• Neuroscience · Apr 2020

    Activation of PGC-1α and Mitochondrial Biogenesis Protects Against Prenatal Hypoxic-ischemic Brain Injury.

    • Lijie Jia, Jianwei Wang, Huimin Cao, Xiaoyu Zhang, Weifang Rong, and Zifeng Xu.
    • Department of Anesthesiology, the International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, 910 Hengshan Road, Shanghai 200030, China.
    • Neuroscience. 2020 Apr 15; 432: 63-72.

    AbstractSurvivals after prenatal hypoxia-ischemia (HI) usually suffer long-lasting cognitive defects. Reduced blood-oxygen supplies and the following reperfusion cause mitochondrial injury. Damaged mitochondria could be replaced by mitochondrial biogenesis program and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) is the specific up-regulator. The objective of this study was to determine whether PGC-1α and mitochondrial biogenesis participate in the resistant responses of an immature brain to prenatal HI. We used a pregnant rat model of transient occlusion of uterine perfusion to induce intrauterine HI associated brain injury. SH-SY5Y cells exposed to oxygen-glucose deprivation was used to investigate the HI induced reactions in vitro. PGC-1α and its downstream signaling pathway (NRF-1 and TFAM) were examined by Western blot and quantitative Real-time PCR. Mitochondrial respiratory enzyme COX-IV was investigated by Western blot and immunohistochemistry. Mitochondrial density and morphology was detected by transmission electron microscopy. The hippocampal injury and cognitive function were examined. We found that the intrauterine HI triggered PGC-1α-NRF-1-TFAM pathway in both protein and mRNA levels. COX-IV expression significantly increased after HI injury. Intrauterine HI induced both mitochondrial impairment and mitochondrial biogenesis. Postnatal administration of pioglitazone further promoted PGC-1α and mitochondrial biogenesis, alleviated hippocampal injury, and improved performance in the behavioral tasks after intrauterine HI. Our investigation implicated activation of PGC-1α, and mitochondrial biogenesis is a neuroprotective mechanism against brain injury caused by systemic prenatal HI. Promotion of PGC-1α by pioglitazone might be a potential treatment for protecting against hippocampal injury and cognitive defects after intrauterine HI.Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

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