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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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References

  1. Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Prim. 2021;7:47.

    Article  PubMed  Google Scholar 

  2. Collaborators GBDPsD. Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17:939–53.

    Article  Google Scholar 

  3. Lindqvist D, Hall S, Surova Y, Nielsen HM, Janelidze S, Brundin L, et al. Cerebrospinal fluid inflammatory markers in Parkinson’s disease-associations with depression, fatigue, and cognitive impairment. Brain Behav Immun. 2013;33:183–9.

    Article  CAS  PubMed  Google Scholar 

  4. Cheng J, Liao Y, Dong Y, Hu H, Yang N, Kong X, et al. Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice. Autophagy. 2020;16:2193–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mittal S, Bjornevik K, Im DS, Flierl A, Dong X, Locascio JJ, et al. beta2-Adrenoreceptor is a regulator of the alpha-synuclein gene driving risk of Parkinson’s disease. Science. 2017;357:891–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lemos M, Venezia S, Refolo V, Heras-Garvin A, Schmidhuber S, Giese A, et al. Targeting alpha-synuclein by PD03 AFFITOPE(R) and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance. Transl Neurodegener. 2020;9:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Suresh SN, Chavalmane AK, Dj V, Yarreiphang H, Rai S, Paul A, et al. A novel autophagy modulator 6-Bio ameliorates SNCA/alpha-synuclein toxicity. Autophagy. 2017;13:1221–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Issa AR, Sun J, Petitgas C, Mesquita A, Dulac A, Robin M, et al. The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA-induced Parkinson disease-like symptoms in the Drosophila brain. Autophagy. 2018;14:1898–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mor DE, Sohrabi S, Kaletsky R, Keyes W, Tartici A, Kalia V, et al. Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria. Proc Natl Acad Sci USA. 2020;117:26438–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hebron ML, Lonskaya I, Olopade P, Selby ST, Pagan F, Moussa CE. Tyrosine kinase inhibition regulates early systemic immune changes and modulates the neuroimmune response in alpha-synucleinopathy. J Clin Cell Immunol. 2014;5:259.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Olanow CW, Savolainen M, Chu Y, Halliday GM, Kordower JH. Temporal evolution of microglia and alpha-synuclein accumulation following foetal grafting in Parkinson’s disease. Brain. 2019;142:1690–700.

    Article  PubMed  Google Scholar 

  12. Garcia P, Jurgens-Wemheuer W, Uriarte Huarte O, Michelucci A, Masuch A, Brioschi S, et al. Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease. Glia. 2022;70:935–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McFarthing K, Rafaloff G, Baptista MAS, Wyse RK, Stott SRW. Parkinson’s disease drug therapies in the clinical trial pipeline: 2021 update. J Parkinsons Dis. 2021;11:891–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Badanjak K, Fixemer S, Smajic S, Skupin A, Grunewald A. The contribution of microglia to neuroinflammation in Parkinson’s disease. Int J Mol Sci. 2021;22:4647.

    Article  Google Scholar 

  15. Lempriere S. Age-related microglial activation accelerated in AD. Nat Rev Neurol. 2019;15:369.

    Article  PubMed  Google Scholar 

  16. Kim BW, Koppula S, Kumar H, Park JY, Kim IW, More SV, et al. alpha-Asarone attenuates microglia-mediated neuroinflammation by inhibiting NF kappa B activation and mitigates MPTP-induced behavioral deficits in a mouse model of Parkinson’s disease. Neuropharmacology. 2015;97:46–57.

    Article  CAS  PubMed  Google Scholar 

  17. More S, Choi DK. Neuroprotective role of Atractylenolide-I in an in vitro and in vivo model of Parkinson’s disease. Nutrients. 2017;9:451.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang GQ, Li DD, Huang C, Lu DS, Zhang C, Zhou SY, et al. Icariin reduces dopaminergic neuronal loss and microglia-mediated inflammation in vivo and in vitro. Front Mol Neurosci. 2017;10:441.

    Article  PubMed  Google Scholar 

  19. Chen H, Zhang SM, Hernan MA, Schwarzschild MA, Willett WC, Colditz GA, et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol. 2003;60:1059–64.

    Article  PubMed  Google Scholar 

  20. Gagne JJ, Power MC. Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology. 2010;74:995–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guo CH, Cao T, Zheng LT, Waddington JL, Zhen XC. Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson’s disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin. Acta Pharmacol Sin. 2020;41:499–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ren ZX, Zhao YF, Cao T, Zhen XC. Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson’s disease by suppressing glycogen synthase kinase-3 beta activity. Acta Pharmacol Sin. 2016;37:1315–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun J, Li H, Jin Y, Yu J, Mao S, Su KP, et al. Probiotic Clostridium butyricum ameliorated motor deficits in a mouse model of Parkinson’s disease via gut microbiota-GLP-1 pathway. Brain Behav Immun. 2021;91:703–15.

