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  2. The Small Molecule P7C3-A20 Exerts Neuroprotective Effects in a Hypoxic-ischemic Encephalopathy Model via Activation of PI3K/AKT/GSK3β Signaling

The Small Molecule P7C3-A20 Exerts Neuroprotective Effects in a Hypoxic-ischemic Encephalopathy Model via Activation of PI3K/AKT/GSK3β Signaling

  • Neuroscience. 2020 Aug 10;441:197-208. doi: 10.1016/j.neuroscience.2020.05.051.
Junjie Bai 1 Shanshan Zeng 1 Jinjin Zhu 1 Changchang Fu 1 Minzhi He 1 Jianghu Zhu 2 Shangqing Chen 1 Xiaoqin Fu 1 Peijun Li 1 Zhenlang Lin 3
Affiliations

Affiliations

  • 1 Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
  • 2 Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: zhujianghu@wmu.edu.cn.
  • 3 Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: linzhenlang@hotmail.com.
Abstract

Hypoxic-ischemic encephalopathy (HIE) in neonates can lead to severe long-term disabilities including cerebral palsy and brain injury. The small molecule P7C3-A20 has been shown to exert neuroprotective effects in various disorders such as ischemic stroke and neurodegenerative diseases. However, it is unclear whether P7C3-A20 has therapeutic potential for the treatment of HIE, and the relationship between P7C3-A20 and neuronal Apoptosis is unknown. To address these questions, the present study investigated whether P7C3-A20 reduces HI injury in vitro using a PC12 cell oxygen-glucose deprivation (OGD) model and in vivo in postnatal day 7 and 14 rats subjected to HI, along with the underlying mechanisms. We found that treatment with P7C3-A20 (40-100 µM) alleviated OGD-induced Apoptosis in PC12 cells. In HI model rats, treatment with 5 or 10 mg/kg P7C3-A20 reduced infarct volume; reversed cell loss in the cortex and hippocampus and improved motor function without causing neurotoxicity. The neuroprotective effects were abrogated by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results demonstrate that P7C3-A20 exerts neuroprotection by activating PI3K/protein kinase B/glycogen synthase kinase 3β signaling and can potentially be used to prevent brain injury in neonates following HIE.

Keywords

P7C3-A20; PI3K/AKT/GSK3β; apoptosis; hypoxic–ischemic encephalopathy; neuroprotection.

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