Minocycline Alleviates Hypoxic-Ischemic Injury to Developing Oligodendrocytes in the Neonatal Rat Brain

Neuroscience. 2006;137(2):425-35. doi: 10.1016/j.neuroscience.2005.09.023. Epub 2005 Nov 14.

Abstract

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 (45 mg/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-1beta 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Antigens, Surface / metabolism
  • Biomarkers / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Carotid Artery, Common
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Disease Models, Animal
  • Free Radicals / metabolism
  • Gliosis / drug therapy
  • Gliosis / physiopathology
  • Gliosis / prevention & control
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / metabolism
  • Hypoxia-Ischemia, Brain / physiopathology
  • Ligation
  • Microglia / drug effects
  • Microglia / metabolism
  • Minocycline / pharmacology*
  • Minocycline / therapeutic use
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / physiopathology
  • Nerve Degeneration / prevention & control
  • Nerve Fibers, Myelinated / drug effects
  • Nerve Fibers, Myelinated / metabolism
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / physiology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Oligodendroglia / drug effects*
  • Oligodendroglia / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Treatment Outcome

Substances

  • Antigens, Surface
  • Biomarkers
  • Free Radicals
  • Neuroprotective Agents
  • Minocycline