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. 2025 Mar 27;33(7):4063–4076. doi: 10.1007/s10787-025-01712-2

Quercetin protects against neuronal toxicity by activating the PI3K/Akt/GSK-3β pathway in vivo models of MPTP-induced Parkinson’s disease

Yajuan Li 1,#, Minghao Man 2,#, Yiyuan Tian 3, Gang Zhao 1, FengZhou Liu 1,4, JingYu Zhao 1,4, Songya Huang 5, Junhui Xue 1,4,✉, Wei Chang 2,✉
PMCID: PMC12354563  PMID: 40146439

Abstract

Background

Quercetin is a flavonoid commonly found in various fruits, vegetables, and grains. Studies have demonstrated that quercetin may help protect neuronal cells from damage caused by neurotoxins associated with Parkinson’s disease, however, the underlying mechanism remains unclear.

Aim

The current study aimed to investigate the neuroprotective effects of quercetin in MPTP-induced Parkinson’s disease mouse models and elucidate its mechanistic role in modulating the PI3K/Akt/GSK-3β signaling pathway.

Materials and methods

Male C57BL/6 mice were divided into control, MPTP, quercetin, and MPTP + quercetin groups. The protective effects of quercetin on Parkinson’s disease in mice were evaluated using animal behaviour analysis, histopathological examination, and immunofluorescence staining. Subsequently, network pharmacology was utilized to determine the primary target sites of quercetin in Parkinson’s disease. Finally, western blotting and molecular docking techniques were applied to validate the identified targets.

Results

Quercetin significantly improved motor deficits in MPTP mice, reduced neuronal atrophy, and preserved TH+ dopaminergic neurons. Western blotting analysis revealed quercetin upregulated anti-inflammatory IL-10 (p < 0.01) and TGF-β (p < 0.01) while suppressing pro-inflammatory IL-1β (p < 0.01) and iNOS (p < 0.01). It activated the PI3K/Akt/GSK-3β pathway by increasing phosphorylation of PI3K (p < 0.01), Akt (p < 0.01), and GSK-3β (p < 0.01). Quercetin also elevated anti-apoptotic Bcl-2 (p < 0.01) and reduced pro-apoptotic Bax (p < 0.01) and Caspase-9 (p < 0.01). Molecular docking confirmed strong binding between quercetin and PI3K/Akt/GSK-3β (binding energies: −6.44 to −5.24 kcal/mol).

Conclusion

Quercetin alleviates Parkinson’s disease pathology by inhibiting neuroinflammation, reducing apoptosis, and activating the PI3K/Akt/GSK-3β pathway. These findings underscore its potential as a multi-target therapeutic agent for Parkinson’s disease.

Graphical abstract

graphic file with name 10787_2025_1712_Figa_HTML.jpg

Keywords: Quercetin, Parkinson’s disease, MPTP, PI3K/Akt/GSK-3β pathway

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopamine neuron in the substantia nigra and the accumulation of alpha-synuclein, resulting in both motor and non-motor symptoms (Wang et al. 2024a). The global incidence of PD is increasing, imposing significant burdens on families and society. The symptoms include movement disorders, rigidity, tremors, cognitive decline, sleep disturbances, olfactory dysfunction, and constipation (Alarcón et al. 2023).

While the precise mechanism underlying Parkinson’s disease is still not fully understood, research has shown that microglia-mediated neuroinflammation is prevalent in both brain aging and various neurodegenerative disorders, including Parkinson’s (Jadhav 2024; Li et al. 2023b; Salama et al. 2024). The phosphatidylinositol3-kinase/protein kinase B (PI3K/Akt) pathway has the capacity to modulate this inflammation in Parkinson’s (Alkholifi et al. 2023; Wang et al. 2024c). Moreover, glycogen synthase kinase3 beta (GSK-3β), a significant substrate within the PI3K/Akt signaling pathway, plays a crucial role in the survival of dopaminergic neurons by regulating oxidative stress (Ali et al. 2018; Zhang et al. 2022). The inhibition of GSK-3β has proven to be effective in reducing neuroinflammation (Liao et al. 2020).

