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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner
Xiaoyang Wang1, Linnea Stridh, Wenli Li
1Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
Insights
Myeloid differentiation factor 88 (MyD88) is crucial in potentiating perinatal brain injury from infection and hypoxia-ischemia. MyD88 knockout mice showed no increased brain damage, indicating MyD88’s essential role in this process.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Perinatal infections are linked to neurological deficits like cerebral palsy.
- Lipopolysaccharide (LPS) exposure potentiates hypoxic-ischemic (HI) brain injury.
- LPS signaling involves Toll-like receptor 4 (TLR4) and adaptor proteins like MyD88.
Purpose of the Study:
- To investigate the role of MyD88 in LPS-sensitized neonatal brain injury.
- To determine if MyD88 mediates the potentiation of HI brain injury by LPS.
Main Methods:
- Used MyD88 knockout (KO) and wild-type (WT) mice subjected to HI and LPS administration.
- Assessed brain tissue loss, NF-kappaB activation, cytokine-chemokine expression, microglial activation, and caspase-3 activity.
Main Results:
- In WT mice, LPS pre-exposure significantly increased HI brain injury.
- MyD88 KO mice showed no potentiation of brain injury with LPS-HI.
- MyD88 KO mice exhibited reduced inflammation and NF-kappaB activation but increased microglial and caspase-3 activity.
Conclusions:
- MyD88 plays a critical role in LPS-sensitized HI neonatal brain injury.
- The MyD88-dependent pathway involves inflammatory and caspase-dependent mechanisms.
Abstract:
Neurological deficits in children, including cerebral palsy, are associated with prior infection during the perinatal period. Experimentally, we have shown that pre-exposure to the Gram-negative component LPS potentiates hypoxic-ischemic (HI) brain injury in newborn animals. LPS effects are mediated by binding to TLR4, which requires recruitment of the MyD88 adaptor protein or Toll/IL-1R domain-containing adapter inducing IFN-beta for signal transduction. In this study, we investigated the role of MyD88 in neonatal brain injury. MyD88 knockout (MyD88 KO) and wild-type mice were subjected to left carotid artery ligation and 10% O(2) for 50 min on postnatal day 9. LPS or saline were administered i.p. at 14 h before HI. At 5 days after HI in wild-type mice, LPS in combination with HI caused a significant increase in gray and white matter tissue loss compared with the saline-HI group. By contrast, in the MyD88 KO mice there was no potentiation of brain injury with LPS-HI. MyD88 KO mice exhibited reduced NFkappaB activation and proinflammatory cytokine-chemokine expression in response to LPS. The number of microglia and caspase-3 activation was increased in the brain of MyD88 KO mice after LPS exposure. Collectively, these findings indicate that MyD88 plays an essential role in LPS-sensitized HI neonatal brain injury, which involves both inflammatory and caspase-dependent pathways.
