1. ¹Department of Pediatrics, Lund University, Lund, Sweden
2. ²Department of Neurology, Lund University, Lund, Sweden
3. ³Department of Clinical Sciences, Cellular Autoimmunity Unit, Lund University, Malmö University Hospital, Malmö, Sweden
4. ⁴Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
5. ⁵Department of Experimental Brain Research, Lund University, Lund, Sweden

Correspondence: T Markus, Department of Pediatrics, Lund University, Tornav 10, Lund S-221 85, Sweden. E-mail: Tina.Markus@med.lu.se

Received 5 March 2008; Revised 10 June 2008; Accepted 14 July 2008; Published online 27 August 2008.

Abstract

Inflammation and ischemia have a synergistic damaging effect in the immature brain. The role of tumor necrosis factor (TNF) receptors 1 and 2 in lipopolysaccharide (LPS)-induced sensitization and tolerance to oxygen–glucose deprivation (OGD) was evaluated in neonatal murine hippocampal organotypic slices. Hippocampal slices from balb/c, C57BL/6 TNFR1^-/-, TNFR2^-/-, and wild-type (WT) mice obtained at P6 were grown in vitro for 9 days. Preexposure to LPS immediately before OGD increased propidium iodide-determined cell death in regions CA1, CA3, and dentate gyrus from 4 up to 48 h after OGD (P<0.001). Extending the time interval between LPS exposure and OGD to 72 h resulted in tolerance, that is reduced neuronal cell death after OGD (P<0.05). Slices from TNFR1^-/- mice showed neither LPS-induced sensitization nor LPS-induced tolerance to OGD, whereas both effects were present in slices from TNFR2^-/- and WT mice. Cytokine secretion (TNF and interleukin-6) during LPS exposure was decreased in TNFR1^-/- slices and increased in TNFR2^-/- as compared with WT slices. We conclude that LPS induces sensitization or tolerance to OGD depending on the time interval between exposure to LPS and OGD in murine hippocampal slice cultures. Both paradigms are dependent on signaling through TNFR1.