Flavonoids are natural compounds that play essential roles in treating cancer, infectious diseases, and neurodegenerative disorders (Barreca et al. 2023; Wang et al. 2024b). Quercetin (3,3,4,5,7-pentahydroxyflavone), one of the most widely accessible flavonoids, is especially abundant in fruits and vegetables such as apples, onions, grapes, and leafy greens (Chen et al. 2022a). As its pharmacological properties become clearer, quercetin’s antioxidant, anti-inflammatory, antibacterial, immune-regulating, vascular-protective, and neuroprotective activities have drawn increasing attention (Chen et al. 2022a). The studies indicate it provides substantial support to the nervous system, primarily through its potent anti-inflammatory and antioxidant effects (Ma et al. 2016). Notably, quercetin can penetrate the blood–brain barrier, thereby directly influencing neuronal cells (Wang et al. 2023). Its potential role in managing neurodegenerative conditions, including Parkinson’s and Alzheimer’s diseases, has gained significant recent interest.

Quercetin is widespread throughout the plant kingdom. As a prominent flavonoid and polyphenol, it is recognised for potent antioxidant and anti-inflammatory properties. It frequently occurs as glycosides conjugated with sugar residues (Andres et al. 2018). Quercetin has attracted substantial attention due to its potential benefits in various pathological conditions, including neurodegenerative disorders. It exhibits strong antioxidant effects by neutralising excess free radicals and mitigating oxidative stress in neurons (Ho et al. 2022), while simultaneously boosting antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) (Chen et al. 2022b). Furthermore, it inhibits central inflammatory pathways, notably nuclear factor kappa-B (NF-κB), thereby reducing pro-inflammatory cytokines including Inducible Nitric Oxide Synthase (iNOS), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which helps alleviate neuroinflammation (Adeoluwa et al. 2023). Beyond its anti-inflammatory actions, quercetin minimises neuronal damage by regulating excessive microglial activation and apoptosis-related proteins—such as Bcl-2, Bax, and Caspase9—to prevent neuronal cell death (Phoraksa et al. 2023). It also maintains mitochondrial function, stabilises energy metabolism, and may enhance neurogenesis, a vital process for post-injury recovery (Houghton et al. 2018; Lee et al. 2023; Pan et al. 2019). As a versatile compound, quercetin demonstrates potential in slowing Parkinson’s disease progression through its antioxidant and anti-inflammatory mechanisms, with studies suggesting it reduces α-synuclein accumulation in neurons (Wang et al. 2021). Its therapeutic value encompasses mitigating oxidative stress, reducing inflammation, preventing α-synuclein aggregation, preserving mitochondrial function, and facilitating neurogenesis, though further investigation is required to confirm its efficacy.

This study used the MPTP-induced PD mouse model to investigate the role of quercetin in Parkinson’s disease. It linked quercetin’s neuroprotective effects to the PI3K/Akt/GSK-3β signalling pathway and confirmed its binding to these proteins through molecular docking, providing mechanistic evidence. The research combined network pharmacology with experimental validation, identifying 57 core targets and emphasizing 11. It assessed quercetin’s effects on motor function, neuronal survival, microglial activation, and inflammatory cytokines through various analyses. The findings attributed quercetin’s effects to inhibiting microglial activation and regulating cytokines and apoptosis-related proteins, highlighting its connection to the PI3K/Akt/GSK-3β pathway. This underscores quercetin’s potential as a therapeutic target for PD and offers insights for developing strategies to address its complex neurodegenerative mechanisms.

Materials and methods

Modelling and grouping of experimental animals

This experiment utilized male C57BL/6J mice, each weighing between 18 and 22 g and aged 6–8 weeks. The mice were sourced from the Experimental Animal Center of the Air Force Medical University. Upon arrival, they were housed in an animal facility maintained at a temperature range of 20–25 °C for acclimatization and breeding. The laboratory environment was regulated with a 12-h light–dark cycle, allowing the mice unrestricted access to food and water. All procedures involving animals were conducted with approval of the Ethics Committee of the Air Force Medical University [License Number: SCXK (Military) 2017-0021].

