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*Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden;
Department of Pediatrics, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China;
AstraZeneca Research and Development, Mölndal, Sweden;
Department of Rheumatology and Inflammation Research, University of Gothenburg, Göteborg, Sweden;
¶Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; and
||Institute of Reproductive and Developmental Biology, Imperial College, London, United Kingdom
Neurological deficits in children, including cerebral palsy, are associated with prior infection during the perinatal period. Experimentally, we have shown that pre-exposure to the Gram-negative component LPS potentiates hypoxic-ischemic (HI) brain injury in newborn animals. LPS effects are mediated by binding to TLR4, which requires recruitment of the MyD88 adaptor protein or Toll/IL-1R domain-containing adapter inducing IFN-β for signal transduction. In this study, we investigated the role of MyD88 in neonatal brain injury. MyD88 knockout (MyD88 KO) and wild-type mice were subjected to left carotid artery ligation and 10% O2 for 50 min on postnatal day 9. LPS or saline were administered i.p. at 14 h before HI. At 5 days after HI in wild-type mice, LPS in combination with HI caused a significant increase in gray and white matter tissue loss compared with the saline-HI group. By contrast, in the MyD88 KO mice there was no potentiation of brain injury with LPS-HI. MyD88 KO mice exhibited reduced NF
B activation and proinflammatory cytokine-chemokine expression in response to LPS. The number of microglia and caspase-3 activation was increased in the brain of MyD88 KO mice after LPS exposure. Collectively, these findings indicate that MyD88 plays an essential role in LPS-sensitized HI neonatal brain injury, which involves both inflammatory and caspase-dependent pathways.
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1 This work was supported by Swedish Medical Research Council Grants VR K2007-54x-14185-06-3 (to C.M.), VR 2006-3396 (to H.H.), and VR 2009-54X-21119-01-4 (to X.W.); Sixth Framework Program of the European Commission (2006-036534/neobrain), Åhléns stiftelsen, Frimurare barnhusfonden, and Lundgrenska stiftelserna (to C.M.); Swedish governmental grants to researchers in the Public Health Service (ALFGBG2863 to H.H.); and National Natural Science Foundation of China Grant 30973240 (to X.W.).
2 Address correspondence and reprint requests to Dr. Carina Mallard, Perinatal Center, Department of Physiology and Neuroscience, Sahlgrenska Academy, Gothenburg University, Box 432, S-405 30, Goteborg, Sweden. E-mail address: carina.mallard{at}gu.se
3 Abbreviations used in this paper: HI, hypoxia ischemia; WT, wild type; KO, knockout; HET, heterozygotes; PND, postnatal day; MAP-2, microtubule-associated protein-2; MBP, myelin basic protein; Iba-1, ionized calcium binding-adapter molecule 1; Cyt C, cytochrome c; p-IB, phosphorylation of IB.
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