegenerative diseases, with mitochondrial dysfunction being particularly prominent in the early stages of AD.[58] Puerarin helps maintain the integrity and clarity of the mitochondrial structure in rat neural cells, suggesting that it may protect neurons by maintaining mitochondrial homeostasis and preventing apoptosis.[59] Mitochondrial autophagy involves kinase protein 1 (Pink1) and E3 ubiquitin ligase (Parkin), with the Pink1/Parkin pathway widely recognized as the main mechanism for clearing damaged mitochondria.[60] Puerarin can block PINK1–Parkin and Nix-mediated mitochondrial autophagy, inhibit Cd-induced reduction of mitochondria in rat cortical neurons,[61] increase the protein expression levels of mitochondrial PINK1, Parkin, and Nix-like protein X,[62] and reduce the expression of proteins associated with the mitochondrial unfolded protein response following external stimuli.[63] Puerarin exerts a neuroprotective effect by inhibiting the release of mitochondrial cytochrome C and thereby reducing apoptosis.[64] Puerarin can also reduce cytoplasmic hybrid cell apoptosis and lower ROS levels to restore mitochondrial function, thus protecting sporadic alzheimer's disease (SAD), which is closely related to oxidative stress. Additionally, evaluating ATP content and determining the ratio of nicotinamide adenine dinucleotide (NAD⁺/NADH) has shown that puerarin can alleviate mitochondrial damage in the rat cerebral cortex,[65] improve mitochondrial function, and reduce oxidative damage in endothelial cells.[66]

 

MissingLinkText

The Anti-inflammatory Effects of Puerarin

Neuroinflammation is primarily initiated by immune responses triggered by the activation of microglia and astrocytes in the central nervous system.[67] Neuroinflammation contributes to Aβ deposition, neuronal damage, and NFTs, creating a vicious cycle that exacerbates AD.[68] Puerarin can reduce the activation of microglia, decrease the release of proinflammatory factors, and improve the learning and memory abilities of mice.[69] Puerarin can influence the activation of protein kinase C δ (PKC-δ), IκB kinase β (IKKβ) and nuclear factor kappa-B (NF-κB) pathways by inhibiting caspase-8 activation, which reduces caspase-3 activity,[70] [71] and decreases the levels of inflammatory factors such as nitric oxide, TNF-α, and IL-1β, thereby alleviating inflammation. Puerarin activates intracellular phosphatidylinositol kinase and Ras/MAPK signaling pathways, increases the expression of phosphorylated extracellular-regulated protein kinases and brain-derived neurotrophic factors, activates protein kinase B and Bcl-2 genes to reduce astrocyte apoptosis,[72] and inhibits the expression of astrocytes to exert anti-inflammatory effects. Research by Dong et al.[73] found that puerarin can reduce swelling in astrocytes and the expression of lactate dehydrogenase. Additionally, puerarin can protect the brain by inhibiting the inflammation-related NOD-like receptor thermal protein domain associated protein 3/cysteinyl aspartate specific proteinase-1/Gasdermin D (NLRP3/Caspase-1/GSDMD)-mediated pyroptosis pathway and reducing blood–brain barrier damage.[74] Puerarin can also improve changes in inflammatory factors such as TNF-α, interferon-γ (IFN-γ), transforming growth factor-β1 (TGF-β1), and IL-1β in mouse serum, reducing the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) proteins, thus alleviating endothelial cell damage.[75]

 

MissingLinkText

Other Effects

Puerarin can also promote the recovery of rat neural function by repairing synaptic structures and enhancing synaptic transmission function.[76] It can reduce neuronal apoptosis by downregulating the proapoptotic gene Bax, upregulating the antiapoptotic gene Bcl-2, and inhibiting the expression of Caspase-3.[77] Puerarin improves the fluidity of neuronal cell membrane lipids and protects neural cells. Experimental studies have shown that puerarin pretreatment can prevent ischemia–reperfusion injury in brain tissue by alleviating microvascular damage, increasing recanalization, reducing blood–brain barrier permeability and alleviating brain edema, and it also protects vascular endothelial cells and reduces endothelial cell dysfunction under pathological conditions.[78]

 

MissingLinkText

 

MissingLinkText

Conclusion

In summary, puerarin has shown potential therapeutic effects for AD in various aspects, including regulating Aβ expression, inhibiting abnormal phosphorylation of Tau proteins, scavenging oxygen free radicals, resisting oxidation activity, regulating metal metabolism, and eliminating inflammation.[79] Given the highly complex pathological mechanisms of AD, puerarin, as one of the main active ingredients in pueraria, still has many unresolved mysteries in its pharmacological effects. The specific mechanisms by which puerarin protects cortical neurons in the brain are not yet fully understood. Some hypothetical therapeutic pathways require further scientific verification to be confirmed. Therefore, to comprehensively reveal the practical effects of puerarin in the prevention and treatment of AD and the underlying mechanisms, there is an urgent need for more systematic clinical trials and basic research. This is of great significance for establishing puerarin's important position in future prevention and treatment strategies for AD.

