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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Prenatal inflammation exacerbates hyperoxia-induced neonatal brain injury
Meray Serdar1, Kay-Anja Walther1, Markus Gallert1
1Department of Paediatrics I, Neonatology and Experimental perinatal Neurosciences, Centre for Translational Neuro- and Behavioural Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Insights
Combining prenatal inflammation with postnatal hyperoxia in a rodent model worsens white matter injury (WMI) and inflammatory responses. This combined insult model offers a better understanding of WMI's complex causes and potential therapies.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatology
Background:
- Premature infants face high risks of white matter injury (WMI), with hyperoxia and perinatal inflammation as key risk factors.
- Existing research often isolates these insults, yet clinical WMI is multifactorial, necessitating models that reflect combined triggers.
Purpose of the Study:
- To establish a clinically relevant rodent model of WMI by combining prenatal inflammation and postnatal hyperoxia.
- To investigate the individual, additive, or synergistic effects of these combined insults on inflammatory processes, myelination, and grey matter development.
Main Methods:
- Pregnant Wistar rats received lipopolysaccharide (LPS) or saline at embryonic day 20.
- Offspring were exposed to hyperoxia (80% O2) or normoxia (21% O2) from postnatal day 3 to 5.
- Brain tissues and serum were analyzed using immunohistochemistry, western blotting, qPCR, and multiplex protein analysis.
Main Results:
- Combined prenatal inflammation and postnatal hyperoxia led to reduced body weight, decreased brain volume, and hypomyelination.
- Severe myelination deficits and increased microglia activation with elevated inflammatory cytokines in the brain were observed.
- Additive or synergistic effects were detected for most pathological changes, including brain size and myelination deficits.
Conclusions:
- The combined prenatal inflammation and postnatal hyperoxia model significantly aggravates myelination deficits and inflammatory responses.
- This model is crucial for understanding the complex pathophysiology of WMI and for evaluating novel therapeutic strategies.
Background:
Premature born infants are at high risk to develop white matter injury (WMI). Hyperoxia and perinatal inflammation are main risk factors for preterm birth and associated brain injury. To date the majority of experimental studies have focused on isolated insults. However, clinically, WMI injury is a multifactorial disorder caused by a variety of triggers. To establish a clinically relevant rodent model of WMI, we combined prenatal inflammation with postnatal hyperoxia to investigate individual, and additive or synergistic effects on inflammatory processes, myelination and grey matter development.
Methods:
At embryonic day 20, pregnant Wistar rat dams received either a single intraperitoneal injection of 100 µg/ kg lipopolysaccharide (LPS) or sodium chloride. Offspring were either exposed to hyperoxia (80% O2) or normoxia (21% O2) from postnatal day 3 to 5. Animals were sacrificed immediately after hyperoxia or 6 days later, corresponding to term-equivalent age. White and grey matter development and neuroinflammatory responses were investigated at cellular and molecular levels applying immunohistochemistry, western blotting, real time PCR in brain tissues and multiplex protein expression analysis on serum samples.
Results:
Prenatal inflammation combined with postnatal hyperoxia resulted in reduced body weight and length in the offspring, accompanied by increased serum leptin levels at term equivalent age. The altered body parameters, like body weight, were associated with decreased brain volume, thinning of deep cortical layers and hypomyelination. As potential underlying mechanisms, we identified severe myelination deficits and an increased microglia activation associated with elevated inflammatory cytokine expression in brain tissues, while peripheral cytokine levels were reduced. Interestingly, effects on body size were mainly mediated by prenatal LPS, independent of hyperoxia, while oligodendrocyte degeneration was mainly induced by postnatal hyperoxia, independent of prenatal inflammation. However, for the majority of pathological changes, including brain size, myelination deficits, microglia activation and inflammatory cytokine expression, additive or synergistic effects were detected.
Conclusion:
Prenatal inflammation combined with postnatal hyperoxia results in aggravated myelination deficits and inflammatory responses compared to single insults, making it an ideal model to improve our understanding of the complex pathophysiology underlying WMI and to evaluate urgently needed therapies.
