Journal Article

Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway

Gonçalves, Carlos Alberto, Fróes, Fernanda, Bobermin, Larissa Daniele, Vizuete, Adriana Fernanda K., Seady, Marina, Wajner, Moacir, Roginski, Ana Cristina, Zanotto, Caroline, Quincozes-Santos, André

2022

Overview

Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo ) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1β and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes. Highlights LPS-induced neuroinflammation promotes metabolic reprogramming. Neuroinflammation increased glycolytic flow and lactate release. Inhibitors of different glycolytic reactions prevented the inflammatory response. S100B changes suggest a role for astrocytes in this metabolic shift. The glycolytic pathway should be target for new anti-inflammatory strategies. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acids / Adapter proteins / Antibiotics / Astrocytes / Bioenergetics / Biomedical and Life Sciences / Biomedicine / Brain / Care and treatment / Central nervous system / Composition / Cytokines / Energy consumption / Energy expenditure / Energy metabolism / Enzymatic activity / Gene expression / Glial cells / Glucose uptake / Glycolysis / Health aspects / Hippocampus / IL-1β / Immune response / Immunology / Inflammasomes / Inflammation / Kinases / Laboratory animals / Lactic acid / Lipopolysaccharides / Metabolism / Metformin / Methods / Microglia / Minocycline / Mitochondria / Neurobiology / Neurodegenerative diseases / Neuroinflammation / Neurological diseases / Neurology / Neuronal-glial interactions / Neurosciences / Neurotoxicity / Pathogens / PFK1 / Physiology / Protein kinase / S100B / S100b protein / Tricarboxylic acid cycle / Tumor necrosis factor-TNF