title: TLR-3 receptor activation protects the very immature brain from ischemic injury.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Hui
authors: H
authors: Shi
authors: Nadia
authors: N
authors: Gabarin
authors: Edward
authors: E
authors: Hickey
authors: Rand
authors: R
authors: Askalan
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D001930:Brain Injuries / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007369:Interferon Inducers / Q000494:pharmacology / Q000627:therapeutic use; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007511:Ischemia / Q000150:complications*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005904:Glial Fibrillary Acidic Protein; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D010751:Phosphopyruvate Hydratase; D011070:Poly I-C; D051196:Toll-Like Receptor 3; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C530472:TLR3 protein, rat
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