Minocycline protects the immature white matter against hyperoxia

• Published in: Experimental neurology Vol. 254; pp. 153 - 165
• Main Authors: Schmitz, Thomas, Krabbe, Grietje, Weikert, Georg, Scheuer, Till, Matheus, Friederike, Wang, Yan, Mueller, Susanne, Kettenmann, Helmut, Matyash, Vitali, Bührer, Christoph, Endesfelder, Stefanie
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.04.2014; Elsevier
• Subjects: Age Factors; Animals; Animals, Newborn; Anti-Bacterial Agents - pharmacology; Biological and medical sciences; Diffusion Tensor Imaging; Disease Models, Animal; Female; Humans; Hyperoxia; Hyperoxia - drug therapy; Hyperoxia - pathology; Hypomyelination; Immature brain; Infant, Newborn; Leukoencephalopathies - pathology; Leukoencephalopathies - prevention & control; Male; Medical sciences; Microglia - cytology; Microglia - drug effects; Microglial activation; Minocycline; Minocycline - pharmacology; Nerve Fibers, Myelinated - drug effects; Neurology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; Oligodendroglia - cytology; Oligodendroglia - drug effects; Pharmacology. Drug treatments; Pregnancy; Preterm infants; Primary Cell Culture; Rats; Rats, Wistar; White matter damage; Neuroprotection; MHC II; OPC; MRI; PFA; TNF; IFN; Immature brain; TUNEL; WM; Minocycline; iNOS; MBP; EC; Microglial activation; CC; White matter damage; IL; Hypomyelination; ROI; SOX10; WMD; Hyperoxia; Preterm infants; FA; NGS; Olig2; Nervous system diseases; Central nervous system; White matter; Encephalon; Antibiotic; Prematurity; Antibacterial agent
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2014.01.017

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. •In preterm infants, hyperoxia is a risk factor for white matter damage.•In our rat experiments, hyperoxia causes oligodendroglial injury and partial microglial activation.•Minocycline prevents hyperoxia-induced changes in oligodendroglia and in microglia.•Minocycline preserves myelination of the developing rat brain exposed to hyperoxia.•Benefits of minocycline extend to improved white matter diffusivity until adult ages.