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

作　　者：Hong-yang Sun Jin Wu Rui Wang Shun Zhang Hao Xu Еlena Kaznacheyeva Xiao-jun Lu Hai-gang Ren Guang-hui Wang 

机构地区：[1]Laboratory of Molecular Neuropathology,Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China [2]Institute of Cytology of Russian Academy of Sciences,Saint-Petersburg 194064,Russia [3]Department of Neurosurgery,the First People’s Hospital of Taicang,Taicang Affiliated Hospital of Soochow University,Suzhou 215400,China [4]Center of Translational Medicine,the First People’s Hospital of Taicang,Taicang Affiliated Hospital of Soochow University,Suzhou 215400,China

出　　处：《Acta Pharmacologica Sinica》2023年第6期1135-1148,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.32271039,32070970,31970966);the Joint Program RFBR-BRICS(No.17-54-80006);a Project Funded by the Priority Academic Program Development of JiangsuHigherEducationInstitutions.

摘　　要：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-αas 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(1,5,10μM)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.

关 键 词：Parkinson’s disease NEUROINFLAMMATION PAZOPANIB MEK4-JNK-AP-1 pathway drug repositioning 

分 类 号：R285.5[医药卫生—中药学]