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Changsong Chu: Project administration and validation. Yaquan Jia: Conceptualization, data curation, and writing—original draft. Yuan Liu: Data curation, methodology, and writing—review and editing. Ruofei Du: Data curation and software. Zichuang Wang: Methodology and writing—review and editing. Zhenqiang Zhang: Formal analysis and investigation. Wanchun Zheng: validation. Junying Song: Data curation.

• References

• 1 Lopez JaS, Gonzalez HM, Leger GC. Alzheimer's disease. Handb Clin Neurol 2019; 167: 231-255
• 2 Li Y, Li H, Li HP. et al. Effects of memantine combined with donepezil in treatment of patients with Alzheimer's disease. Med J Chin People's Health 2024; 36 (13) 37-40
• 3 Philip S, Bart DS, Miia K. et al. Alzheimer's disease. Lancet 2021; 397 (10284): 1577-1590
• 4 Wang H, Dong B, Chang PS. et al. Research on the medicinal properties and functions of Pueraria lobata . Guid J Tradit Chin Med Pharm 2016; 22 (19) 75-77
• 5 Li R, Song ZL, Zhang XK. et al. Research progress of modern pharmacological effects of Pueraria lobata and its compound clinical application. J Hainan Med Coll 2023; [phone]
• 6 Li R, Hao XL, Liu JC. et al. Progress in the mechanism of improving cardiovascular disease by Pueraria puerariae and its active components. Ginseng Res 2021; 33 (04) 59-61
• 7 Xu HX, Li Q, Wang YM. Research progress of puerarin in treatment of Alzheimer's disease. Zhonghua Zhongyiyao Xuekan 2023; 41 (05) 29-33
• 8 Zhang H, Wang Y, Zhang XN. et al. Discuss Lewy body dementia from the perspective of cerebral marrow-brain-brain-brain. Global Tradit Chin Med 2023; 16 (10) 2051-2054
• 9 Zhang S, Wei Y, Li H. Central nervous system regeneration of patients with Alzheimer's disease: Based on the kidney-brain related theory. J Tradit Chin Med 2018; 59 (02) 120-123
• 10 Rostagno AA. Pathogenesis of Alzheimer's disease. Int J Mol Sci 2022; 24 (01) 107
• 11 Gouras GK, Olsson TT, Hansson O. β-Amyloid peptides and amyloid plaques in Alzheimer's disease. Neurotherapeutics 2015; 12 (01) 3-11
• 12 Wang GQ, Cao YP. Advances in the study of Aβ oligomers and Alzheimer's disease. J Apoplexy Nerv Dis 2023; 40 (07) 579-583
• 13 Yao Y, Bao YT, Wu YS. et al. Influence of puerarin on the level of Tau hyperphosphorylation and β-amyloid peptide 40/42 protein expression induced by β-amyloid peptide 1–42 in SH-SY5Y cells. Chin J Clin Pharmacol Ther 2016; (11) 1258-1262
• 14 Mei ZR, Tan XP, Huang HH. et al. Puerarin against Alzheimer's disease by inhibition β-amyloid protein. Chin J Mod Appl Pharm 2015; (01) 5-9
• 15 Zhang HY, Yi XN, Liu YH, Lao ML, Zhang XF. The protective effect of puerarin on Abeta(25-35)-induced PC12 cell injury [in Chinese]. Zhong Yao Cai 2010; 33 (05) 763-767
• 16 Yan FL, Lu G, Wang YQ. et al. Effect of puerarin on the expression of Aβ1–40 and Bax in brain of AD rats induced by Aβ25–35. Chin J Neuromed 2006; 5: 158-161
• 17 Li L, Xue Z, Chen L, Chen X, Wang H, Wang X. Puerarin suppression of Aβ_1-42-induced primary cortical neuron death is largely dependent on ERβ. Brain Res 2017; 1657: 87-94
• 18 Lu XL, Liu JX, Wu Q. et al. Protective effects of puerarin against Aβ40-induced vascular dysfunction in zebrafish and human endothelial cells. Eur J Pharmacol 2014; 732: 76-85
• 19 Wegmann S, Biernat J, Mandelkow E. A current view on Tau protein phosphorylation in Alzheimer's disease. Curr Opin Neurobiol 2021; 69: 131-138
• 20 Chen XC. Mechanism of action of puerarin against Alzheimer's disease based on wnt/β-catenin (GSK-3β) pathway. Zhejiang: Zhejiang University of Traditional Chinese Medicine; 2024
