Background And Purpose: Perinatal hypoxia-ischemia (HI) produces acute and prolonged inflammation of the brain. Mast cells (MCs), numerous in the pia and CNS of neonatal rats, can initiate inflammation attributable to preformed mediators. MCs contribute to HI brain damage in the neonatal rat; MC stabilization protects through 48 hours of reperfusion. Here we hypothesize that HI induces early MC migration, activation, and release of proinflammatory molecules.
Methods: HI was induced by right CCA ligation and 75 minutes 8% oxygen. Histochemistry and immunocytochemistry described the time course of early cellular changes in the CNS. For neuroprotection by MC stabilization, pups were treated with Cromolyn (CR) during the initial 24 hours post-HI; brains were examined through 4 weeks.
Results: Brain MC number and activation were elevated in ipsilateral hemisphere immediately after HI (P<0.05), before detection of cleaved caspase-3 in neurons (NeuN+; 2 hours post-HI), astroglial activation (GFAP+ with swollen cell body, 4 hours post-HI), or microglial activation (OX42+, 4 hours post-HI). TNF-alpha-positive MCs were present in a subpopulation of MCs in control animals and the percent of TNF-alpha MCs increased dramatically ipsilaterally immediately after HI (P<0.01). Microglial TNF-alpha was evident at 4 hours; endothelial cells had no detectable TNF-alpha until 48 hours post-HI. Cromolyn prevented MC migration, reduced brain damage/neuronal loss, glial activation, and brain atrophy through 4 weeks of recovery (P<0.05).
Conclusions: MCs are early responders to HI in neonatal brain. MC stabilization provides lasting protection and suggests a new target for therapeutic interventions.
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| http://dx.doi.org/10.1161/STROKEAHA.109.549691 | DOI Listing |
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