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Published on: January 30, 2014
Inter-alpha inhibitor proteins attenuate lipopolysaccharide-induced blood-brain barrier disruption in neonatal mice
Aric F Logsdon1, Michelle A Erickson1, Melanie J Herbert2
1Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
Insights
Inter-alpha Inhibitor Proteins (IAIPs) protect neonatal mice from brain injury by reducing blood-brain barrier (BBB) disruption caused by lipopolysaccharide (LPS). IAIPs offer a potential neuroprotective strategy for neonates.
Area of Science:
- Neonatal neuroscience
- Neuroprotection strategies
- Blood-brain barrier research
Background:
- Limited information exists on neuroprotective pharmacological strategies for neonatal brain injury.
- Lipopolysaccharide (LPS) is known to disrupt the blood-brain barrier (BBB) and increase inflammation in both adult and neonatal models.
- Human blood-derived Inter-alpha Inhibitor Proteins (IAIPs) have demonstrated neuroprotective effects and improved survival in neonatal models post-LPS exposure.
Purpose of the Study:
- To investigate if LPS disrupts BBB function in neonatal mice.
- To determine if IAIPs can attenuate LPS-induced BBB disruption in both male and female neonatal mice.
- To explore the potential of IAIPs as a neuroprotective agent in neonatal brain injury.
Main Methods:
- Neonatal mice were exposed to low-dose (1 mg/kg) lipopolysaccharide (LPS).
- Inter-alpha Inhibitor Proteins (IAIPs) were administered post-LPS exposure.
- Blood-brain barrier (BBB) permeability was quantified using intravenous 14C-sucrose and 99mTc-albumin.
Main Results:
- Low-dose LPS (1 mg/kg) induced BBB disruption in both male and female neonatal mice with manageable mortality rates.
- IAIP treatment significantly attenuated the LPS-induced BBB disruption.
- LPS exposure elevated IAIP concentrations in blood but did not significantly increase systemic levels of Pre-alpha inhibitor (PaI).
Conclusions:
- IAIPs effectively attenuate lipopolysaccharide-induced blood-brain barrier disruption in neonatal mice of both sexes.
- IAIPs represent a promising therapeutic candidate for mitigating neonatal brain injury.
- Further research into IAIPs' mechanism of action in neonatal neuroprotection is warranted.
Abstract:
There is a paucity of information regarding efficacious pharmacological neuroprotective strategies to attenuate or reduce brain injury in neonates. Lipopolysaccharide (LPS) disrupts blood-brain barrier (BBB) function in adult rodents and increases inflammation in adults and neonates. Human blood-derived Inter-alpha Inhibitor Proteins (IAIPs) are neuroprotective, improve neonatal survival after LPS, and attenuate LPS-induced disruption of the BBB in adult male mice. We hypothesized that LPS also disrupts the function of the BBB in neonatal mice and that IAIPs attenuate the LPS-induced BBB disruption in male and female neonatal mice. IAIPs were administered to neonatal mice after LPS and BBB permeability quantified with intravenous 14C-sucrose and 99mTc-albumin. Although repeated high doses (3 mg/kg) of LPS in neonates resulted in high mortality rates and a robust increase in BBB permeability, repeated lower doses (1 mg/kg) of LPS resulted in lower mortality rates and disruption of the BBB in both male and female neonates. IAIP treatment attenuated disruption of the BBB similarly to sucrose and albumin after exposure to low-dose LPS in neonatal mice. Exposure to low-dose LPS elevated IAIP concentrations in blood, but it did not appear to increase the systemic levels of Pre-alpha inhibitor (PaI), one of the family members of the IAIPs that contains heavy chain 3. We conclude that IAIPs attenuate LPS-related disruption of the BBB in both male and female neonatal mice.
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