Protective Effects of Mdivi-1 on Cognition Disturbance Following Sepsis in Mice via Alleviating Microglia Activation and Polarization
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Updated: Jun 3, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Chen Hong1, Li Wang1, Xiaowei Zhou1
1Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
Background:
Neuroinflammation is one of the essential pathogeneses of cognitive damage suffering from sepsis-associated encephalopathy (SAE). Lots of evidences showed the microglia presented mitochondrial fragmentation during SAE. This study investigated the protective effects and novel mechanisms of inhibiting microglia mitochondrial fragmentation via mitochondrial division inhibitor 1 (Mdivi-1) on cognitive damage in SAE.
Methods:
The SAE model was performed by cecal ligation and puncture (CLP), and Mdivi-1 was administrated via intraperitoneal injection. Morris water maze was performed to assess cognitive function. Mitochondrial morphology was observed by electron microscope or MitoTracker staining. The qRT-PCR, immunofluorescence staining, and western blots were used to detect the inflammatory factors and protein content, respectively. Flow cytometry was used to detect the polarization of hippocampal microglia. Bioinformatics analysis was used to verify hypotheses.
Results:
Mdivi-1 administration alleviated sepsis-induced mitochondrial fragmentation, microglia activation, polarization, and cognitive damage. The mechanisms study showed neuroinflammation and oxidative stress were suppressed via NF-κB and Keap1/Nrf2/HO-1 pathways following Mdivi-1 administration; meanwhile, pyroptosis in microglia was reduced, which was associated with enhanced autophagosome formation via p62 elevation following Mdivi-1 administration.
Conclusion:
Inhibition of microglia mitochondrial fragmentation is beneficial to SAE cognitive disturbance, the mechanisms are related to alleviating neuroinflammation, oxidative stress, and pyroptosis.
Insights
Mitochondrial division inhibitor 1 (Mdivi-1) protects against sepsis-associated encephalopathy (SAE) by reducing neuroinflammation and cognitive damage. It achieves this by inhibiting microglia mitochondrial fragmentation and associated cellular stress pathways.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Sepsis-associated encephalopathy (SAE) causes cognitive damage, with neuroinflammation and microglia mitochondrial fragmentation being key pathological features.
- Microglia play a critical role in the neuroinflammatory response during SAE.
- Targeting microglia mitochondrial dynamics presents a potential therapeutic strategy for SAE.
Purpose of the Study:
- To investigate the protective effects of inhibiting microglia mitochondrial fragmentation using mitochondrial division inhibitor 1 (Mdivi-1) on cognitive deficits in SAE.
- To elucidate the underlying mechanisms by which Mdivi-1 exerts its neuroprotective effects in SAE.
Main Methods:
- A cecal ligation and puncture (CLP) model was used to induce SAE in rodents.
- Mdivi-1 was administered intraperitoneally; cognitive function was assessed using the Morris water maze.
- Mitochondrial morphology, microglia activation and polarization, inflammatory factors, oxidative stress markers, and pyroptosis were analyzed using various molecular and imaging techniques.
Main Results:
- Mdivi-1 treatment significantly alleviated cognitive impairment, reduced microglia mitochondrial fragmentation, and suppressed microglia activation and polarization in the SAE model.
- Mechanistically, Mdivi-1 inhibited neuroinflammation and oxidative stress by modulating the NF-κB and Keap1/Nrf2/HO-1 pathways.
- Mdivi-1 also reduced microglia pyroptosis, which was linked to enhanced autophagosome formation via p62 elevation.
Conclusions:
- Inhibiting microglia mitochondrial fragmentation with Mdivi-1 offers a promising therapeutic approach for cognitive dysfunction in SAE.
- The protective mechanisms involve the suppression of neuroinflammation, oxidative stress, and microglia pyroptosis, alongside the promotion of autophagy.
