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Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway

Acta Pharmacologica Sinica volume 44, pages 1135–1148 (2023)Cite this article

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy bodies (LB) in the substantia nigra (SN). Evidence shows that microglia-mediated neuroinflammation plays a key role in PD pathogenesis. Using TNF-α as an indicator for microglial activation, we established a cellular model to screen compounds that could inhibit neuroinflammation. From 2471 compounds in a small molecular compound library composed of FDA-approved drugs, we found 77 candidates with a significant anti-inflammatory effect. In this study, we further characterized pazopanib, a pan-VEGF receptor tyrosine kinase inhibitor (that was approved by the FDA for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma). We showed that pretreatment with pazopanib (1, 5, 10 μM) dose-dependently suppressed LPS-induced BV2 cell activation evidenced by inhibiting the transcription of proinflammatory factors iNOS, COX2, Il-1β, and Il-6 through the MEK4-JNK-AP-1 pathway. The conditioned medium from LPS-treated microglia caused mouse DA neuronal MES23.5 cell damage, which was greatly attenuated by pretreatment of the microglia with pazopanib. We established an LPS-stimulated mouse model by stereotactic injection of LPS into mouse substantia nigra. Administration of pazopanib (10 mg·kg-1·d-1, i.p., for 10 days) exerted significant anti-inflammatory and neuronal protective effects, and improved motor abilities impaired by LPS in the mice. Together, we discover a promising candidate compound for anti-neuroinflammation and provide a potential repositioning of pazopanib in the treatment of PD.

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Fig. 1: Anti-neuroinflammatory small molecule compound screening and validation.
Fig. 2: Pazopanib inhibits LPS-induced activation of BV2 cells
Fig. 3: Pazopanib inhibits the transcription of proinflammatory factors.
Fig. 4: The anti-inflammatory effect of pazopanib is independent of the NF-κB pathway.
Fig. 5: Pazopanib alleviates LPS-induced inflammation through the AP-1 pathway.
Fig. 6: Pazopanib suppressed microglia-mediated MES23.5 cell death.
Fig. 7: Pazopanib inhibits in vivo neuroinflammation and protects dopaminergic neurons.
Fig. 8: Pazopanib alleviates LPS-induced inflammation through the MEK4-JNK-AP-1 pathway.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 32271039, 32070970, and 31970966), the Joint Program RFBR-BRICS (No. 17-54-80006) and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Hong-yang Sun, Jin Wu, Rui Wang, Shun Zhang, Hao Xu, Hai-gang Ren & Guang-hui Wang

  2. Institute of Cytology of Russian Academy of Sciences, Saint-Petersburg, 194064, Russia

    Еlena Kaznacheyeva

  3. Department of Neurosurgery, the First People’s Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, 215400, China

    Xiao-jun Lu

  4. Center of Translational Medicine, the First People’s Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, 215400, China

    Guang-hui Wang

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  1. Hong-yang Sun
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Contributions

HYS and GHW designed the study. HYS performed most of the experiments. JW, RW, SZ, and HX performed some of the biochemical and cellular experiments. XJL, HGR, and EK analyzed the data. HYS drafted the manuscript, and GHW revised the manuscript. All authors read and approved the manuscript.

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Correspondence to Guang-hui Wang.

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Sun, Hy., Wu, J., Wang, R. et al. Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway. Acta Pharmacol Sin 44, 1135–1148 (2023). https://doi.org/10.1038/s41401-022-01030-1

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Keywords

  • Parkinson’s disease
  • neuroinflammation
  • pazopanib
  • MEK4-JNK-AP-1 pathway
  • drug repositioning

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