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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain
Saskia Eklind1, Carina Mallard, Pernilla Arvidsson
1Dept. of Obstetrics and Gynecology, Sahlgrenska University Hospital, 413-45 Goteborg, Sweden. saskia.eklind@vgregion.se
Insights
Bacterial products like lipopolysaccharide (LPS) can increase perinatal brain injury risk. This study shows LPS can either protect or worsen brain injury depending on the timing of exposure in developing rats.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Bacterial products, such as lipopolysaccharide (LPS), are implicated in perinatal brain injury.
- Previous research showed LPS administration 4 hours before hypoxia-ischemia (HI) exacerbates brain injury in developing rats.
- This contrasts with a protective preconditioning effect observed in adult animals when LPS is given days before ischemia.
Purpose of the Study:
- To investigate how the time interval between LPS administration and HI influences brain injury in developing rats.
- To determine the impact of varying LPS-HI intervals (2-72 hours), HI duration (20 or 50 minutes), and pup age (postnatal day 4 or 7) on brain injury outcomes.
Main Methods:
- Rats at postnatal days 4 or 7 received LPS at varying intervals before undergoing hypoxia-ischemia (HI) of 20 or 50 minutes.
- Brain injury was quantified by assessing specific brain regions.
- The study analyzed the effects of LPS administration at 2, 4, 6, 24, and 72 hours prior to HI.
Main Results:
- LPS administration 24 hours before 50 minutes of HI significantly reduced brain injury by 78%.
- Conversely, LPS given 6 hours before 20 or 50 minutes of HI increased brain injury by 2026% and 137%, respectively.
- LPS administered 72 hours before HI also increased injury in both 4-day-old (446%) and 7-day-old (77%) pups.
Conclusions:
- Lipopolysaccharide (LPS) exposure can enhance vulnerability to brain injury in the developing brain during both acute (4-6 hours) and chronic (72 hours) phases.
- An intermediate interval (24 hours) between LPS administration and HI demonstrated a protective effect, reducing brain injury.
- The findings reveal a complex, time-dependent relationship between LPS exposure and brain injury susceptibility in early development, including a previously undescribed long-term sensitizing effect.
Abstract:
Data indicate that bacterial products in combination with other antenatal or postnatal exposures increase the risk of perinatal brain injury. We have previously shown that administration of lipopolysaccharide (LPS) 4 h before hypoxia-ischemia (HI) increases brain injury in 7-d-old rats. The mechanisms behind such sensitization are unclear, but contrasts against a preconditioning effect of LPS given 1-3 d before ischemia in adult animals. To investigate how the effects of LPS depend on the time interval between administration and HI in the developing brain, we evaluated the effect of varying time interval (2-72 h) between LPS and HI, the duration of HI (20 or 50 min), and age of the rat pups (postnatal d 4 or 7). Outcome was assessed by brain injury scoring of specific regions. We found that LPS reduced brain injury (by 78%) when administered 24 h before 50 min of HI. However, when LPS was administered 6 h before either 20 or 50 min of HI, brain injury was increased by 2026% and 137%, respectively. Even LPS given 72 h before HI increased injury, both when LPS was administered at postnatal d 4 (by 446%) and 7 (by 77%). In conclusion, LPS enhanced vulnerability in the developing brain both in the acute (4-6 h) and the chronic (72 h) phase after administration, whereas an intermediate interval between LPS and HI had the opposite effect. The long-term sensitizing effect of LPS has not been previously described.
