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Updated: Dec 27, 2025
A Cell Culture Model for Studying the Role of Neuron-Glia Interactions in Ischemia
Published on: November 14, 2020
Glutaminase 1 Regulates Neuroinflammation After Cerebral Ischemia Through Enhancing Microglial Activation and
Ge Gao1, Congcong Li1, Jie Zhu1
1Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.
Abstract:
Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release in vitro. However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.
Insights
Glutaminase 1 (GLS1) drives neuroinflammation after cerebral ischemia by activating microglia and releasing exosomes. Inhibiting GLS1 reduces this inflammatory response, offering a potential therapeutic target for brain injury.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Cerebral ischemia triggers neuroinflammation via microglial activation, releasing damaging molecules.
- Glutaminase 1 (GLS1) is elevated in chronic CNS disorders and promotes microglial pro-inflammatory responses.
- The role of GLS1 in acute brain injury neuroinflammation is not well understood.
Purpose of the Study:
- To investigate the role of GLS1 in microglia-mediated neuroinflammation following focal cerebral ischemia.
- To explore GLS1 as a potential therapeutic target for mitigating inflammatory damage post-stroke.
Main Methods:
- Induction of focal cerebral ischemia in a rat model.
- Assessment of microglial activation, GLS1 expression, and pro-inflammatory exosome accumulation.
- Pharmacological inhibition of GLS1 using CB839 and exosome secretion using GW4869.
Main Results:
- Focal cerebral ischemia led to increased microglial activation, elevated GLS1 expression, and pro-inflammatory exosomes.
- CB839 treatment reversed ischemia-induced microglial activation, inflammation, and exosome release.
- GW4869 exhibited similar anti-inflammatory effects, implicating GLS1-mediated exosome release.
Conclusions:
- GLS1 plays a critical role in mediating neuroinflammation and exosome release in cerebral ischemia.
- GLS1 inhibition represents a promising therapeutic strategy for neuroprotection in acute brain injury.
- Targeting GLS1-mediated exosome pathways could be key to managing the neuroinflammatory microenvironment post-ischemia.
