Inhibition of neuroinflammation prevents injury to the serotonergic network after hypoxia-ischemia in the immature rat brain.

The phenotypic identities and characterization of neural networks disrupted after neonatal hypoxia-ischemia (HI) in the preterm brain remain to be elucidated. Interruption of the central serotonergic (5-hydroxytryptamine [5-HT]) system can lead to numerous functional deficits, many of which match those in human preterm neonates exposed to HI. How the central serotonergic network is damaged after HI and mechanisms underlying such injury are not known. We used a Postnatal Day 3 rat model of preterm HI and found parallel reductions in the 5-HT transporter expression, 5-HT levels and numbers of 5-HT-positive dorsal raphe neurons 1 week after insult. Post-HI administration of minocycline, an inhibitor of activated microglia, attenuated HI-induced damage to the serotonergic network. Minocycline effects seemed to be region specific, that is, where there was micro-glial activation and increases in tumor necrosis factor-α and inter-leukin 1β. The concurrent improvement in serotonergic outcomes suggests that inhibition of neuroinflammation prevented damage to the serotonergic neurons rather than affected the regulation of 5-HT or serotonin transporter. These data elucidate the mechanisms of serotonergic network injury in HI, and despite the known adverse effects associated with the use of minocycline in neonates, postinsult administration of minocycline may represent a novel approach to counter neuroinflammation and preserve the integrity of the central serotonergic network in the preterm neonate.