Inhibition of microglial activation by minocycline reduced preoligodendrocyte injury in a neonatal rat brain slice model

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: congenital heart defect; microglia; minocycline; preoligodendrocyte; white-matter.