110 The Hmgb1 Receptor Rage Mediates Hypoxic Ischemic Brain Damage in Neonatal Mice

Abstract

Background and aims: Hypoxic ischemic (HI) brain injuries provoke cellular damage and subsequent inflammation that can lead to secondary brain injury. Recent data suggest that the receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 (HMGB1) are powerful mediators of ischemic inflammation and neurodegeneration in the adult brain, whereas its effects in the immature brain has not been studied. The aim of the present study was to investigate whether HMGB1 is present in the neonatal brain after HI and whether inactivation/deletion of RAGE affects neonatal brain damage. Method: We induced brain injury in neonatal mice pups in 10-day-old RAGE wild type (+/+) and knockout -/- mice using a modification of the Vannucci method. Briefly, we electrocoagulated the left common carotid artery and subjected the mice pups to hypoxia (10% O2) for 60 min. The injury was evaluated 2 weeks after HI using immunohistochemistry and beam walking, a test of balance and coordination. Results: First we confirmed that HMGB-1 is expressed in the neonatal mouse brain. We then found that immunoreactivity increased in the injured area. In the RAGE -/- mice, the brain damage was reduced by more than 70% compared with RAGE +/+ mice (p< 0.01). A better functional outcome after HI was seen in RAGE -/- mice compared with RAGE +/+ mice using the beam walking test (p< 0.001). Conclusions: There is a major detrimental effect of RAGE receptor activation in neonatal mice and HMGB1-RAGE receptor signaling represents an interesting target for neonatal neuroprotection.