• 21 Giovinazzo D, Bursac B, Sbodio JI. et al. Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation. Proc Natl Acad Sci U S A 2021; 118 (04) e2017225118
• 22 Yao Y, Chen X, Bao Y, Wu Y. Puerarin inhibits β–amyloid peptide 1–42–induced tau hyperphosphorylation via the Wnt/β–catenin signaling pathway. Mol Med Rep 2017; 16 (06) 9081-9085
• 23 Hong XP, Chen T, Yin NN. et al. Puerarin ameliorates D-galactose induced enhanced hippocampal neurogenesis and tau hyperphosphorylation in rat brain. J Alzheimers Dis 2016; 51 (02) 605-617
• 24 Yu YL. Effect of puerarin on tau hyperphosphorylation in the Alzheimer's and type 2 diabetes rat brain and the underlying mechanisms. Wuhan: Hubei University of Traditional Chinese Medicine; 2018
• 25 Hong XP, Chen T, Zhou Z. et al. Effects of puerarin on learning and memory function and phosphorylation level of tau protein in the hippocampus in aged rats. Zhongguo Laonianxue Zazhi 2015; (14) 3802-3805
• 26 Xu ZD. Molecular dynamics study of heat shock protein B5 to inhibit β-amyloid and Tau protein aggregation: a preliminary study on the mechanism of exercise delaying Alzheimer's disease. Shanghai: Shanghai University of Sport; 2024
• 27 Brieger K, Schiavone S, Miller Jr FJ, Krause KH. Reactive oxygen species: from health to disease. Swiss Med Wkly 2012; 142: w13659
• 28 Bai R, Guo J, Ye XY, Xie Y, Xie T. Oxidative stress: The core pathogenesis and mechanism of Alzheimer's disease. Ageing Res Rev 2022; 77: 101619
• 29 Chen BX, Liu YN, Li HY. et al. Neuroprotective effect of puerarin on ischemic brain injury in mice by antioxidant stress. Chin J Clin Pharmacol 2021; 11: 1355-1357
• 30 Zhao SS, Yang WN, Jin H, Ma KG, Feng GF. Puerarin attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice. Neurotoxicology 2015; 51: 166-171
• 31 Zhou W, He H, Wei Q. et al. Puerarin protects against acetaminophen-induced oxidative damage in liver through activation of the Keap1/Nrf2 signaling pathway. Food Sci Nutr 2023; 11 (10) 6604-6615
• 32 Li R, Zheng N, Liang T, He Q, Xu L. Puerarin attenuates neuronal degeneration and blocks oxidative stress to elicit a neuroprotective effect on substantia nigra injury in 6-OHDA-lesioned rats. Brain Res 2013; 1517: 28-35
• 33 Zhang H, Liu Y, Lao M, Ma Z, Yi X. Puerarin protects Alzheimer's disease neuronal cybrids from oxidant-stress induced apoptosis by inhibiting pro-death signaling pathways. Exp Gerontol 2011; 46 (01) 30-37
• 34 Xu SJ, Jiang L, Xie B. et al. The role of miRNA in the pathogenesis of AD and its regulatory mechanism. Shijiazhuang: The First Hospital of Hebei Medical University; 2018
• 35 Xu SJ, Xie B, Zhang R. et al. Study on the regulatory mechanism of miRNAs in the pathogenesis of AD induced by oxidative stress. Shijiazhuang: The First Hospital of Hebei Medical University; 2015
• 36 Wang B, Ma W, Yang H. Puerarin attenuates hypoxia-resulted damages in neural stem cells by up-regulating microRNA-214. Artif Cells Nanomed Biotechnol 2019; 47 (01) 2746-2753
• 37 Liu F, Zhang Z, Zhang L. et al. Effect of metal ions on Alzheimer's disease. Brain Behav 2022; 12 (03) e2527
• 38 Peng Y, Chang X, Lang M. Iron homeostasis disorder and Alzheimer's disease. Int J Mol Sci 2021; 22 (22) 12442
• 39 Lee J, Hyun DH. The interplay between intracellular iron homeostasis and neuroinflammation in neurodegenerative diseases. Antioxidants 2023; 12 (04) 918
• 40 Zhang TC, Lin YC, Sun NN. et al. Icariin, astragaloside a and puerarin mixture attenuates cognitive impairment in APP/PS1 mice via inhibition of ferroptosis-lipid peroxidation. Neurochem Int 2024; 175: 105705
