ABCG2 shields against epilepsy, relieves oxidative stress and apoptosis via inhibiting the ISGylation of STAT1 and mTOR
Chang Li,
Yi Cai,
Yongmin Chen,
Jingyi Tong,
Youbin Li,
Dong Liu,
Yun Wang,
Zhiping Li,
Yan Wang,
Qifu Li
Affiliations
Chang Li
Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Key Laboratory for Research and Development of Tropical Herbs, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China; International Joint Research Center of Human-machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, China
Yi Cai
Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Key Laboratory for Research and Development of Tropical Herbs, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, China
Yongmin Chen
Department of Functional Diagnosis, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
Jingyi Tong
Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Key Laboratory for Research and Development of Tropical Herbs, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, China
Youbin Li
International Joint Research Center of Human-machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China
Dong Liu
International Joint Research Center of Human-machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China
Yun Wang
Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Key Laboratory for Research and Development of Tropical Herbs, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, China
Zhiping Li
Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China; Department of Clinical Pharmacy, Kunshan Maternity and Children's Health Care Hospital, Children's Hospital of Fudan University Kunshan Branch, Kunshan, Jiangsu, China; Corresponding author. Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, China.
Yan Wang
Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Key Laboratory for Research and Development of Tropical Herbs, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China; International Joint Research Center of Human-machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China; Corresponding author. Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, No. 3 Xueyuan Road, Haikou, 571199, China.
Qifu Li
Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Key Laboratory for Research and Development of Tropical Herbs, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, China; Corresponding author. Department of Neurology, The First Affiliated Hospital of Hainan Medical University, 31 Longhua Road, Haikou, 570102, China.
The transporter protein ABC subfamily G member 2 (ABCG2) is implicated in epilepsy; however, its specific role remains unclear. In this study, we assessed changes in ABCG2 expression and its role in epilepsy both in vitro and in vivo. We observed an instantaneous increase in ABCG2 expression in epileptic animals and cells. Further, ABCG2 overexpression significantly suppressed the oxidative stress and apoptosis induced by glutamate, kainic acid (KA), and lipopolysaccharide (LPS) in neuronal and microglia cells. Furthermore, inhibiting ABCG2 activity offset this protective effect. ABCG2-deficient mice (ABCG2−/−) showed shorter survival times and decreased survival rates when administered with pentylenetetrazole (PTZ). We also noticed the accumulation of signal transducer and activator of transcription 1 (STAT1) and decreased phosphorylation of mammalian target of rapamycin kinase (mTOR) along with increased ISGylation in ABCG2−/− mice. ABCG2 overexpression directly interacted with STAT1 and mTOR, leading to a decrease in their ISGylation. Our findings indicate the rapid increase in ABCG2 expression acts as a shield in epileptogenesis, indicating ABCG2 may serve as a potential therapeutic target for epilepsy treatment.
