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

Background: 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). 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.methods: tlr-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.results: tlr-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.conclusion: tlrs 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. © 2013 shi et al.; licensee biomed central ltd.