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Wuzi Yanzong Pill Plays A Neuroprotective Role in Parkinson’s Disease Mice via Regulating Unfolded Protein Response Mediated by Endoplasmic Reticulum Stress

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Abstract

Objective

To investigate the protective effects and its possible mechanism of Wuzi Yanzong Pill (WYP) on Parkinson’s disease (PD) model mice.

Methods

Thirty-six C57BL/6 male mice were randomly assigned to 3 groups including normal, PD, and PD+WYP groups, 12 mice in each group. One week of intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish the classical PD model in mice. Meanwhile, mice in the PD+WYP group were administrated with 16 g/kg WYP, twice daily by gavage. After 14 days of administration, gait test, open field test and pole test were measured to evaluate the movement function. Tyrosine hydroxylase (TH) neurons in substantia nigra of midbrain and binding immunoglobulin heavy chain protein (GRP78) in striatum and cortex were observed by immunohistochemistry. The levels of TH, GRP78, p-PERK, p-eIF2α, ATF4, p-IRE1α, XBP1, ATF6, CHOP, ASK1, p-JNK, Caspase-12, -9 and -3 in brain were detected by Western blot.

Results

Compared with the PD group, WYP treatment ameliorated gait balance ability in PD mice (P<0.05). Similarly, WYP increased the total distance and average speed (P<0.05 or P<0.01), reduced rest time and pole time (P<0.05). Moreover, WYP significantly increased TH positive cells (P<0.01). Immunofluorescence showed WYP attenuated the levels of GRP78 in striatum and cortex. Meanwhile, WYP treatment significantly decreased the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, p-IRE1 α, XBP1, CHOP, Caspase-12 and Caspase-9 (P<0.05 or P<0.01).

Conclusions

WYP ameliorated motor symptoms and pathological lesion of PD mice, which may be related to the regulation of unfolded protein response-mediated signaling pathway and inhibiting the endoplasmic reticulum stress-mediated neuronal apoptosis pathway.

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Abbreviations

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PI3K:

phosphatidylinositol 3 kinase

Akt:

protein kinase B

ER:

endoplasmic reticulum

PBS:

phosphate-buffered saline

BSA:

bovine serum albumin

RIPA:

radio-immunoprecipitation assay

PMSF:

phenylmethylsulfonyl fluoride

SDS-PAGE:

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

GRP78:

glucose-regulated protein 78

PERK:

proteinkinaseR-like ER kinase

p-PERK:

Phospho PKR like ER kinase

ATF4:

activating transcription factor4

eIF2α:

eukaryotic translation initiation factor 2α

p-eIF2α:

phospho eukaryotic translation initiationfactor 2α

IRE1 α:

inositol requiring enzyme1 α

p-IRE1 α:

phospho inositol requiring enzyme1 α

XBP1:

X-boxbinding protein1

ATF6:

activating transcription factor 6

CHOP:

CCAAT/enhancer-binding protein homologous protein

ASK1:

apoptosis signal regulating kinase 1

JNK:

C-Jun N terminal kinase

p-JNK:

phospho C-Jun Nterminal kinase

Caspase-12:

cysteinyl aspartate specific proteinase 12

Caspase-9:

cysteinyl aspartate specific proteinase 9

Caspase-3:

cysteinyl aspartate specific proteinase 3

ISR:

integrated stress response

ERAD:

ER-related degradation

TRAF2:

TNF receptor-associated factor 2.

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Authors and Affiliations

  1. The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong, Shanxi Province, 030619, China

    Yan-rong Li, Hui-jie Fan, Rui-rui Sun, Lu Jia, Li-yang Yang, Cun-gen Ma &  Zhi Chai

  2. Institute of Brain Science Department, Neurology of First Affiliated Hospital, Shanxi Datong University, Datong, Shanxi Province, 037009, China

    Hai-fei Zhang & Cun-gen Ma

  3. Department of Anatomy and Cell Biology, Department of Neurological Surgery, Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Xiao-ming Jin

  4. Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200025, China

    Bao-guo Xiao

Authors
  1. Yan-rong Li
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  2. Hui-jie Fan
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  4. Lu Jia
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Contributions

Li YR and Fan HJ contributed equally to this work. Li YR, Fan HJ, and Sun RR carried out the studies, participated in collecting data, and drafted the manuscript. Chai Z, Ma CG and Xiao BG performed the statistical analysis and participated in its design. Jin XM, Zhang HF, Yang LY and Jia L participated in acquisition, analysis, or interpretation of data. All authors read and approved the final version.

Corresponding author

Correspondence to Zhi Chai.

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The authors declare no conflict of interest.

Additional information

Supported by the National Natural Science Foundation of China (Nos. 81703978 and 81102552), the Special Fund for Science and Technology Innovation Team of Shanxi University of Chinese Medicine (No. 2022TD1013), the Natural Science Foundation of Shanxi Province (No. 201901D111334), the Returned Chinese Scholars Technology Activities Preferred Project, Shanxi Province of China (No. 20200026), the Research Project supported by Shanxi Scholarship Council of China (No. 2021-142), Shanxi University Science and Technology Innovation Project (No. 2019L0724), the Key Science and technology R&D project of Jinzhong (No.Y213004), and the Young Scientist Cultivation Program Project, Shanxi University of Chinese Medicine (No. 2021PY-QN-03)

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Li, Yr., Fan, Hj., Sun, Rr. et al. Wuzi Yanzong Pill Plays A Neuroprotective Role in Parkinson’s Disease Mice via Regulating Unfolded Protein Response Mediated by Endoplasmic Reticulum Stress. Chin. J. Integr. Med. 29, 19–27 (2023). https://doi.org/10.1007/s11655-022-3727-0

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