• 41 Dong XH, Chai XQ. Effects of epimedium herb, Astragalus membranaceus and Pueraria lobata on cerebral cortical neurons DMT1 and C in transgenic mice with Alzheimer's disease. Chin Minkang Med 2015; (14) 169
• 42 Wang DJ, He M. Protective effect of puerarin on damage induced by iron overload in human umbilical vein endothelial cells. J Nanchang Univ 2019; 59 (06) 6-8 (Med Sci)
• 43 Dey M, Singh RK. Neurotoxic effects of aluminium exposure as a potential risk factor for Alzheimer's disease. Pharmacol Rep 2022; 74 (03) 439-450
• 44 Yu J, Ding Y, Wu D, Liu P. Rutin, puerarin and silymarin regulated aluminum-induced imbalance of neurotransmitters and metal elements in brain of rats. Biol Trace Elem Res 2024; 202 (02) 548-557
• 45 Ren N. Effects of flavonoids on the regulation of neurotransmitters and the protection of antioxidant system in rats exposed to aluminum. Ji'nan: Shandong University; 2019
• 46 Cascella R, Cecchi C. Calcium dyshomeostasis in Alzheimer's disease pathogenesis. Int J Mol Sci 2021; 22 (09) 4914
• 47 Ren HW, Chen M, Wang HQ. et al. Puerarin reduces intracellular Ca2+ concentration and upregulates BDNF to protect hippocampal neurons in vascular dementia rats. Xi'an Jiaotong Daxue Xuebao Yixue Ban 2023; [phone]
• 48 Lin F, Xin Y, Wang J. et al. Puerarin facilitates Ca(2+)-induced Ca(2+) release triggered by KCl-depolarization in primary cultured rat hippocampal neurons. Eur J Pharmacol 2007; 570 (1-3): 43-49
• 49 Wang K, Zhu X, Zhang K. et al. Neuroprotective effect of puerarin on glutamate-induced cytotoxicity in differentiated Y-79 cells via inhibition of ROS generation and Ca(2+) influx. Int J Mol Sci 2016; 17 (07) 1109
• 50 Hampel H, Mesulam MM, Cuello AC. et al. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain 2018; 141 (07) 1917-1933
• 51 Liu CM, Zheng GH, Ming QL, Sun JM, Cheng C. Protective effect of puerarin on lead-induced mouse cognitive impairment via altering activities of acetyl cholinesterase, monoamine oxidase and nitric oxide synthase. Environ Toxicol Pharmacol 2013; 35 (03) 502-510
• 52 Koirala P, Seong SH, Jung HA, Choi JS. Comparative evaluation of the antioxidant and anti-alzheimer's disease potential of coumestrol and puerarol isolated from Pueraria lobata using molecular modeling studies. Molecules 2018; 23 (04) 785
• 53 Qiu ZK, Zhong DS, He JL, Liu X, Chen JS, Nie H. The anxiolytic-like effects of puerarin are associated with the changes of monoaminergic neurotransmitters and biosynthesis of allopregnanolone in the brain. Metab Brain Dis 2018; 33 (01) 167-175
• 54 Wu KJ, Lien JC, Wu CR. Puerarin attenuates cycloheximide-induced oxidative damage and memory-consolidation impairment in rats. J Integr Neurosci 2024; 23 (01) 17
• 55 Zhao ZH, Li AY, Guan CH. Effects of puerarin on behavior, monoamine transmitters and inflammation in rats with post-traumatic stress disorder based on IKK/IκBα/NF-κB pathway. Zhonghua Zhongyiyao Xuekan 2023; (11) 230-237
• 56 Mei ZG, Wang MZ, Liu XJ. et al. Effect of puerarin on mRNA expression of α7nAChR, NF-κBp65 and STAT3 in brain after cerebral ischemia-reperfusion in rats. Chin J Tradit Chin Med Pharm 2013; 28 (01) 113-117
• 57 Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell 2012; 148 (06) 1145-1159
• 58 Maruszak A, Żekanowski C. Mitochondrial dysfunction and Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35 (02) 320-330
• 59 Mi XX, Xu MC, Wang L. et al. Puerarin alleviates cadmium-induced mitochondrial structural damage and Pink1/Parkin-mediated mitophagy in neuronal cells of rats. Chin Vet Sci 2024; 54 (02) 276-281
• 60 Li J, Yang D, Li Z. et al. PINK1/Parkin-mediated mitophagy in neurodegenerative diseases. Ageing Res Rev 2023; 84: 101817
