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Updated: Jul 20, 2026
A Cell Culture Model for Studying the Role of Neuron-Glia Interactions in Ischemia
Published on: November 14, 2020
2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation
Payam Gharibani1, Yu Guo2, Shruthi Shanmukha3
1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Abstract:
Neuroinflammation plays a central role in a wide spectrum of neurological diseases, driven generally by reactive microglia and astrocytes. Inflammatory stimulation of microglia and astrocytes leads to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, which is required to support pro-inflammatory effector functions. This metabolic reprogramming is associated with impaired mitochondrial dynamics, including reduced biogenesis, increased fragmentation, and loss of membrane potential. Targeting microglia and astrocyte metabolism may offer a novel therapeutic approach for modulating neuroinflammation and restoring homeostatic immune functions. Here, we examined the potential of 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, to attenuate neuroinflammation by restoring mitochondrial dynamics. In BV2 and primary glial cultures, low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring OXPHOS, reducing mitochondrial fragmentation, and enhancing biogenesis. In vivo, it preserved spare respiratory capacity and increased complex-V activity in brain mitochondria from LPS-treated mice without affecting oxidative stress. At a mechanistic level, 2DG restored activation of AMP-activated protein kinase, a master regulator of mitochondrial dynamics. In conjunction with these metabolic effects, 2DG suppressed LPS-induced pro-inflammatory gene expression while enhancing markers associated with the resolution of inflammation and tissue repair. Critically, systemic low-dose 2DG reduced neuroinflammation and restored immune homeostasis in two LPS-induced mouse models, highlighting its therapeutic potential in neurological disorders.
Insights
2-Deoxy-D-Glucose (2DG) can reduce neuroinflammation by shifting glial cell metabolism back to oxidative phosphorylation, improving mitochondrial function and restoring immune balance in neurological diseases.
Area of Science:
- Neuroscience
- Immunology
- Metabolic pathways
Background:
- Neuroinflammation, driven by microglia and astrocytes, is implicated in neurological diseases.
- Inflammatory stimuli induce a metabolic shift to glycolysis in glial cells, impairing mitochondrial function.
- Mitochondrial dysfunction, including fragmentation and reduced biogenesis, is linked to neuroinflammation.
Purpose of the Study:
- To investigate if 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, can mitigate neuroinflammation.
- To determine if 2DG can restore mitochondrial dynamics and homeostatic immune functions.
Main Methods:
- Utilized BV2 and primary glial cell cultures and LPS-induced mouse models.
- Administered low-dose 2DG to assess effects on glial cell metabolism and mitochondrial dynamics.
- Analyzed mitochondrial respiration, biogenesis, fragmentation, and gene expression.
- Investigated the role of AMP-activated protein kinase (AMPK) activation.
Main Results:
- Low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring oxidative phosphorylation (OXPHOS) and enhancing mitochondrial biogenesis.
- 2DG reduced mitochondrial fragmentation and preserved respiratory capacity in vivo.
- Mechanistically, 2DG restored AMPK activation, a key regulator of mitochondrial dynamics.
- 2DG suppressed pro-inflammatory gene expression and promoted markers of inflammation resolution.
Conclusions:
- 2DG effectively attenuates neuroinflammation by restoring glial cell metabolism and mitochondrial dynamics.
- Systemic administration of low-dose 2DG shows therapeutic potential for neurological disorders characterized by neuroinflammation.
- Targeting glial cell metabolism represents a promising strategy for restoring immune homeostasis in the brain.
