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Updated: Jan 23, 2026
Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
Early Pro-inflammatory Microglia Activation After Inflammation-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal
Meray Serdar1, Karina Kempe1, Mandana Rizazad1
1Department of Pediatrics I, Neonatology and Experimental Perinatal Neuroscience, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Insights
Inflammation worsens brain injury in newborns after perinatal asphyxia. Early microglia activation drives this pro-inflammatory response, suggesting new therapeutic targets for neonatal encephalopathy.
Area of Science:
- Neuroscience
- Immunology
- Neonatal Research
Background:
- Perinatal asphyxia causes neonatal encephalopathy, a major cause of child mortality.
- Therapeutic hypothermia is only partially effective and fails in inflammation-sensitized cases.
- Microglia are implicated in inflammation-sensitized hypoxic-ischemic (HI) brain injury.
Purpose of the Study:
- Investigate early microglia phenotype polarization in an animal model of inflammation-sensitized HI brain injury.
- Understand the pathophysiological processes underlying this injury.
- Identify potential therapeutic targets.
Main Methods:
- Wistar rat pups received E. coli lipopolysaccharide (LPS) or vehicle, followed by hypoxia-ischemia (HI).
- Groups included Sham, LPS only, Veh/HI, and LPS/HI.
- Gene expression and immunohistochemistry analyzed microglia polarization on postnatal days 8 and 14.
Main Results:
- LPS pre-sensitization significantly increased brain area loss and neuronal injury after HI.
- Microglia activation was observed following inflammation-sensitized HI.
- Pro-inflammatory genes, including NLRP-3 inflammasome, were upregulated 24 hours post-HI.
Conclusions:
- Microglia are early key mediators in inflammation-sensitized HI brain injury.
- Microglia adopt a pro-inflammatory phenotype 24 hours after HI.
- Targeting microglia polarization may offer new treatment strategies for neonatal brain injury.
Abstract:
Background: Perinatal asphyxia, leading to neonatal encephalopathy, is one of the leading causes for child mortality and long-term morbidities. Neonatal encephalopathy rates are significantly increased in newborns with perinatal infection. Therapeutic hypothermia is only neuroprotective in 50% of cooled asphyxiated newborns. As shown experimentally, cooling has failed to be neuroprotective after inflammation-sensitized hypoxic ischemic (HI) brain injury. Microglia are thought to be key players after inflammation-sensitized HI brain injury. We performed this study investigating early microglia phenotype polarization in our newborn animal model of inflammation-sensitized HI brain injury, better understanding the underlying pathophysiological processes. Methods: Seven days old Wistar rat pups were injected with either vehicle (NaCl 0.9%) or E. coli lipopolysaccharide (LPS), followed by left carotid ligation combined with global hypoxia inducing a mild unilateral hypoxic-ischemic injury. Pups were randomized to (1) Sham group (n = 41), (2) LPS only group (n = 37), (3) Veh/HI group (n = 56), and (4) LPS/HI group (n = 79). On postnatal days 8 and 14 gene-expression analysis or immunohistochemistry was performed describing early microglia polarization in our model. Results: We confirmed that LPS pre-sensitization significantly increases brain area loss and induced microglia activation and neuronal injury after mild hypoxia-ischemia. Additionally, we show that microglia upregulate pro-inflammatory genes involving NLRP-3 inflammasome gene expression 24 h after inflammation-sensitized hypoxic-ischemic brain injury. Conclusion: These results demonstrate that microglia are early key mediators of the inflammatory response following inflammation-sensitized HI brain injury and that they polarize into a predominant pro-inflammatory phenotype 24 h post HI. This may lead to new treatment options altering microglia phenotype polarization early after HI brain injury.
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