Method Article

Synergistic Neuroprotective Effects of Traditional Chinese Medicine and Levodopa in Parkinson's Disease: A Behavioral and Pharmacokinetic Study

DOI:

10.3791/69260

⸱

October 17th, 2025

 , 
1Department Four of Brain Disease, Xi'an TCM Hospital of Encephalopathy, 2Department Two of Internal Medicine, Xi'an TCM Hospital of Encephalopathy

In This Article

Summary

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This pre-clinical study demonstrates that ZXFD and Levodopa safely and effectively improve motor skills and cognitive function in animal models of Parkinson's disease. Clinical research is necessary to confirm these findings and explore the potential of this therapy to alleviate symptoms and enhance life quality.

Abstract

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Parkinson's disease (PD) is a complex neurological disorder that causes debilitating motor symptoms such as tremors, rigidity, and bradykinesia. TCM formulations, such as Zhengan Xifeng Decoction (ZXFD) in combination with Western medicine (Levodopa), are being examined for Parkinson's disease treatment. However, the absence of reliable and interpretable experimental models has hampered mechanism elucidation. This study evaluated the neuroprotective effects of ZXFD in a rat model of PD, assessing its efficacy and safety when combined with Western medicine (WM). 240 mice with MPTP-induced PD-like symptoms were separated into two groups: the intervention group (IG, n = 120) got ZXFD + levodopa, and the control group (CG, n = 120) received only levodopa. Rotarod, open field, raised maze, Morris water maze, and tail suspension tests assessed motor function and cognitive performance after 12 weeks of therapy. Secondary outcome variables included ZXFD-Levodopa pharmacokinetic interactions and adverse event characteristics. Both treatment methods increase mouse motor function and cognitive functioning, as seen by improved scores on all behavioral tests. However, the ZXFD+ Levodopa group improved more significantly. Rotarod, Open Field, Morris water maze, and tail suspension scores improved significantly. We found significant ZXFD-Levodopa pharmacokinetic interactions in both groups. In the CG, Cmax was 150.9 ± 35.6 ng/mL, Tmax was 1.8 ± 0.5 h, AUC0-∞ was 654.2 ± 153.9 ng.h/mL, clearance was 23.4 ± 5.6 L/h, and half-life was 4.2 ± 1.0 h. In contrast, the IG showed a Cmax of 421.9 ± 93.5 ng/mL, Tmax of 3.2 ± 1.1 h, AUC0-∞ of 2431.9 ± 561.2 ng.h/mL, and clearance of 10.3 L/h, with reduced adverse events and mortality. According to this study, ZXFD + Levodopa could be a safe and effective treatment for Parkinson's disease-like symptoms. These findings indicate that this combined therapy strategy requires more clinical investigation to prove its efficacy and safety.

Introduction

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Parkinson's disease (PD) represents a complex and multifactorial neurodegenerative disorder that impacts millions of individuals globally, exhibiting a prevalence of approximately 1% among those over the age of 601,2. This disorder is characterized by the progressive loss of dopamine-producing neurons in the substantia nigra, a region of the brain that plays a critical role in motor control3. The degeneration of these neurons results in a deficiency of dopamine, a neurotransmitter that regulates movement, motivation, and reward processing4. The motor symptoms of PD, such as tremors, rigidity, bradykinesia, and postural instability, are well-established and have undergone extensive study. Non-motor symptoms, including cognitive impairment, depression, anxiety, and sleep disturbances, frequently occur in patients with Parkinson's disease and significantly affect their quality of life5,6.

Current treatments for PD primarily emphasize dopamine replacement therapy (DRT) and deep brain stimulation (DBS). DRT involves administering levodopa, a precursor to dopamine, to provide symptomatic relief and improve motor function in patients with PD7,8,9. Long-term treatment with levodopa results in the development of motor fluctuations, dyskinesias, and potential neurotoxicity10,11,12. Deep brain stimulation (DBS) involves the implantation of an electrode in the brain and provides significant improvements in motor function and quality of life for patients with PD13. DBS represents a highly invasive procedure that carries significant risks and complications14,15.