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), also known as a dopamine neurotoxin, is commonly used to induce Parkinson’s disease animal models in primates, rats, and mice. The mice were randomly divided into four groups (8 mice per group): Group 1 (Control) received daily intraperitoneal injections of 0.9% sodium chloride for 21 days; Group 2 (quercetin) received 4 mg/kg quercetin dissolved in 0.9% sodium chloride daily for 21 days; Group 3 (MPTP) received 25 mg/kg MPTP dissolved in 0.9% sodium chloride daily for 21 days; and Group 4 (MPTP + quercetin) received 25 mg/kg MPTP daily for 21 days, followed by 4 mg/kg quercetin 1 h after each MPTP injection. The grouping diagram is as follows:graphic file with name 10787_2025_1712_Figb_HTML.jpg

Open-field test

The open-field test is a behavioural research method designed to assess animals’ innate exploration tendencies and anxiety levels in a novel environment. The experimental setup consists of a square chamber with white inner walls, each side measuring 40 cm. During the trial, mice are introduced headfirst into the enclosure and their behaviour is monitored for 3 min (Li et al. 2021). Key metrics recorded include grid crossings, rearing instances, entries into the central area, time spent in the centre, grooming behaviours, and faecal pellet count within the open field.

Rotarod test

The rotarod test is employed to assess mice’s motor coordination and balance comprehensively. The mice underwent a pre-training phase on the rotarod apparatus over three consecutive days, exposed to varying speeds from 1 to 30 rpm, with each session exceeding 300 s. Subsequently, each mouse participated in three test sessions, each lasting 5 min. The time taken by each mouse to fall from the rod is measured and recorded as the latency to fall (Rozas and Labandeira García 1997).

Pole test

The pole climbing experiment aimed to assess limb movement coordination in mice. After randomisation and before administering the model, training for the pole-climbing task was conducted to exclude animals with movement disorders. A 50-cm tall wooden pole, 0.5 cm in diameter, was constructed and wrapped in gauze to prevent slipping. A rubber ball was placed at the top to discourage the mice from perching there. To measure behaviour, each mouse was positioned head-up at the top, and the time taken for the mouse to turn its head and descend was recorded. If a mouse did not descend within 60 s, it was guided down. Each animal underwent three trials, with 5-min intervals between them during the training. After dosing, three measurements of the mice’s head-turning time and total descent time were taken in a continuous trial (Ogawa et al. 1985).

Haematoxylin–eosin staining

After model preparation, euthanasia is administered to all mice via intraperitoneal injection of an overdose of 1.5% pentobarbital sodium. The brains are then rapidly extracted on ice, fixed in a 4% paraformaldehyde solution for a week, dehydrated with different concentrations of ethanol, and processed into paraffin sections using a standard protocol. The sections are deparaffinised to water before undergoing the staining sequence: haematoxylin staining for 10 min, differentiation in hydrochloric acid alcohol for 2 s, rinsing with tap water for 3 min for bluing, eosin staining for 3 min, and finally rinsed with water for 1 min. The slices were sealed and dried at room temperature. Finally, the sections were examined under a microscope to evaluate the staining results (Liu et al. 2024a).

Nissl staining

The paraffin-embedded brain tissue sections were dried at 65 °C for 30 min. Subsequently, the sections underwent deparaffinisation by immersing in xylene for two cycles of 5 min each, followed by dehydration in graded ethanol solutions of 95% and 100%. The sections were immersed in Nissl staining solution for 5 min. Two quick rinses were performed with absolute ethanol to clear excess stain. The sections were cleaned and a clearing agent was applied to seal them. Finally, the staining outcomes were evaluated using a microscope (Zhang et al. 2019a).

Immunofluorescence

The frozen coronal sections of mouse brain, with a thickness of 10 μm and encompassing the striatum region, are preserved in 0.01 mol/L phosphate-buffered saline (PBS). Following washing with PBS, the sections are incubated for 30 min in 0.3% Triton X-100 and subsequently fixed using 1% foetal bovine serum. The primary antibodies are applied and incubated overnight at 4 °C, at a dilution ratio of 1:100. Afterward, the sections are treated with the corresponding secondary antibodies at room temperature. Furthermore, a 4′,6-diamidino-2-phenylindole (DAPI) staining solution is introduced, which is followed by a PBS wash, sealing with glycerol, and examination under a fluorescence microscope for image acquisition (Zhang et al. 2019a). The antibodies utilized in this study include anti-tyrosine hydroxylase (TH, 1:200, Proteintech 66,334–1-Ig, China), anti–Iba1 (1:200, Proteintech, 26,177-1-AP, China).

