Post-insult minocycline treatment attenuates hypoxia-ischemia-induced neuroinflammation and white matter injury in the neonatal rat: a comparison of two different dose regimens

Abstract

An increase in the number of activated microglia in the brain is a key feature of neuroinflammation after a hypoxic–ischemic insult to the preterm neonate and can contribute to white matter injury in the brain. Minocycline is a potent inhibitor of microglia and may have a role as a neuroprotective agent that ameliorates brain injury after hypoxia–ischemia in neonatal animal models. However to date large doses, pre-insult administration and short periods of treatment after hypoxia–ischemia have mostly been investigated in animal models making it difficult to translate minocycline's potential applicability to protect the human preterm neonatal brain exposed to hypoxia–ischemia. We investigated whether repeated doses of minocycline can minimize white matter injury and neuroinflammation one week after hypoxia–ischemia (right carotid artery ligation and 30min 6% O2) in the post-natal day 3 rat pup. Two dosage regimens of minocycline were administered for one week; a high dose of 45mg/kg 2h after hypoxia–ischemia then 22.5mg/kg daily or a low dose 22.5mg/kg 2h after hypoxia–ischemia then 10mg/kg. Post-natal day 3 hypoxia–ischemia significantly reduced myelin content, numbers of O1- and O4-positive oligodendrocyte progenitor cells and increased activated microglia one week later on post-natal day 10. The low dose minocycline regimen was as effective as the high dose in ameliorating neuroinflammation after post-natal day 3 hypoxia–ischemia. However only the high dose regimen significantly attenuated reductions in O1- and O4-positive oligodendrocyte progenitor cells and myelin content. The low dose only significantly attenuated the reduction in O1-positive oligodendrocyte cell counts. Repeated, daily, post-insult treatment with minocycline abolished neuroinflammation and may provide neuroprotection to white matter for up to one week after hypoxia–ischemia in a rodent preterm model. The present findings suggest the potential clinical relevance of a repeated, daily minocycline treatment strategy, administered after a hypoxia–ischemia insult, as a therapeutic intervention for hypoxia–ischemia-affected preterm neonates.