    Article  CAS  PubMed  Google Scholar 

  24. Hao Z, Liu L, Tao Z, Wang R, Ren H, Sun H, et al. Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR. Nat Commun. 2019;10:2906.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cao M, Chen F, Xie N, Cao MY, Chen P, Lou Q, et al. c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities. Cell Death Dis. 2018;9:1140.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Yu YX, Li YP, Gao F, Hu QS, Zhang Y, Chen D, et al. Vitamin K2 suppresses rotenone-induced microglial activation in vitro. Acta Pharmacol Sin. 2016;37:1178–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guo DK, Zhu Y, Sun HY, Xu XY, Zhang S, Hao ZB, et al. Pharmacological activation of REV-ERBalpha represses LPS-induced microglial activation through the NF-kappaB pathway. Acta Pharmacol Sin. 2019;40:26–34.

    Article  PubMed  Google Scholar 

  28. Han CJ, Zheng JY, Sun L, Yang HC, Cao ZQ, Zhang XH, et al. The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-kappaB pathway. Acta Pharmacol Sin. 2019;40:1292–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gu C, Hu Q, Wu J, Mu C, Ren H, Liu CF, et al. P7C3 inhibits LPS-induced microglial activation to protect dopaminergic neurons against inflammatory factor-induced cell death in vitro and in vivo. Front Cell Neurosci. 2018;12:400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fang J, She J, Lin F, Wu JC, Han R, Sheng R, et al. RRx-001 exerts neuroprotection against LPS-induced microglia activation and neuroinflammation through disturbing the TLR4 pathway. Front Pharmacol. 2022;13:889383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yan XL, Xu FY, Ji JJ, Song P, Pei YQ, He MJ, et al. Activation of UCP2 by anethole trithione suppresses neuroinflammation after intracerebral hemorrhage. Acta Pharmacol Sin. 2022;43:811–28.

    Article  CAS  PubMed  Google Scholar 

  32. Lee HG, Wheeler MA, Quintana FJ. Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov. 2022;21:339–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Limvorasak S, Posadas EM. Pazopanib: therapeutic developments. Expert Opin Pharmacother. 2009;10:3091–102.

    Article  CAS  PubMed  Google Scholar 

  35. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–10.

    Article  CAS  PubMed  Google Scholar 

  36. Backert S, Naumann M. What a disorder: proinflammatory signaling pathways induced by Helicobacter pylori. Trends Microbiol. 2010;18:479–86.

    Article  CAS  PubMed  Google Scholar 

  37. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9:798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nagamoto-Combs K, Combs CK. Microglial phenotype is regulated by activity of the transcription factor, NFAT (nuclear factor of activated T cells). J Neurosci. 2010;30:9641–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. O’Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13:453–60.

    Article  PubMed  Google Scholar 

  40. Dainichi T, Matsumoto R, Mostafa A, Kabashima K. Immune control by TRAF6-Mediated pathways of epithelial cells in the EIME (Epithelial Immune Microenvironment). Front Immunol. 2019;10:1107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Colonna M, Brioschi S. Neuroinflammation and neurodegeneration in human brain at single-cell resolution. Nat Rev Immunol. 2020;20:81–2.

    Article  CAS  PubMed  Google Scholar 

  42. Beers DR, Appel SH. Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies. Lancet Neurol. 2019;18:211–20.

    Article  CAS  PubMed  Google Scholar 

  43. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 2006;21:404–12.

    Article  CAS  PubMed  Google Scholar 

  44. Zhen XC, Chu HY. Emerging novel approaches to drug research and diagnosis of Parkinson’s disease. Acta Pharmacol Sin. 2020;41:439–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fletcher EJR, Kaminski T, Williams G, Duty S. Drug repurposing strategies of relevance for Parkinson’s disease. Pharm Res Perspect. 2021;9:e00841.

    Article  Google Scholar 

  46. Arbo BD, Schimith LE, Goulart Dos Santos M, Hort MA. Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation. Eur J Pharmacol. 2022;919:174800.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang G, Chen S, Jia J, Liu C, Wang W, Zhang H, et al. Development and evaluation of novel metformin derivative metformin threonate for brain Ischemia treatment. Front Pharmacol. 2022;13:879690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Janelidze S, Mattsson N, Stomrud E, Lindberg O, Palmqvist S, Zetterberg H, et al. CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurology. 2018;91:e867–e77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xu Z, Han K, Chen J, Wang C, Dong Y, Yu M, et al. Vascular endothelial growth factor is neuroprotective against ischemic brain injury by inhibiting scavenger receptor A expression on microglia. J Neurochem. 2017;142:700–9.

    Article  CAS  PubMed  Google Scholar 

  50. Lonskaya I, Hebron ML, Selby ST, Turner RS, Moussa CE. Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer’s disease models. Neuroscience. 2015;304:316–27.

    Article  CAS  PubMed  Google Scholar 

  51. Palomo V, Nozal V, Rojas-Prats E, Gil C, Martinez A. Protein kinase inhibitors for amyotrophic lateral sclerosis therapy. Br J Pharmacol. 2021;178:1316–35.

    Article  CAS  Google Scholar 

  52. Lee S, Kim S, Park YJ, Yun SP, Kwon SH, Kim D, et al. The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson’s disease mouse model. Hum Mol Genet. 2018;27:2344–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Imamura K, Izumi Y, Watanabe A, Tsukita K, Woltjen K, Yamamoto T, et al. The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci Transl Med. 2017;9:eaaf3962.