Western blotting

After euthanizing the mice, the striatum was carefully dissected for protein extraction. Each sample underwent electrophoresis, with proteins transferred onto a polyvinylidene fluoride (PVDF) membrane (Millipore, Burlington, MA, USA; #IPVH00010). The membrane was blocked in a buffer solution containing 50 g/L skim milk (pH 8.0), 10 mmol/L Tris–HCl, 150 mmol/L NaCl, and 0.2% Tween-20 (TBST) for 1 h. Various primary antibodies were then applied and incubated overnight at 4 °C. The following day, the membrane was washed three times with TBST (each wash lasting 10 min) and subsequently exposed to secondary antibodies at room temperature for 2 h. Thereafter, the membrane was washed three times with TBST (each wash lasting 10 min) before the application of an enhanced chemiluminescence reagent (Beyotime; #P0018AM) for band visualization on X-ray film. Densitometry analysis of each target protein band was conducted using the Fusion-FX system (Vilber Bio Imaging, Paris, France, www.Vilber.com) and normalized against density of the β-actin band in the corresponding sample (Li et al. 2021). The antibodies used in the experiment included: anti-IL10 (1:1000, Proteintech, 60,269-1-Ig, China), anti–IL1β (1:1000, Proteintech, 26,048-1-AP, China), TGFβ(1:2500, Proteintech, 21,898-1-AP, China), iNOS(1:1000, Proteintech, 18,985-1-AP, China), PI3K(1:300, Proteintech, 20,584-1-AP, China), p-PI3K(1:1000, CST, #4228, USA), AKT(1:1000, Proteintech, 10,176-2-AP, China), p-AKT(1:1000, Proteintech, 66,444-1-Ig, China), GSK-3β(1:1000, AbSmart, YHH9963S, China), p-GSK-3β(1:1000, AbSmart, T40070, China), Bcl2(1:1000, AbSmart, T40056S, China), Bax(1:1000, AbSmart, T40051S, China), Caspase9(1:1000, Proteintech, 10,380-1-AP, China).

Network pharmacology

Obtaining potential targets of quercetin and Parkinson’s disease

The chemical structure and Canonical SMILES of quercetin were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/). This data were subsequently uploaded to the PharmMapper server (https://www.lilab-ecust.cn/pharmmapper/) and Swiss Target Prediction platform (http://www.swisstargetprediction.ch/) to identify targets associated with quercetin. Potential PD targets were identified by utilizing the term “Parkinson’s disease” in the Genetic Association Database (https://www.genecards.org/). The overlap between quercetin and PD targets was then ascertained through analysis using Venny software (https://bioinfogp.cnb.csic.es/tools/venny/).

Network construction

Protein–protein interactions were examined utilizing the STRING database (https://string-db.org/). Cytoscape software (version 3.9.1) was used to generate visual representations of these interactions and to perform comprehensive topology analysis on the network.

Bioinformatic analysis

Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analyses were conducted on an online bioinformatics platform (https://www.genedenovo.com/) to highlight key signalling pathways and identify the biological processes (BP), cellular components (CC), and molecular functions (MF) associated with quercetin’s potential therapeutic targets.

Molecular docking

The core target protein structures (PI3K/AKT/GSK-3β) were retrieved from the PDB database (https:/www.rcsb.org/). The molecular structure of quercetin was obtained from the PubChem database. AutoDock software was utilised to pre-process and convert these structure files, analyse the protein binding sites, and identify the corresponding docking activity pockets. After importing the structure files of each core target protein and the quercetin into AutoDock, the coordinates of the docking site were established, and docking verification was carried out to assess the binding affinity between quercetin and each core target protein, with visualisation facilitated by PyMOL software.

Statistical analysis

All results represent three independent experiments. Data are presented as individual values with mean ± SEM and were statistically analysed using GraphPad Prism 9.5 software. The comparisons between groups were conducted using the independent sample t-test, and differences were deemed statistically significant at p < 0.05.

