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

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.

Keywords: Ischemic stroke; cerebral ischemia/reperfusion injury; gliocyte; metabolic reprogramming; oxidative stress.; pathophysiology.

Fig. (1)

CI/RI activates microglia and astrocytes and induces metabolic reprogramming. M1 microglia increased glycolysis, PPP, fatty acid synthesis, released cytokines and, chemokines and MPPs, generated ROS and RNS, and exerted a pro-neuroinflammatory effect. M2 microglia increased OXPHOS and fatty acid oxidation, released trophic factors, repaired the damaged block, and exerted an anti-neuroinflammatory effect. Reactive astrocytes upregulate glycolysis and PPP and downregulate glycogenolysis and glutamate uptake, which may synergize with microglia to promote neuroinflammation. They also secrete trophic factors, inhibit the toxicity of excitatory amino acids and generate glial scarring to protect neurons. Abbreviations: CI/RI, cerebral ischemia/reperfusion injury; PPP, pentose phosphate pathway; ROS, reactive oxygen species; RNS, reactive nitrogen species; OXPHOS, oxidative phosphorylation; MMP, matrix metalloprotein. (Created with BioRender.com).

Fig. (2)

Metabolic reprogramming of microglia in CI/RI. Abbreviations: GLUT1, glucose transporter protein type 1; G6PD, glucose-6-phosphate dehydrogenase; NADPH, triphosphopyridine nucleotide; HK, hexokinase; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; PEP, phosphoenolpyruvate; F-2,6P, fructose 2,6-bisphosphate; PFKFB3, fructose-2,6-bisphosphatase; PKM2, pyruvate kinase type M2; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; LDHA, lactate dehydrogenase A; HIF-1, hypoxia-inducible factor 1; TIGAR, TP53-induced glycolysis and apoptosis regulator; PPP, pentose phosphate pathway; G6PD, glucose-6-phosphate dehydrogenase; NOX2, NADPH oxidase 2; OXPHOS, mitochondrial oxidative phosphorylation; TCA cycle, tricarboxylic acid cycle; iNOS, inducible nitric oxide synthase;Arg-1, arginase 1; GABA, gamma-aminobutyric acid; SNAT1, sodium-coupled neutral amino acid transporter 1;GPR120, G protein-coupled receptor 120; DHA, Docosahexaenoic acid. (Created with BioRender.com).

Fig. (3)

Metabolic reprogramming of astrocytes in CI/RI. Abbreviations: STAT3, signal transducer and activator of transcription 3; PKM2, pyruvate kinase type M2; HK2, hexokinase 2; GP, glycogen phosphorylase; G6P, glucose 6-phosphate; PEP, phosphoenolpyruvate; PhK, phosphorylase kinase; PKA, protein kinase A; HIF, hypoxia-inducible factor; LDH, lactate dehydrogenase; PPP, pentose phosphate pathway; NADPH, triphosphopyridine nucleotide; GSH, reduced glutathione; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; GS, glutamine synthetase; SNAT1, sodium-coupled neutral amino acid transporter 1; GLT-1, glutamate transporter 1; MCT, monocarboxylate transporter. (Created with BioRender.com).