Western medicine, including DRT and DBS, serves as the primary approach to PD treatment, while traditional Chinese medicine (TCM) gains recognition as a complementary therapy16,17. Traditional Chinese Medicine (TCM) has been increasingly recognized as a viable adjunctive therapy for Parkinson's disease (PD), with evidence suggesting its potential efficacy in modulating disease progression and mitigating adverse effects associated with dopaminergic therapy. A systematic review and meta-analysis conducted by Zhang et al (2015)18 demonstrated that TCM adjuvant therapy was generally safe and well-tolerated in patients with idiopathic PD, yielding significant improvements in motor function and symptom management. Furthermore, Pan et al (2013)19 reported that TCM intervention resulted in notable enhancements in sleep quality, as well as improvements in detrended fluctuation analysis (DFA) parameters, indicative of enhanced autonomic nervous system function. These findings underscore the potential benefits of integrating TCM into the therapeutic regimen for PD patients, particularly in ameliorating motor and non-motor symptoms. Zhengan Xifeng Decoction (ZXFD), a traditional Chinese medicine formula, serves to address symptoms resembling Parkinson's disease, such as tremors, rigidity, and bradykinesia20,21. ZXFD comprises multiple herbs, including Panax ginseng, Scutellaria baicalensis, and Astragalus membranaceus. TCM herbs, such as those found in ZXFD, demonstrate neuroprotective effects, which include anti-inflammatory, antioxidant, and anti-apoptotic properties. Panax ginseng, a crucial element of ZXFD, modulates dopamine levels and enhances motor function in animal models of PD22,23,24. Furthermore, the combination of TCM with Levodopa may yield enhanced effects, enhance efficacy, and reduce the side effects associated with conventional treatments. The efficacy and safety of ZXFD in combination with Levodopa for the treatment of PD remain unclear. This observational study examines the therapeutic efficacy and safety profile of the combined treatment regimen of ZXFD and Levodopa in a murine model of PD, aiming to evaluate the potential enhanced effects of this dual therapy.

The study's use of a murine model of Parkinson's disease ensures that the findings are relevant to the disease's pathophysiology. The results may be applicable to other animal models, providing a foundation for further research and potentially informing our understanding of ZXFD's mechanisms of action. The study's findings have significant implications for clinical practice. If ZXFD is found to be effective in combination with Levodopa, it could lead to a new treatment strategy for Parkinson's disease patients. This integrative approach could enhance efficacy, reduce side effects, and improve quality of life for patients. The results may also inform the design of future clinical trials, paving the way for ZXFD's potential use in clinical practice and offering new hope for patients with Parkinson's disease.

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Protocol

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​All animal procedures were conducted in accordance with institutional guidelines and approved by the Animal Care and Use Committee of the Institutional Animal Care and Use Committee (2024-154) of Xi'an Hospital of Traditional Chinese Medicine Encephalopathy. The study adhered to established ethical principles for animal research.

1. Mice model

  1. Acquire male C57BL/6 mice aged 8-10 weeks from a certified laboratory animal vendor. House the mice in a temperature-controlled environment set at 22 ± 2 °C. Maintain a 12 h light-dark cycle and ensure they have ad libitum access to food and water.

2. Inducing Parkinson's disease model

  1. Administer 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)25,26 to the mice to induce the Parkinson's disease model. Administer MPTP dissolved in saline intraperitoneally at a dose of 30 mg/kg/day for 5 consecutive days. Administer an equal volume of saline to the control group.

3. Preparation of the Zhengan Xifeng Decoction (ZXFD)

NOTE: FD is a traditional Chinese medicine formula that includes various herbs like Panax ginseng, Scutellaria baicalensis, and Astragalus membranaceus27. The herbs were obtained from Beijing Tongrentang, and a qualified herbalist authenticated them.

  1. Prepare the ZXFD using a standardized extraction process. Conduct a hydro-extraction of 100 g of the dried herbal mixture by soaking it in deionized water at a ratio of 1:10 (w/v) for 1 h at room temperature, ensuring the temperature remains between 20-25 °C. Decoct the mixture twice, with each decoction lasting for 30 min, utilizing a heat-controlled extractor set at 100 °C.
  2. Combine the resulting decoctions, filter them, and concentrate the mixture to a final volume of 50 mL using a rotary evaporator set at 50 °C and 50 rpm.
  3. Centrifuge the concentrated decoction at 1000 x g for 20 min at 4 °C to eliminate any precipitates. Collect the supernatant and utilize it as the ZXFD decoction.

4. Preparation of Western Medicine (WM)

NOTE: Utilize levodopa, a dopamine precursor commonly used in the treatment of Parkinson's disease.