Results

Effects of quercetin on behaviour in MPTP-induced mice

To evaluate the effectiveness of the PD model and quercetin’s intervention on MPTP-treated mice, the Open-field test was conducted after 3 weeks of MPTP treatment. MPTP-treated mice exhibited a significantly reduced travel distance in 3 min compared to controls (Fig. 1a, p < 0.01). In contrast, the MPTP + quercetin group demonstrated a significant increase in travel distance compared to the MPTP group (p < 0.01). Figure 1e presents movement trajectories, illustrating normal motor function in the control and quercetin groups, while the MPTP group showed evident motor impairment with reduced travel distance. The MPTP + quercetin group displayed marked motor improvements over the MPTP group. The rotorod test assessed motor skills by measuring the duration mice remained on before falling. The MPTP group spent significantly less time on the rotorod compared to controls, whereas the MPTP + quercetin group stayed on significantly longer than the MPTP group (Fig. 1b, p < 0.01). The climbing test evaluated coordination, revealing that the MPTP group had increased turning and climbing times compared to controls, while the MPTP + quercetin group showed reduced times compared to the MPTP group (Fig. 1c–d, p < 0.01).

Fig. 1.

Fig. 1

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Quercetin improved MPTP-induced motor deficits in mice. a A bar graph of walking distance in the Open-field test. e the movement trajectory map in the Open-field test. b, c, and d Indicate the time on the rotorod, turning time, and total climbing time in the pole test, respectively. n = 8 per group. All results are representative of three independent experiments. Data expressed as individual values with mean ± SEM. **p < 0.01 vs. Con group, ##p < 0.01 vs. MPTP group

Quercetin provides neuroprotection in MPTP-induced mice by reducing dopaminergic neurotoxicity

We assessed striatal changes post-MPTP treatment and quercetin administration using HE and Nissl staining. The MPTP group showed expanded striatal tissue spaces, increased neuronal atrophy, nuclear hyperchromasia, and significant structural damage compared to controls. In contrast, the MPTP + quercetin group exhibited notably reduced neuronal damage (Fig. 2a). Nissl staining confirmed severe neuronal damage in the MPTP group, while quercetin provided significant neuroprotection (Fig. 2a, b). To further evaluate dopaminergic neuron loss, TH protein levels in the striatum were analysed via immunofluorescence staining. The results indicated a significant loss of TH-positive neurons in the MPTP group, whereas TH levels significantly increased with quercetin, demonstrating its capacity to counteract MPTP-induced TH loss and dopaminergic neurotoxicity in PD mice (Fig. 2c, d).

Fig. 2.

Fig. 2

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The effects of Quercetin on the brain tissue of mice with Parkinson’s disease. a HE staining and Nissl staining of the striatum, scale bar: 100 μm. b A bar graph of Nissl body statistics. c A bar graph showing the quantity of TH+ cells. n = 3 per group. d The immunofluorescence staining of TH protein in the striatum, scale bar: 100 μm. All results are representative of three independent experiments. Data expressed as individual values with mean ± SEM. **p < 0.01 vs. Con group, ##p < 0.01 vs. MPTP group

Therapeutic targets of quercetin in Parkinson’s disease treatment

Quercetin is a flavonoid found in plants. We identified 106 potential targets using the Swiss Target Prediction and PharmMapper databases (Fig. 3b). GeneCards identified 3624 Parkinson’s disease-related targets (Fig. 3a). A Venn diagram revealed 57 common targets between quercetin and Parkinson’s disease (Fig. 3c, d). Cytoscape analysis highlighted 10 core targets (Fig. 3e). KEGG enrichment analysis, combined with STRING database input, formed a PPI network, suggesting quercetin might treat Parkinson’s through pathways like Proteoglycans in cancer, PI3K-Akt signalling, MAPK signalling, Oestrogen signalling, and Prolactin signalling (Fig. 3f, g). GO analysis categorized these targets into biological processes, cellular components, and molecular functions, linked to metabolic regulation, cellular activities, binding, and anatomical entities (Fig. 3h).

