Abstract
BackgroundWe have shown that preconditioning by lipopolysaccharide (LPS) will result in 90% reduction in ischemic brain damage in P7 rats. This robust LPS neuroprotection was not observed in P3 or P5 pups (corresponding to human premature infant). LPS is a known Toll-like receptor 4 (TLR-4) ligand. We hypothesized that TLRs other than TLR-4 may mediate preconditioning against cerebral ischemic injury in the developing brain.MethodsTLR-2, TLR-3, TLR-4, and TLR-9 expression was detected in brain sections from P3, P5, and P7 rats by immuno-staining. In subsequent experiments, P5 rats were randomly assigned to TLR-3 specific agonist, poly I:C, or saline treated group. At 48 h after the injections, hypoxic-ischemic (HI) injury was induced by unilateral carotid artery ligation followed by hypoxia for 65 min. Brains were removed 1 week after HI injury and infarct volumes were compared in H&E stained sections between the two groups.ResultsTLR-2 and TLR-3 were highly expressed in brains of P3 and P5 but not in P7 rats. The number of TLR-4 positive cells was lower in P3 and P5 compared to P7 brains (P <0.05). TLR-3 was predominately expressed in P5 pups (P <0.05). There was no significant difference in TLR-9 expression in the three age groups. There was a significant reduction in infarct volume (P = 0.01) in poly I:C compared to saline pre-treated P5 pups. Pre-treatment with poly I:C downregulated NF-κB and upregulated IRF3 expression in P5 rat ischemic brains. Pre-treatment with poly I:C did not offer neuroprotection in P7 rat brains.ConclusionTLRs expression and function is developmentally determined. Poly I:C-induced preconditioning against ischemic injury may be mediated by modulation of TLR-3 signaling pathways. This is the first study to show that TLR-3 is expressed in the immature brain and mediates preconditioning against ischemic injury.
Highlights
We have shown that preconditioning by lipopolysaccharide (LPS) will result in 90% reduction in ischemic brain damage in P7 rats
Toll-like receptors (TLRs) expression is modulated by brain maturity In this study, we examined the expression of TLR-2, TLR-3, Toll-like receptor 4 (TLR-4), and TLR-9 in the brains of P3, postnatal day 5 (P5), and P7 rat pups
TLR-2 and TLR-3 cortical expression were significantly higher in P3 and P5 compared to P7 rats, with the highest expression of TLR-3 in P5 rats (P
Summary
We have shown that preconditioning by lipopolysaccharide (LPS) will result in 90% reduction in ischemic brain damage in P7 rats. This robust LPS neuroprotection was not observed in P3 or P5 pups (corresponding to human premature infant). Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors that play a key role in host defense against pathogen infection. These receptors recognize a variety of pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, peptidoglycan, bacterial DNA, and double-stranded RNA [1]. The role of TLRs in ischemic injury of the developing brain is yet to be determined
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