Glycogenolysis Is Crucial for Astrocytic Glycogen Accumulation and Brain Damage after Reperfusion in Ischemic Stroke

Yanhui Cai; Haiyun Guo; Ze Fan; Xinlei Zhang; Di Wu; Wenhong Tang; Tingting Gu; Shiquan Wang; Anqi Yin; Liang Tao; Xunming Ji; Hailong Dong; Yan Li; Lize Xiong

doi:10.1016/j.isci.2020.101136

Glycogenolysis Is Crucial for Astrocytic Glycogen Accumulation and Brain Damage after Reperfusion in Ischemic Stroke

iScience. 2020 May 6;23(5):101136. doi: 10.1016/j.isci.2020.101136. eCollection 2020 May 22.

Authors

Yanhui Cai¹, Haiyun Guo¹, Ze Fan¹, Xinlei Zhang², Di Wu³, Wenhong Tang¹, Tingting Gu¹, Shiquan Wang¹, Anqi Yin¹, Liang Tao¹, Xunming Ji³, Hailong Dong¹, Yan Li⁴, Lize Xiong^{1

5}

Affiliations

¹ Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
² Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
³ China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
⁴ Center for Brain Science & Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
⁵ Translational Research Institute of Brain and Brain-Like Intelligence & Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200081, China.

Abstract

Astrocytic glycogen is an important energy reserve in the brain and is believed to supply fuel during energy crisis. However, the pattern of glycogen metabolism in ischemic stroke and its potential therapeutic impact on neurological outcomes are still unknown. Here, we found extensive brain glycogen accumulation after reperfusion in ischemic stroke patients and primates. Glycogenolytic dysfunction in astrocytes is responsible for glycogen accumulation, caused by inactivation of the protein kinase A (PKA)-glycogen phosphorylase kinase (PhK)-glycogen phosphorylase (GP) cascade accompanied by the activation of glycogen synthase kinase-3β (GSK3β). Genetic or pharmacological augmentation of astrocytic GP could promote astrocyte and neuron survival and improve neurological behaviors. In addition, we found that insulin exerted a neuroprotective effect, at least in part by rescuing the PKA-PhK-GP cascade to maintain homeostasis of glycogen metabolism during reperfusion. Together, our findings suggest a promising intervention for undesirable outcomes in ischemic stroke.

Keywords: Cellular Neuroscience; Molecular Neuroscience; Neuroscience.