title: Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain.
abstract: Acute exposure to subclinical infection modulates subsequent hypoxia-ischemia (HI) injury in a time-dependent manner, likely by cross-talk through Toll-like receptors (TLRs), but the specific pathways are unclear in the preterm-equivalent brain. In the present study, we tested the hypothesis that repeated low-dose exposure to lipopolysaccharide (LPS) before acute ischemia would be associated with induction of specific TLRs that are potentially neuroprotective. Fetal sheep at 0.65 gestation (term is ∼145 days) received intravenous boluses of low-dose LPS for 5 days (day 1, 50 ng/kg; days 2-5, 100 ng/kg) or the same volume of saline. Either 4 or 24 h after the last bolus of LPS, complete carotid occlusion was induced for 22 min. Five days after LPS, brains were collected. Pretreatment with LPS for 5 days decreased cellular apoptosis, microglial activation and reactive astrogliosis in response to HI injury induced 24 but not 4 h after the last dose of LPS. This was associated with upregulation of TLR4, TLR7 and IFN-β mRNA, and increased fetal plasma IFN-β concentrations. The association of reduced white matter apoptosis and astrogliosis after repeated low-dose LPS finishing 24 h but not 4 h before cerebral ischemia, with central and peripheral induction of IFN-β, suggests the possibility that IFN-β may be an important mediator of endogenous neuroprotection in the developing brain.
authors.affiliation: Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Simerdeep K
authors.initials: SK
authors.lastname: Dhillon
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
authors.forename: Yewon
authors.initials: Y
authors.lastname: Jung
authors.forename: Sam
authors.initials: S
authors.lastname: Mathai
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.forename: Mhoyra
authors.initials: M
authors.lastname: Fraser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000196:embryology* / Q000276:immunology; D001930:Brain Injuries / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D005333:Fetus / Q000187:drug effects / Q000276:immunology; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology*; D016899:Interferon-beta / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D049188:Prenatal Injuries / Q000276:immunology*; D034561:Sheep, Domestic; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D016899:Interferon-beta