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
Affiliations
Yanhui Cai
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Haiyun Guo
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Ze Fan
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Xinlei Zhang
Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Di Wu
China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
Wenhong Tang
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Tingting Gu
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Shiquan Wang
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Anqi Yin
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Liang Tao
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Xunming Ji
China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
Hailong Dong
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Yan Li
Center for Brain Science & Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Corresponding author
Lize Xiong
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; 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; Corresponding author
Summary: 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.
