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Cannabinoid type 2 receptor activation inhibits MPP+-induced M1 differentiation of microglia through activating PI3K/Akt/Nrf2 signal pathway

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Abstract

Background

Growing evidence indicates that cannabinoid type 2 (CB2) receptor activation inhibits neuroinflammation in the pathogenesis of Parkinson’s disease (PD). Nonetheless, the precise mechanisms of CB2 receptor-mediated neuroprotection have not been fully elucidated. The differentiation of microglia from the M1 to M2 phenotype plays a vital role in neuroinflammation.

Methods

In the present study, we investigated the effect of CB2 receptor activation on the M1/M2 phenotypic transformation of microglia treated with 1-methyl-4-phenylpyridinium (MPP+). The M1 phenotype microglia markers, including inducible nitric oxide (iNOS), interleukin 6 (IL-6), and CD86, and the M2 phenotype microglia markers, including arginase-1 (Arg-1), IL-10, and CD206, were detected by western blots and flow cytometry. The levels of phosphoinositide-3-kinase (PI3K)/Akt and nuclear factor erythroid 2-related factor 2 (Nrf2) were determined by Western blots. Subsequent addition of Nrf2 inhibitors initially revealed the specific mechanism by which CB2 receptors affect phenotypic changes in microglia.

Results

Our results showed that pretreatment with JWH133 significantly inhibited the MPP+-induced up-regulation of M1 phenotype microglia markers. Meanwhile, JWH133 increased the levels of M2 phenotype microglia markers. JWH133-mediated effects were blocked by co-treatment with AM630. Mechanism studies found that MPP+ treatment downregulated PI3K, Akt phosphorylated proteins, and nuclear Nrf2 protein. JWH133 pretreatment promoted PI3K/Akt activation and facilitated nuclear translocation of Nrf2, which was reversed by the PI3K inhibitor. Further studies showed that Nrf2 inhibitors inverted the effect of JWH133 on microglia polarization.

Conclusion

The results indicate that CB2 receptor activation promotes MPP+-induced microglia transformation from M1 to M2 phenotype through PI3K/Akt/Nrf2 signaling pathway.

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Data availability

The present work did not create or analyze new data, so no data sharing was applicable.

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Funding

The authors gratefully acknowledge the financial supports by the Key Research and Development Program of Shandong Province (Grant No. 2019GSF108095).

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Authors and Affiliations

  1. Department of Physiology, School of Basic Medicine, Institute of Brain Science and Disorders, Qingdao University, Qingdao, 266071, China

    Mengya Wang, Man Liu & Zegang Ma

Authors
  1. Mengya Wang
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  2. Man Liu
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  3. Zegang Ma
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Contributions

All the authors mentioned above participated in this work. MW: methodology, formal analysis, investigation, writing: original draft. ML: methodology, formal analysis. ZM: writing: review & editing, funding acquisition, supervision.

Corresponding author

Correspondence to Zegang Ma.

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All authors claim that there are no conflicts of interest.

Ethics approval

All procedures were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals, and were approved by the Animal Ethics Committee of Qingdao University.

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Wang, M., Liu, M. & Ma, Z. Cannabinoid type 2 receptor activation inhibits MPP+-induced M1 differentiation of microglia through activating PI3K/Akt/Nrf2 signal pathway. Mol Biol Rep 50, 4423–4433 (2023). https://doi.org/10.1007/s11033-023-08395-4

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  • DOI: https://doi.org/10.1007/s11033-023-08395-4

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