Minocycline alleviates hypoxic–ischemic injury to developing oligodendrocytes in the neonatal rat brain

The role of minocycline in preventing white matter injury, in particular the injury to developing oligodendrocytes was examined in a neonatal rat model of hypoxia–ischemia. Hypoxia–ischemia was achieved through bilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen) for 15 min in postnatal day 4 Sprague–Dawley rats. A sham operation was performed in control rats. Minocycline (45mg/kg) or normal phosphate-buffered saline was administered intraperitoneally 12 h before and immediately after bilateral carotid artery occlusion+hypoxia and then every 24 h for 3 days. Nissl staining revealed pyknotic cells in the white matter area of the rat brain 1 and 5 days after hypoxia–ischemia. Hypoxia–ischemia insult also resulted in apoptotic oligodendrocyte cell death, loss of O4+ and O1+ oligodendrocyte immunoreactivity, and hypomyelination as indicated by decreased myelin basic protein immunostaining and by loss of mature oligodendrocytes in the rat brain. Minocycline significantly attenuated hypoxia–ischemia-induced brain injury. The protective effect of minocycline was associated with suppression of hypoxia–ischemia-induced microglial activation as indicated by the decreased number of activated microglia, which were also interleukin-1β and inducible nitric oxide synthase expressing cells. The protective effect of minocycline was also linked with reduction in hypoxia–ischemia-induced oxidative and nitrosative stress as indicated by 4-hydroxynonenal and nitrotyrosine positive oligodendrocytes, respectively. The reduction in hypoxia–ischemia-induced oxidative stress was also evidenced by the decreases in the content of 8-isoprostane in the minocycline-treated hypoxia–ischemia rat brain as compared with that in the vehicle-treated hypoxia–ischemia rat brain. The overall results suggest that reduction in microglial activation may protect developing oligodendrocytes in the neonatal brain from hypoxia–ischemia injury.