  1. Dissolve levodopa in distilled water to prepare a solution with a concentration of 10 mg/mL.

5. Individual treatment with ZXFD and WM

  1. Have one group of mice receive ZXFD treatment, while another group receives WM treatment. This experimental design allows for the evaluation of the individual effects of each treatment on Parkinson's disease-like symptoms in mice.

6. Treatment groups

  1. Divide the mice into two treatment groups: the Control group (CG), which receives WM (levodopa) only, and the Intervention group (IG), which receives a combination of ZXFD and WM (levodopa).
  2. Follow the treatment schedule, which consists of two distinct phases:
    1. Administer MPTP at a dosage of 30 mg/kg/day via intraperitoneal injection from days 1 to 7.
    2. Administer MPTP, and then provide ZXFD (200 mg/kg/day, oral gavage) and WM (levodopa, 20 mg/kg/day, oral gavage) from days 8 to 84 in the IG and CG, respectively28. Perform oral gavage using a sterile gavage needle or tube. Carefully insert the tube or the gavage needle into the stomach through the esophagus by trained personnel to minimize stress and potential complications. During the procedure, gently restrain the mice, and advance the gavage needle slowly and carefully to avoid trauma to the esophagus or trachea.
      ​NOTE: To minimize complications, precautions included proper training of personnel, use of sterile equipment, gentle restraint of animals, and close monitoring for signs of distress, such as labored breathing, lethargy, or loss of appetite. Over the course of 70+ consecutive days of administration, no significant complications were observed, and the procedure was well-tolerated by the mice.
    3. Validate the Parkinson's disease (PD) model by performing immunohistochemical staining for tyrosine hydroxylase (TH)29, a marker of dopamine neurons, in the substantia nigra of MPTP-administered mice.

7. Primary and secondary outcomes

  1. Implement a comprehensive behavioral assessment protocol to evaluate the motor function and cognitive performance of the mice as primary outcomes.
    1. Rotarod test
      NOTE: Include the rotarod test30, which assesses motor coordination and balance, essential aspects of motor function frequently compromised in PD. Integrate sensory, motor, and cognitive processes to maintain balance and coordination on the rotating rod during the test.
      1. Conduct the rotarod test using a Rotarod apparatus featuring a rod diameter of 3 cm and a length of 30 cm. Set the rotarod speed to accelerate from 4 to 40 rpm within 5 min.
      2. Place the mouse on the rotarod apparatus and measure the time it stays on the rod. Repeat this procedure three times each day for three consecutive days, ensuring a 30min interval between trials. Record the latency to fall in seconds during each trial. This will provide a measure of the mouse's motor coordination and balance.
    2. Open field test
      ​NOTE: Assess locomotor activity and exploratory behavior in the open field test31, as these are essential components of motor function often affected in PD. Evaluate spontaneous motor activity, exploratory behavior, and habituation to a novel environment with this test.
      1. Conduct the open field test in an arena measuring 40 cm × 40 cm × 30 cm. Ensure the floor and walls are made of white Plexiglas, and illuminate the space with a 60W light bulb placed 1.5 m above the center of the arena.
      2. Place the mouse in the center of the open field arena and allow it to explore for 5 min. Utilize a video tracking system to record the total distance traveled, time spent in the center, and time spent in the periphery. This will provide measures of locomotor activity and exploratory behavior.
    3. Elevated plus maze test
      ​NOTE: Evaluate anxiety-like behaviors using the elevated plus maze test32, a common non-motor symptom of Parkinson's disease. Measure anxiety-like behavior by observing the natural aversion of mice to open spaces and their tendency to avoid the open arms of the elevated plus maze.
      1. Conduct the elevated plus maze test on an apparatus with two open arms (30 cm × 5 cm) and two closed arms (30 cm × 5 cm × 15 cm), elevated 50 cm above the floor. Illuminate the maze with a 60W light bulb positioned 1.5 m above the center of the maze.
      2. Perform the test by placing the mouse in the center of the elevated plus maze, facing an open arm, and allowing it to explore for 5 min. During this time, ensure a video tracking system records the time spent in the open arms, closed arms, and center zone, providing a measure of anxiety-like behavior.
    4. Cognitive and motor function assessments
      1. Assess spatial learning and memory: Conduct the Morris water maze test33 to evaluate spatial learning and memory in mice with Parkinson's disease (PD). Use spatial cues to allow mice to navigate and locate the hidden platform within the water-filled maze.
      2. Evaluate antidepressant-like behavior and motor function: Perform the tail suspension test34 to evaluate antidepressant-like behavior and motor function. Measure the immobility time in this test as an indicator of antidepressant-like activity. Evaluate motor function by assessing the mouse's ability to move and struggle when suspended by its tail.
      3. Pharmacokinetic analysis and adverse event assessment: Conduct pharmacokinetic analysis. Assess the following adverse events: lethargy, loss of appetite, Diarrhea, vomiting, seizures, and mortality .

