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A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing
Gang Luo1, Xiaofeng Wang1, Yongchen Cui1
1Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 600 Yishan Road, Shanghai, 200233, China.
Background:
Microglial polarization toward pro-inflammatory M1 phenotype are major contributors to the development of perioperative neurocognitive disorders (PNDs). Metabolic reprogramming plays an important role in regulating microglial polarization. We therefore hypothesized that surgical trauma can activate microglial M1 polarization by metabolic reprogramming to induce hippocampal neuroinflammation and subsequent postoperative cognitive impairment.
Methods:
We used aged mice to establish a model of PNDs, and investigated whether surgical trauma induced metabolic reprograming in hippocampus using PET/CT and GC/TOF-MS based metabolomic analysis. We then determined the effect of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on hippocampal microglial M1 polarization, neuroinflammation, and cognitive function at 3 d after surgery.
Results:
We found that surgery group had less context-related freezing time than either control or anesthesia group (P < 0.05) without significant difference in tone-related freezing time (P > 0.05). The level of Iba-1 fluorescence intensity in hippocampus were significantly increased in surgery group than that in control group (P < 0.05) accompanied by activated morphological changes of microglia and increased expression of iNOS/CD86 (M1 marker) in enriched microglia from hippocampus (P < 0.05). PET/CT and metabolomics analysis indicated that surgical trauma provoked the metabolic reprogramming from oxidative phosphorylation to glycolysis in hippocampus. Inhibition of glycolysis by 2-DG significantly alleviated the surgical trauma induced increase of M1 (CD86+CD206-) phenotype in enriched microglia from hippocampus and up-regulation of pro-inflammatory mediators (IL-1β and IL-6) expression in hippocampus. Furthermore, glycolytic inhibition by 2-DG ameliorated the hippocampus dependent cognitive deficit caused by surgical trauma.
Conclusions:
Metabolic reprogramming is crucial for regulating hippocampal microglial M1 polarization and neuroinflammation in PNDs. Manipulating microglial metabolism might provide a valuable therapeutic strategy for treating PNDs.
Insights
Surgical trauma triggers metabolic changes in the brain, promoting inflammation and cognitive decline in aged mice. Inhibiting this metabolic shift with 2-deoxy-D-glucose (2-DG) can reduce neuroinflammation and improve cognitive function, offering a potential treatment for postoperative neurocognitive disorders (PNDs).
Area of Science:
- Neuroscience
- Metabolic Biology
- Immunology
Background:
- Pro-inflammatory M1 microglial polarization contributes significantly to perioperative neurocognitive disorders (PNDs).
- Metabolic reprogramming is a key regulator of microglial polarization.
- Surgical trauma is hypothesized to induce M1 polarization via metabolic reprogramming, leading to neuroinflammation and cognitive impairment.
Purpose of the Study:
- To investigate if surgical trauma induces metabolic reprogramming in the aged mouse hippocampus.
- To determine the effect of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on microglial polarization, neuroinflammation, and cognitive function post-surgery.
Main Methods:
- Aged mice were used to model PNDs.
- Positron emission tomography/computed tomography (PET/CT) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS) metabolomic analyses were employed.
- The impact of 2-DG on hippocampal microglia, neuroinflammation markers, and cognitive function was assessed 3 days after surgery.
Main Results:
- Surgical trauma led to increased M1 microglial markers (iNOS/CD86) and neuroinflammation in the hippocampus, accompanied by a shift from oxidative phosphorylation to glycolysis.
- 2-DG treatment significantly reduced M1 polarization and pro-inflammatory mediator expression (IL-1β, IL-6).
- Inhibition of glycolysis by 2-DG ameliorated surgery-induced, hippocampus-dependent cognitive deficits.
Conclusions:
- Metabolic reprogramming is critical for regulating M1 microglial polarization and neuroinflammation in PNDs.
- Targeting microglial metabolism presents a promising therapeutic avenue for managing PNDs.
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