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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
07:36

Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats

Published on: November 20, 2015

TLR-3 receptor activation protects the very immature brain from ischemic injury

Hui Shi, Nadia Gabarin, Edward Hickey

    Journal of Neuroinflammation
    |August 23, 2013
    PubMed

    Insights

    Toll-like receptor 3 (TLR-3) agonist poly I:C preconditioning significantly reduces ischemic brain damage in immature P5 rats. This neuroprotection is mediated by TLR-3 signaling, highlighting its role in the developing brain.

    Area of Science:

    • Neuroscience
    • Immunology
    • Developmental Biology

    Background:

    • Lipopolysaccharide (LPS) preconditioning effectively reduces ischemic brain damage in P7 rats, but not in younger P3 or P5 pups.
    • LPS is a Toll-like receptor 4 (TLR-4) ligand, suggesting other TLRs may mediate neuroprotection in the immature brain.
    • Cerebral ischemic injury in developing brains of premature infants remains a significant clinical concern.

    Purpose of the Study:

    • To investigate the role of Toll-like receptors (TLRs) other than TLR-4 in mediating preconditioning against cerebral ischemic injury in the developing rat brain.
    • To determine the expression patterns of TLR-2, TLR-3, TLR-4, and TLR-9 in rat brains at different postnatal ages (P3, P5, P7).
    • To evaluate the neuroprotective effect of a TLR-3 specific agonist, poly I:C, in P5 rats subjected to hypoxic-ischemic (HI) injury.

    Main Methods:

    • Immunohistochemical staining was used to detect TLR-2, TLR-3, TLR-4, and TLR-9 expression in rat brains at P3, P5, and P7.
    • P5 rats were pre-treated with either poly I:C (TLR-3 agonist) or saline.
    • Hypoxic-ischemic (HI) injury was induced 48 hours post-injection, and infarct volumes were quantified 1 week later.

    Main Results:

    • TLR-2 and TLR-3 expression was high in P3 and P5 rat brains, while TLR-4 expression was lower compared to P7.
    • TLR-3 was predominantly expressed in P5 pups.
    • Poly I:C pre-treatment significantly reduced infarct volume in P5 rats, downregulating NF-κB and upregulating IRF3.
    • Poly I:C did not provide neuroprotection in P7 rat brains.

    Conclusions:

    • Toll-like receptor expression and function are developmentally regulated.
    • TLR-3 signaling pathways are implicated in poly I:C-induced preconditioning against ischemic injury in the immature brain.
    • This study is the first to demonstrate TLR-3 expression in the immature brain and its role in mediating neuroprotection against ischemic injury.
    Abstract

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