8. Pharmacokinetic analysis

  1. Conduct the pharmacokinetic analysis as follows:
    1. Administer orally a single dose of ZXFD (200 mg/kg, p.o.) and Levodopa (50 mg/kg, p.o.) to the mice.
    2. Measure plasma concentrations of active compounds using HPLC35with the following conditions: C18 column (150 mm x 4.6 mm, 5 µm) at 30 °C, Mobile phase: 0.1% formic acid in water and acetonitrile, gradient elution, Flow rate: 1.0 mL/min, Detection wavelength: 280 nm.
    3. Inject 20 µL of plasma samples and analyze chromatograms using suitable software.
    4. Calculate peak areas and determine the plasma concentrations using a calibration curve.

9. Conduct statistical analysis

  1. Assess normality of data
    1. Utilize SPSS 26.036 or GraphPad Prism 8.037 to perform the Shapiro-Wilk test to determine if the data follow a normal distribution.
    2. Create normal Q-Q plots38,39to visually assess normality.
  2. Present normally distributed data as mean ± standard error (SEM).
  3. Perform comparisons: For two groups, use Student's unpaired two-tailed t-test40,41. For multiple groups, use: One-way ANOVA or two-way ANOVA followed by Tukey's post-hoc test (for normally distributed data) and Kruskal-Wallis H test with Bonferroni correction (for non-normally distributed data)42,43.
  4. Determine significance based on the obtained p-value with statistical significance at p < 0.0544.

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Results

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This study investigates the therapeutic efficacy of ZXFD in combination with Levodopa (WM) in a murine model of PD. A total of 240 mice exhibiting MPTP-induced PD-like symptoms were enrolled and randomly assigned to either the intervention group (IG, n = 120), which received ZXFD + Levodopa, or the control group (CG, n = 120), which received WM alone, as illustrated in Figure 1. Through Immunohistochemical Staining for Tyrosine Hydroxylase, it was found that ...

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Discussion

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Zhengan Xifeng Decoction serves as a TCM formula utilized in the treatment of PD and various neurodegenerative disorders. The formula comprises a combination of herbs, including ginseng, ginkgo biloba, and astragalus membranaceus, which are believed to work synergistically to alleviate PD symptoms45,46. The ZXFD+ Levodopa combination therapy effectively reduces PD symptoms through several mechanisms. These actions encompass halting cell death and promoting neurog...

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Disclosures

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The authors declare that they have no competing financial interests or conflicts of interest related to this work.

Acknowledgements

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We would like to acknowledge the contributions of WN and LL, who conceptualized and designed the study. WN and LL were also responsible for analyzing the data, developing the methodology, and conducting the investigation. LL drafted the manuscript, while WN and LL collected the data, assisted in data analysis, and critically revised the manuscript.

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
EvaporatorShanghai Linbel Instrument Co., LtdLB-EL-01
High-performance liquid chromatography (HPLC)Shimadzu, Kyoto, JapanLC-20AT
LevodopaXi'an Tian Guangyuan Biotech Co., Ltd (China)TY-001
MPTP, or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineSigma-Aldrich, Inc.,United StatesM-102
Shimadzu LC Solution softwareShimadzu, Kyoto, Japanhttps://www.sigmaaldrich.com/IN/en/product/sigma/m0896
Zhengan Xifeng Decoction (ZXFD)Kamwo / Meridian Pro FormulasSKU / MPF: MPF20131

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Parkinson s DiseaseTraditional Chinese MedicineLevodopa TherapyNeuroprotective EffectsZhengan Xifeng DecoctionBehavioral AssessmentPharmacokinetic InteractionMotor Function TestCognitive PerformanceMPTP Rat Model

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