• 61 Wen S, Wang L, Wang T. et al. Puerarin alleviates cadmium-induced mitochondrial mass decrease by inhibiting PINK1-Parkin and Nix-mediated mitophagy in rat cortical neurons. Ecotoxicol Environ Saf 2022; 230: 113127
• 62 Wen SQ. Puerarin alleviates cadmium-induced neurotoxicity mediated by mitochondrial damage in rat cerebral cortical neurons. Yangzhou: Yangzhou University; 2024
• 63 Zhang WH. Puerarin alleviates oxidative damage and mitochondrial unfolded protein response induced by cadmium in rat neurocyte. Yangzhou: Yangzhou University; 2023
• 64 Peng F, Hu QP. A protective study of puerarin on hippocampal neurons in rats with pilocarpine epilepsy. J Anhui Med Univ 2020; 55 (12) 1888-1892
• 65 Huang XY, Xu MC, Zhang WH. et al. Protective effect of puerarin on mitochondrial damage caused by cadmium in the cerebral cortices of rat. Chin Vet Sci 2024; 54 (04) 560-565
• 66 Sun SC, Gong DF, Yuan TY. et al. Puerarin reduces oxidative damage to vascular endothelial cells by improving mitochondrial respiratory function. Yao Xue Xue Bao 2022; 57 (05) 1352-1360
• 67 Zhang W, Xiao D, Mao Q, Xia H. Role of neuroinflammation in neurodegeneration development. Signal Transduct Target Ther 2023; 8 (01) 267
• 68 Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers Dement 2016; 12 (06) 719-732
• 69 Liu M, Meng QH, Guo H. et al. To investigate the effect of acetyl puerarin on the expression of microglia and PKC-δ in AD rats. J Shandong Second Med Univ 2013; 35 (01) 4-7
• 70 Li M, Meng HQ, Cai QY. et al. Effect of acetylpuerarin on expression of caspase-8 and caspase-3 in BV-2 mouse microglia cell line induced by Aβ(25–35). Basic Clin Med 2016; 36 (10) 1369-1373
• 71 Cai QY, Meng QH, Li M. et al. Effect of acetylpuerarin on the expression of NF-κBp65 and iNOS in BV-2 microglia cells induced by Aβ(25–35). Shenjing Jiepouxue Zazhi 2016; 32 (03) 397-402
• 72 Wang N, Zhang Y, Wu L. et al. Puerarin protected the brain from cerebral ischemia injury via astrocyte apoptosis inhibition. Neuropharmacology 2014; 79: 282-289
• 73 Dong LP, Han M, Yuan F, Xu LX, Wang TY. The protective effect of puerarin on cultured rat cerebral cortical astrocytes [in Chinese]. Chung Kuo Ying Yung Sheng Li Hsueh Tsa Chih 2001; 17 (02) 141-143
• 74 Zhou S, Li Y, Hong Y, Zhong Z, Zhao M. Puerarin protects against sepsis-associated encephalopathy by inhibiting NLRP3/Caspase-1/GSDMD pyroptosis pathway and reducing blood-brain barrier damage. Eur J Pharmacol 2023; 945: 175616
• 75 Zhou J, Zhang DD, Tao Y. et al. Puerarin attenuates the inflammatory response of vascular endothelial cells in KKAy mice. Basic Clin Med 2023; 43 (03) 433-437
• 76 Li XW, Wang Y, Han S. et al. Effects of puerarin on neurological function, and synaptic morphological structure and parameter of cerebral cortex in cerebral ischemia-reperfusion rats. Chin J Pathophysiol 2018; (11) 2043-2047
• 77 Huang XF, Chen Q, Ren Y. Effects of puerarin on the expressions of Bcl-2, Bax and Caspase-3 in the motor cortex of mice with traumatic brain injury. Clin J Chin Med 2019; (25) 13-15
• 78 Ma KP, Han S, Zhao SM. et al. Preventive protective effect of puerarin pretreatment on cerebral ischemia-reperfusion cerebral cortical microvessels and blood-brain barrier. Chin J Anat 2015; 38 (06) 694-697
• 79 Kim MH, Kim SH, Yang WM. Mechanisms of action of phytochemicals from medicinal herbs in the treatment of Alzheimer's disease. Planta Med 2014; 80 (15) 1249-1258

Publication History

Received: 08 November 2024

Accepted: 12 January 2025

Article published online:
08 April 2025