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Research
Robert Galinsky
Hudson Institute of Medical Research
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6374-9372
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Increased systemic and tissue levels of interleukin(IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration can attenuate neuroinflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS).
Methods
Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline (control, n=9), LPS infusions (0 h=300 ng, 24 h=600 ng, 48 h=1200 ng, n=8) or LPS plus 3 infusions of IL-1Ra (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n=9). Sheep were euthanized 4 days after starting infusions for histology.
Results
LPS infusions were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P<0.05 vs. control). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, apoptosis and microglial activation, and reduced astrocyte and total oligodendrocyte survival, but did not change myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and apoptosis, and improved total oligodendrocyte survival.
Conclusion
IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss, but did not improve survival of astrocytes after LPS-induced inflammation in near-term fetal sheep. Further studies of long term brain maturation are now needed.
Keywords
inflammation, brain, interleukin-1
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Received 28 Feb, 2021
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Reviewer #2 agreed
On 07 Feb, 2021
Reviewer #1 agreed
On 07 Feb, 2021
Reviews received
Received 07 Feb, 2021
Reviewers invited
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Subject Areas
Neurobiology of Disease
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A new preprint design is coming!
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This preprint is under consideration at Journal of Neuroinflammation. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Robert Galinsky
Hudson Institute of Medical Research
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6374-9372
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 17 Feb, 2021
No community comments so far
Editorial decision: Major Revision
On 15 Mar, 2021
Review #1 received
Received 28 Feb, 2021
Review #2 received
Received 28 Feb, 2021
Reviewer #2 agreed
On 07 Feb, 2021
Reviewer #1 agreed
On 07 Feb, 2021
Reviews received
Received 07 Feb, 2021
Reviewers invited
Invitations sent on 05 Feb, 2021
Editor invited
On 04 Feb, 2021
Editor assigned
On 04 Feb, 2021
Submission checks complete
On 04 Feb, 2021
First submitted
On 02 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Increased systemic and tissue levels of interleukin(IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration can attenuate neuroinflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS).
Methods
Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline (control, n=9), LPS infusions (0 h=300 ng, 24 h=600 ng, 48 h=1200 ng, n=8) or LPS plus 3 infusions of IL-1Ra (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n=9). Sheep were euthanized 4 days after starting infusions for histology.
Results
LPS infusions were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P<0.05 vs. control). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, apoptosis and microglial activation, and reduced astrocyte and total oligodendrocyte survival, but did not change myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and apoptosis, and improved total oligodendrocyte survival.
Conclusion
IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss, but did not improve survival of astrocytes after LPS-induced inflammation in near-term fetal sheep. Further studies of long term brain maturation are now needed.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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