Metabolic Reprogramming in Gliocyte Post-cerebral Ischemia/ Reperfusion: From Pathophysiology to Therapeutic Potential


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Abstract

Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/ reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes to be reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.

About the authors

Lipeng Gong

Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine

Email: info@benthamscience.net

Junjie Liang

Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine

Email: info@benthamscience.net

Letian Xie

Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine

Email: info@benthamscience.net

Zhanwei Zhang

Department of Neurosurgery, First Affiliated Hospita, Hunan University of Traditional Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

Zhigang Mei

Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

Wenli Zhang

School of Pharmacy, Hunan University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

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