Fig. 3.

Fig. 3

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Network pharmacology analysis of quercetin. a and b The potential targets of PD and Quercetin. c A Venn diagram showing the active components of Quercetin and Parkinson’s disease targets. d Construction of the PPI network of Quercetin for Parkinson’s disease. e Cytoscape analysis highlighted 10 core targets. f, g KEGG pathway analysis. h GO functional analysis

Quercetin is capable of inhibiting the neuroinflammatory response induced by MPTP

Neuroinflammation plays a crucial role in MPTP-induced PD, with microglia being key contributors (Alarcón et al. 2023). We used immunofluorescence to measure allograft inflammatory factor 1 (Iba-1), a marker of activated microglia, and observed a significant increase in the brain tissue of MPTP-treated mice, which quercetin effectively suppressed (Fig. 4a, b). Western blotting demonstrated that anti-inflammatory factors IL-10 and TGF-β were reduced in the MPTP group but increased with quercetin treatment. Conversely, MPTP elevated pro-inflammatory factors IL-1β and iNOS, but quercetin significantly lowered their levels (Fig. 4c, d). These findings suggest that microglia-mediated neuroinflammation is crucial in MPTP-induced PD, and quercetin can effectively inhibit this process.

Fig. 4.

Fig. 4

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Quercetin inhibits MPTP-induced neuroinflammation in mice. a The immunofluorescence staining of Iba-1 protein in the striatum, scale bar: 100 μm. b A bar graph showing the quantity of Iba-1+ cells. c relative protein expression of IL-10, TGF-β, IL-1β and iNOS. d A bar graph of the statistical results from the Western blotting. n = 6 per group. All results are representative of three independent experiments. Data expressed as individual values with mean ± SEM. *p < 0.05, **p < 0.01 vs. Con group, #p < 0.05, ##p < 0.01 vs. MPTP group

Quercetin enhances the activation of the PI3K/AKT/GSK-3β signalling pathway and suppresses apoptosis

Based on previous experimental results, we identified ESR1, AKT1, HSP90AA1, and GSK-3β as the core targets of quercetin in PD (Fig. 3e). The PI3K/Akt pathway is known to be involved in PD-related neuroinflammation (Wang et al. 2024c), and although GSK-3β, as an important substrate of PI3K/Akt, is significant in neuroinflammation, its role in PD remains unclear (Zhang et al. 2022). We investigated the effects of quercetin on the PI3K/Akt/GSK-3β signalling pathway in the striatum of MPTP-induced PD mice. Western blotting results showed that quercetin restored the damage to the PI3K, AKT, and GSK-3β signalling pathways caused by MPTP (Fig. 5a–d). Additionally, we further validated the effect of quercetin on MPTP-induced apoptosis. As shown in Fig. 5e–H, the expression of the anti-apoptotic protein Bcl-2 decreased, while the expression of the pro-apoptotic proteins Bax and Caspase-9 increased in the striatum of MPTP-induced PD mice. However, quercetin was able to reverse this trend.

Fig. 5.

Fig. 5

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Expression of PI3K/AKT/GSK-3β pathway proteins. a Expression of PI3K, AKT, GSK-3β, p-PI3K, p-Akt and p-GSK-3β proteins. b–d Relative protein expression of p-PI3K, p-Akt and p-GSK-3β of PI3K, AKT and GSK-3β. e expression of Bcl-2, Bax and Caspase9 proteins. f–H Relative protein expression of Bcl-2, Bax and Caspase9. n = 6 per group. All results are representative of three independent experiments. Data expressed as individual values with mean ± SEM. *p < 0.05, **p < 0.01 vs. Con group, #p < 0.05, ##p < 0.01 vs. MPTP group

Molecular docking

A general binding energy of less than 0 kcal/mol indicates that the ligand and acceptor can bind spontaneously. The binding energy of quercetin-PI3K (Fig. 6a), quercetin-AKT1 (Fig. 6b) and quercetin-GSK3β (Fig. 6c) was −6.44 kcal/mol, −5.32 kcal/mol, and −5.24 kcal/mol, respectively, all of which indicated good affinity, high conformational stability, and low interaction energy of the complexes formed, as shown in Fig. 6 and Table 1.