    Article  PubMed  Google Scholar 

  54. Lee HJ, Jeon SG, Kim J, Kang RJ, Kim SM, Han KM, et al. Ibrutinib modulates Abeta/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer’s disease. Aging Cell. 2021;20:e13332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kim J, Park JH, Park SK, Hoe HS. Sorafenib modulates the LPS- and abeta-induced neuroinflammatory response in cells, wild-type mice, and 5xFAD mice. Front Immunol. 2021;12:684344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Han KM, Kang RJ, Jeon H, Lee HJ, Lee JS, Park H, et al. Regorafenib regulates AD pathology, neuroinflammation, and dendritic spinogenesis in cells and a mouse model of AD. Cells. 2020;9:1655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Crespo O, Kang SC, Daneman R, Lindstrom TM, Ho PP, Sobel RA, et al. Tyrosine kinase inhibitors ameliorate autoimmune encephalomyelitis in a mouse model of multiple sclerosis. J Clin Immunol. 2011;31:1010–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Echeverria V, Burgess S, Gamble-George J, Zeitlin R, Lin X, Cao C, et al. Sorafenib inhibits nuclear factor kappa B, decreases inducible nitric oxide synthase and cyclooxygenase-2 expression, and restores working memory in APPswe mice. Neuroscience. 2009;162:1220–31.

    Article  CAS  PubMed  Google Scholar 

  59. Bowman GL, Dayon L, Kirkland R, Wojcik J, Peyratout G, Severin IC, et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimers Dement. 2018;14:1640–50.

    Article  PubMed  Google Scholar 

  60. Janelidze S, Lindqvist D, Francardo V, Hall S, Zetterberg H, Blennow K, et al. Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology. 2015;85:1834–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, et al. Microglial control of astrocytes in response to microbial metabolites. Nature. 2018;557:724–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wekerle H. Brain inflammatory cascade controlled by gut-derived molecules. Nature. 2018;557:642–3.

    Article  CAS  PubMed  Google Scholar 

  63. Cirac A, Tsaktanis T, Beyer T, Linnerbauer M, Andlauer T, Grummel V, et al. The Aryl hydrocarbon receptor-dependent TGF-alpha/VEGF-B ratio correlates with disease subtype and prognosis in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;8:e1043.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Waetzig V, Czeloth K, Hidding U, Mielke K, Kanzow M, Brecht S, et al. c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. Glia. 2005;50:235–46.

    Article  PubMed  Google Scholar 

  65. Liu Z, Yao X, Sun B, Jiang W, Liao C, Dai X, et al. Pretreatment with kaempferol attenuates microglia-mediate neuroinflammation by inhibiting MAPKs-NF-kappaB signaling pathway and pyroptosis after secondary spinal cord injury. Free Radic Biol Med. 2021;168:142–54.

    Article  CAS  PubMed  Google Scholar 

  66. Wu B, Zhang S, Guo Z, Bi Y, Zhou M, Li P, et al. The TGF-beta superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation. Immunity. 2021;54:308–23 e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang J, Liu Y, Zheng Y, Luo Y, Du Y, Zhao Y, et al. TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus. J Neuroinflammation. 2020;17:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Plastira I, Bernhart E, Joshi L, Koyani CN, Strohmaier H, Reicher H, et al. MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia. J Neuroinflammation. 2020;17:127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Caliz AD, Yoo HJ, Vertii A, Dolan AC, Tournier C, Davis RJ, et al. Mitogen kinase kinase (MKK7) controls cytokine production in vitro and in vivo in mice. Int J Mol Sci. 2021;22:9364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Preston SP, Doerflinger M, Scott HW, Allison CC, Horton M, Cooney J, et al. The role of MKK4 in T-cell development and immunity to viral infections. Immunol Cell Biol. 2021;99:428–35.

    Article  CAS  PubMed  Google Scholar 

  71. Yu T, Wang Z, Jie W, Fu X, Li B, Xu H, et al. The kinase inhibitor BX795 suppresses the inflammatory response via multiple kinases. Biochem Pharmacol. 2020;174:113797.

    Article  CAS  PubMed  Google Scholar 

  72. Wang MJ, Huang HY, Chen WF, Chang HF, Kuo JS. Glycogen synthase kinase-3beta inactivation inhibits tumor necrosis factor-alpha production in microglia by modulating nuclear factor kappaB and MLK3/JNK signaling cascades. J Neuroinflammation. 2010;7:99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lee N, Heo YJ, Choi SE, Jeon JY, Han SJ, Kim DJ, et al. Anti-inflammatory effects of empagliflozin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-kappaB, MKK7/JNK, and JAK2/STAT1 signalling pathways. J Immunol Res. 2021;2021:9944880.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Deibler KK, Mishra RK, Clutter MR, Antanasijevic A, Bergan R, Caffrey M, et al. A chemical probe strategy for interrogating inhibitor selectivity across the MEK kinase family. ACS Chem Biol. 2017;12:1245–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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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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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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