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Impeding the combination of astrocytic ASCT2 and NLRP3 by talniflumate alleviates neuroinflammation in experimental models of Parkinson's disease

查看全文 作　　者：Yang [2]Liu;Ting [1]Liu;Yuanzhang [1]Zhou;Wenjie [1]Li;Min [3]Wang;Nanshan [1]Song;Wenbin [4]Zhang;Jingwei [5]Jiang;Shengtao [5]Yuan;Jianhua [1]Ding;Gang [1,2]Hu;Ming [1]Lu 高影响力作者 机构地区：[1]Jiangsu Key Laboratory of Neurodegeneration,Department of Pharmacology,Nanjing Medical University,Nanjing 211166,China;[2]Department of Pharmacology,School of Medicine and Holistic Integrative Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China;[3]Department of Geriatrics,Affiliated Brain Hospital of Nanjing Medical University,Nanjing 210029,China;[4]Department of Neurosurgery,Affiliated Brain Hospital of Nanjing Medical University,Nanjing 210029,China;[5]Jiangsu Key Laboratory of Drug Screening,China Pharmaceutical University,Nanjing 211198,China高影响力机构 出　　处：《Acta Pharmaceutica Sinica B》索引2023年第13卷第2期,共16页高影响力期刊 基　　金：the support of the Experiment Center for Science and Technology,Nanjing University of Chinese Medicine(Nanjing,China);supported by grants from the National Key R&D Program of China(No.2021ZD0202903);the National Natural Science Foundation of China(Nos.81922066,82173797,82003725,81991523,and 82003722)。 摘　　要：Alanine-serine-cysteine transporter 2(ASCT2)is reported to participate in the progression of tumors and metabolic diseases.It is also considered to play a crucial role in the glutamate-glutamine shuttle of neuroglial network.However,it remains unclear the involvement of ASCT2 in neurological diseases such as Parkinson’s disease(PD).In this study,we demonstrated that high expression of ASCT2 in the plasma samples of PD patients and the midbrain of MPTP mouse models is positively correlated with dyskinesia.We further illustrated that ASCT2 expressed in astrocytes rather than neurons significantly upregulated in response to either MPP+or LPS/ATP challenge.Genetic ablation of astrocytic ASCT2 alleviated the neuroinflammation and rescued dopaminergic(DA)neuron damage in PD models in vitro and in vivo.Notably,the binding of ASCT2 to NLRP3 aggravates astrocytic inflammasometriggered neuroinflammation.Then a panel of 2513 FDA-approved drugs were performed via virtual molecular screening based on the target ASCT2 and we succeed in getting the drug talniflumate.It is validated talniflumate impedes astrocytic inflammation and prevents degeneration of DA neurons in PD models.Collectively,these findings reveal the role of astrocytic ASCT2 in the pathogenesis of PD,broaden the therapeutic strategy and provide a promising candidate drug for PD treatment. 关 键 词：ASCT2 NLRP3 ASTROCYTES INFLAMMATION NEURODEGENERATION Drug screening Talniflumate Parkinson’s disease
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