Fig. 6.

Fig. 6

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Combination of Quercetin and protein targets. Molecular docking results of Quercetin with the corresponding target proteins: a The binding of Quercetin-PI3K; b The binding of Quercetin-AKT1; c The binding of Quercetin-GSK3β

Table 1.

The docking score of quercetin

Receptor Ligand Docking score (kcal/mol)
PI3K Quercetin −6.44
AKT1 Quercetin −5.32
GSK-3β Quercetin −5.24
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Discussion

This study demonstrates that quercetin, a natural flavonoid, mitigates Parkinson’s disease pathology in MPTP-induced mice by modulating the PI3K/Akt/GSK-3β pathway, suppressing neuroinflammation, and reducing dopaminergic neuron loss. These findings underscore its potential as a multi-target therapeutic agent for neurodegenerative disorders.

Quercetin improved motor function in behavioural tests (open-field, rotarod, pole), preserved striatal TH+ neurons, and attenuated neuronal atrophy, consistent with flavonoid-mediated neuroprotection reported in PD models (Hong et al. 2022; Zhang et al. 2019b). Mechanistically, PI3K/Akt/GSK-3β pathway activation inhibited GSK-3β, reducing oxidative stress and apoptosis. Molecular docking confirmed quercetin’s strong binding affinity (−6.44 to −5.24 kcal/mol) to pathway components, supporting its role as a multi-target agent.

The compound suppressed microglial activation and pro-inflammatory cytokines (IL-1β, iNOS) while upregulating anti-inflammatory mediators (IL-10, TGF-β), reflecting its dual anti-inflammatory/antioxidant action. Apoptosis modulation (Bcl-2↑, Bax↓, Caspase-9↓) further highlighted its neuroprotective efficacy, aligning with findings in Alzheimer’s and PD models (Das et al. 2022; Jain et al. 2022; Wei et al. 2022).

Network pharmacology and molecular docking identified PI3K/Akt as central targets. Pathway activation reduced tau hyperphosphorylation and mitochondrial apoptosis (Liu et al. 2024b), mirroring effects of quercetin in PD models. Quercetin’s inhibition of IL-1β and TNF-α, coupled with its upregulation of IL-10 and TGF-β, mirrors the PI3K/Akt-driven neuroinflammation reduction seen in previous flavonoid studies (Guo et al. 2019; Li et al. 2023a). Previous studies have emphasised that quercetin has good blood–brain barrier permeability, which is a key advantage in treating central nervous system diseases (Shimazu et al. 2021).

Limitations include the MPTP model’s partial recapitulation of human PD pathology and the absence of knock-out models to confirm pathway exclusivity. Future studies should explore α-synuclein transgenic models, broader mechanistic targets, and pharmacokinetic optimisation via nanoformulations.

Conclusion

Quercetin alleviates PD pathology through PI3K/Akt/GSK-3β activation, neuroinflammation suppression, and apoptosis inhibition, positioning it as a promising multi-target therapeutic. These findings advance flavonoid-based strategies for neurodegenerative disease treatment.

Author contributions

Conceptualization, CHANG Wei, XUE Junhui; animal-related experiments, ZHAO Gang and TIAN Yiyuan; network pharmacology, LI Yajuan and CHANG Wei; molecular docking, LI Yajuan and ZHAO JingYu; formal analysis, LI Yajuan and LIU FengZhou; writing—original draft preparation, CHANG Wei and MAN Minghao; writing—review and editing, CHANG Wei and MAN Songya Huang. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the National Natural Science Foundation of China [82100310] and the Shaanxi Provincial Key R & D Plan General Project [2024SF-YBXM-044].

Data availability

The datasets used and/or analyzed in the current study are available from the corresponding authors on reasonable request.

Declarations

Conflict of interest

All authors have no conflicts of interest to declare.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yajuan Li and Minghao Man contributed equally to this work and should be considered co-first-authors.

Contributor Information

Junhui Xue, Email: xuejunhui@fmmu.edu.cn.

Wei Chang, Email: Changwei1003@fmmu.edu.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed in the current study are available from the corresponding authors on reasonable request.

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