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18β-glycyrrhetinic acid ameliorates MPTP-induced neurotoxicity in mice through activation of microglial anti-inflammatory phenotype

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Abstract

Rationale

18β-glycyrrhetinic acid (18β-GA) has been reported to have anti-inflammatory and neuroprotective effects. However, the therapeutic effect of 18β-GA in Parkinson’s disease (PD) has not been defined.

Objective

The current study aimed to evaluate the potential therapeutic effects of 18β-GA in treating PD by mitigating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity.

Results

The study showed that 18β-GA has anti-inflammatory effects by upregulating TREM2 expression in BV2 cells, which correlates with the presence of NF-E2-related factor-2 (Nrf2). 18β-GA reduced inflammation in BV2 cells treated with 1-methyl-4- phenylpyridinium (MPP+) by enhancing TREM2 expression, which promotes an anti-inflammatory microglial phenotype. Repeated administration of 18β-GA in MPTP-treated mice led to therapeutic effects by enhancing TREM2 expression, resulting in the activation of anti-inflammatory microglia. Moreover, 18β-GA attenuated the decrease in brain-derived neurotrophic factor (BDNF) levels in both MPP+-induced BV2 cells and MPTP-intoxicated mice, indicating the involvement of BDNF in the beneficial effects of 18β-GA.

Conclusions

It is probable that activating microglial anti-inflammatory response through TREM2 expression might serve as a novel therapeutic strategy for PD. Additionally, 18β-GA seems to hold potential as a new therapeutic agent for PD.

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Funding

This work is supported by the National Science Foundation of China (82204786 to WY, 81973748, 82174278 to JC, 81973341 to QQ, and 82271563 to JZ), Huang Zhendong Research Fund for Traditional Chinese Medicine of **an University (201911 to JC), Natural Science Foundation of Guangdong Province of China (2022A1515012512 to JZ), and the Medical Joint Fund of **an University.

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Authors and Affiliations

  1. Guangzhou Key Laboratory of Formula-Pattern Research Center, School of Traditional Chinese Medicine, **an University, Guangzhou, 510632, China

    Hanyue Luo, Jia-xu Chen & Wei Yao

  2. Department of Physiology, School of Medicine, **an University, Guangzhou, 510632, China

    Hanyue Luo, Lujuan He, Zefang Lin & Ji-chun Zhang

  3. School of Pharmacy, **an University, Guangzhou, 510632, Guangdong, China

    Caishi Zhang

  4. MOE Key Laboratory of Tumor Molecular Biology, Department of Pharmacology, School of Pharmacy, **an University, Guangzhou, 510632, China

    Qi Qi

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  1. Hanyue Luo
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  2. Caishi Zhang
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  3. Lujuan He
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  4. Zefang Lin
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  5. Ji-chun Zhang
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  6. Qi Qi
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  7. Jia-xu Chen
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  8. Wei Yao
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Contributions

WY, JC, and QQ designed the research and wrote the manuscript. HYL performed the behavior test, qPCR assay, western blotting assay, immunofluorescence staining, and ELSA assay and analyzed the data. CSZ examined the levels of Nrf2 protein in the cytosol and nuclear fractions. LJH and ZFL assisted with the experiments and analyzed the data. JZ revised the manuscript. All authors reviewed the manuscript.

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Correspondence to Qi Qi, Jia-xu Chen or Wei Yao.

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Luo, H., Zhang, C., He, L. et al. 18β-glycyrrhetinic acid ameliorates MPTP-induced neurotoxicity in mice through activation of microglial anti-inflammatory phenotype. Psychopharmacology 240, 1947–1961 (2023). https://doi.org/10.1007/s00213-023-06415-6

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