The PGC-1α Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo.
Yazhou Xu, John Alimamy Kabba, Wenchen Ruan, Yunjie Wang, Shunyi Zhao, Xiaoyue Song, Luyong Zhang, Jia Li, Tao Pang
Author Information
Yazhou Xu: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China.
John Alimamy Kabba: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China.
Wenchen Ruan: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China.
Yunjie Wang: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China.
Shunyi Zhao: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China.
Xiaoyue Song: School of Biological Sciences, University of Liverpool, Brownlow Hill, Liverpool, L69 3BX, UK.
Luyong Zhang: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China.
Jia Li: State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
Tao Pang: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China. tpang@cpu.edu.cn. ORCID
Oxidative stress is a great challenge to neurons following cerebral ischemia. PGC-1α has been shown to act as a potent modulator of oxidative metabolism. In this study, the effects of ZLN005, a small molecule that activate PGC-1α, against oxygen-glucose deprivation (OGD)- or ischemia-induced neuronal injury in vitro and in vivo were investigated. Transient middle cerebral artery occlusion (tMCAO) was performed in rats and ZLN005 was administered intravenously at 2 h, 4 h, or 6 h after ischemia onset. Infarct volume and neurological deficit score were detected to evaluate the neuroprotective effects of ZLN005. Well-differentiated PC12 cells, which were subjected to OGD for 2 h followed by reoxygenation for 22 h, were used as an in vitro ischemic model. Changes in expression of PGC-1α, its related genes, and antioxidant genes were determined by real-time quantitative PCR. The results showed that ZLN005 reduced cerebral infarct volume and improved the neurological deficit in rat with tMCAO, and significantly protected OGD-induced neuronal injury in PC12 cells. Furthermore, ZLN005 enhanced expression of PGC-1α in PC12 cells and in the ipsilateral hemisphere of rats with tMCAO. Additionally, ZLN005 increased antioxidant genes, including SOD1 and HO-1, and significantly prevented the ischemia-induced decrease in SOD activity. Taking together, the PGC-1α activator ZLN005 exhibits neuroprotective effects under ischemic conditions and molecular mechanisms possibly involve activation of PGC-1α signaling pathway and cellular antioxidant systems.
