Minocycline protects the immature white matter against hyperoxia.
Poor neurological outcome in preterm infants is associated with periventricular white matter damage and hypomyelination, often caused by perinatal inflammation, hypoxia-ischemia, and hyperoxia. Minocycline has been demonstrated in animal models to protect the immature brain against inflammation and hypoxia-ischemia by microglial inhibition. Here we studied the effect of minocycline on white matter damage caused by hyperoxia. To mimic the 3- to 4-fold increase of oxygen tension caused by preterm birth, we have used the hyperoxia model in neonatal rats providing 24h exposure to 4-fold increased oxygen concentration (80% instead of 21% O2) from P6 to P7. We analyzed whether minocycline prevents activation of microglia and damage of oligodendroglial precursor cell development, and whether acute treatment of hyperoxia-exposed rats with minocycline improves long term white matter integrity. Minocycline administration during exposure to hyperoxia resulted in decreased apoptotic cell death and in improved proliferation and maturation of oligodendroglial precursor cells (OPC). Minocycline blocked changes in microglial morphology and IL-1β release induced by hyperoxia. In primary microglial cell cultures, minocycline inhibited cytokine release while in mono-cultures of OPCs, it improved survival and proliferation. Long term impairment of white matter diffusivity in MRI/DTI in P30 and P60 animals after neonatal hyperoxia was attenuated by minocycline. Minocycline protects white matter development against oxygen toxicity through direct protection of oligodendroglia and by microglial inhibition. This study moreover demonstrates long term benefits of minocycline on white matter integrity.
Department for Neonatology, Charité University Medical Center, Berlin, Germany. Electronic address: thomas.schmitz@charite.de.
Thomas
T
Schmitz
Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin, Germany.
Grietje
G
Krabbe
Department for Neonatology, Charité University Medical Center, Berlin, Germany.
Georg
G
Weikert
Department for Neonatology, Charité University Medical Center, Berlin, Germany.
Till
T
Scheuer
Department for Neonatology, Charité University Medical Center, Berlin, Germany.
Friederike
F
Matheus
Department for Neonatology, Charité University Medical Center, Berlin, Germany.
Yan
Y
Wang
Berlin Center for Stroke Research, Charité University Medical Center, Berlin, Germany.
Susanne
S
Mueller
Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin, Germany.
Helmut
H
Kettenmann
Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin, Germany.
Vitali
V
Matyash
Department for Neonatology, Charité University Medical Center, Berlin, Germany.
Christoph
C
Bührer
Department for Neonatology, Charité University Medical Center, Berlin, Germany.
Stefanie
S
Endesfelder
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000188:drug therapy* / Q000473:pathology; D007231:Infant, Newborn; D056784:Leukoencephalopathies / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D011247:Pregnancy; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D008911:Minocycline
Hyperoxia; Hypomyelination; Immature brain; Microglial activation; Minocycline; Neuroprotection; Preterm infants; White matter damage