Impeding the combination of astrocytic ASCT2 and NLRP3 by talniflumate alleviates neuroinflammation in experimental models of Parkinson's disease.
10.1016/j.apsb.2022.07.021
- Author:
Yang LIU
1
;
Ting LIU
2
;
Yuanzhang ZHOU
2
;
Wenjie LI
2
;
Min WANG
3
;
Nanshan SONG
2
;
Wenbin ZHANG
4
;
Jingwei JIANG
5
;
Shengtao YUAN
5
;
Jianhua DING
2
;
Gang HU
2
;
Ming LU
2
Author Information
1. Department of Pharmacology, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
2. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, 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.
- Publication Type:Journal Article
- Keywords:
ASCT2;
Astrocytes;
Drug screening;
Inflammation;
NLRP3;
Neurodegeneration;
Parkinson's disease;
Talniflumate
- From:
Acta Pharmaceutica Sinica B
2023;13(2):662-677
- CountryChina
- Language:English
-
Abstract:
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 inflammasome-triggered 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.
