minocycline and Leukomalacia--Periventricular

Periventricular leukomalacia is a common white-matter injury after neonatal cardiac surgery; however, its potential cellular mechanism remains uncertain. There is limited study regarding periventricular leukomalacia treatment.. A neonatal rat brain slice perfusion model was used for reproducing the condition of cardiopulmonary bypass, and oxygen glucose deprivation simulated circulatory arrest. Seven-day-old Sprague-Dawley rats were randomly divided into 7 groups: (1) control group with 36°C; (2) 60 minutes of oxygen glucose deprivation group on 15°C, 25°C, 36°C, respectively; and (3) 60 minutes of oxygen glucose deprivation group on 15°C, 25°C, 36°C, plus minocycline (10 μmol/L), respectively. Immunohistochemistry, Western blot, and inflammatory mediators were compared after the perfusion procedures in the different groups.. This neonatal rat brain slice perfusion with oxygen glucose deprivation model could replicate the pathophysiologic process and injury after cardiopulmonary bypass and hypothermic circulatory arrest. With the increase of oxygen glucose deprivation perfusion temperature, we found that both microglia activation and preoligodendrocyte loss increased. The application of minocycline can significantly inhibit microglial activation and preoligodendrocyte cells loss in the normothermic (36°C) and moderate hypothermia (25°C) oxygen glucose deprivation groups (P < .05), with accompanying significant decreasing microglial inflammatory productions; however, no significant improvement was found in the deep hypothermia (15°C) group.. The microglial activation may play a key role in preoligodendrocyte injury in the ex vivo neonatal rat brain slice perfusion and circulatory arrest model. Inhibition of microglial activation with minocycline may be an attractive target for white-matter protection during cardiopulmonary bypass and hypothermic circulatory arrest.

Topics: Animals; Animals, Newborn; Cardiopulmonary Bypass; Cell Hypoxia; Cell Survival; Female; Glucose; Heart Arrest, Induced; Hypothermia, Induced; In Vitro Techniques; Interleukin-6; Leukomalacia, Periventricular; Male; Microglia; Minocycline; Neuroprotective Agents; Oligodendrocyte Precursor Cells; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Periventricular white matter injury in premature infants occurs following hypoxia/ischaemia and systemic infection, and results in hypomyelination, as well as neuromotor and cognitive deficits later in life. Inflammatory infiltrates are seen within human cerebral white matter from periventricular leucomalacia (PVL) cases.. In this study, we examine the time course of CD-68+ microglial cell responses relative to cell death within white matter following hypoxia/ischaemia in a rat model of PVL. We also tested the efficacy of the minocycline, an agent that suppresses microglial activation, in this model when administered as a post-insult treatment.. We show that preoligodendrocyte injury in the post-natal day 6 begins within 24 h and continues for 48-96 h after hypoxia/ischaemia, and that microglial responses occur primarily over the first 96 h following hypoxia/ischaemia. Minocycline treatment over this 96 h time window following the insult resulted in significant protection against white matter injury, and this effect was concomitant with a reduction in CD-68+ microglial cell numbers.. These results suggest that anti-inflammatory treatments may represent a useful strategy in the treatment of PVL, where clinical conditions would favour a post-insult treatment strategy.

Topics: Animals; Animals, Newborn; Cell Death; Disease Models, Animal; Humans; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Infant, Newborn; Leukomalacia, Periventricular; Microglia; Minocycline; Myelin Basic Protein; Rats; Rats, Long-Evans; Tegmentum Mesencephali

To investigate whether minocycline provides long-lasting protection against neonatal hypoxia-ischemia-induced brain injury and neurobehavioral deficits, minocycline was administered intraperitoneally in postnatal day 4 Sprague-Dawley rats subjected to bilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 15 min). Brain injury and myelination were examined on postnatal day 21 (P21) and tests for neurobehavioral toxicity were performed from P3 to P21. Hypoxic-ischemic insults resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, reduction in numbers of mature oligodendrocytes and tyrosine hydroxylase-positive neurons, damage to axons and dendrites, and impaired myelination, as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. Hypoxic-ischemic insult also significantly affected physical development (body weight gain and eye opening) and neurobehavioral performance, including sensorimotor and locomotor function, anxiety and cognitive ability in the P21 rat. Treatments with minocycline significantly attenuated the hypoxia-ischemia-induced brain injury and improved neurobehavioral performance. The protection of minocycline was associated with its ability to reduce microglial activation. The present results show that minocycline has long-lasting protective effects in the neonatal rat brain in terms of both hypoxia-ischemia-induced brain injury and the associated neurological dysfunction.

Topics: Age Factors; Animals; Animals, Newborn; Brain; Brain Damage, Chronic; Brain Infarction; Cytoprotection; Disease Models, Animal; Female; Fetal Hypoxia; Gliosis; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Injections, Intraperitoneal; Leukomalacia, Periventricular; Male; Minocycline; Nerve Degeneration; Nerve Fibers, Myelinated; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Treatment Outcome