Aims: White matter (WM) injury after intracerebral hemorrhage (ICH) results in poor or even fatal outcomes. As an anti-inflammatory drug, minocycline has been considered a promising choice to treat brain injury after ICH. However, whether minocycline can reduce WM injury after ICH is still controversial. In the present study, we investigate the effect and underlying mechanism of minocycline on WM injury after ICH.
Methods: An ICH model was induced by an injection of autologous blood into the right frontal lobe of piglets. First, transcriptional analysis was performed at day 1 or 3 to investigate the dynamic changes in neuroinflammatory gene expression in WM after ICH. Second, ICH piglets were treated either with minocycline or with vehicle alone. All piglets then underwent magnetic resonance imaging to measure brain swelling. Brain tissue was used for real-time polymerase chain reaction (RT-PCR), immunohistochemistry, Western blot, and electron microscopy.
Results: Transcriptional analysis demonstrated that transforming growth factor-β (TGF-β)/mitogen-activated protein kinase (MAPK) signaling is associated with microglia/macrophage-mediated inflammation activation after ICH and is then involved in WM injury after ICH in piglets. Minocycline treatment results in less ICH-induced brain swelling, fewer neurological deficits, and less WM injury in comparison with the vehicle alone. In addition, minocycline reduces microglial activation and alleviates demyelination in white matter after ICH. Finally, we found that minocycline attenuates WM injury by increasing the expression of TGF-β and suppressing MAPK activation after ICH.
Conclusion: These results indicate that TGF-β-mediated MAPK signaling contributes to WM injury after ICH, which can be altered by minocycline treatment.
Keywords: intracerebral hemorrhage; minocycline; mitogen-activated protein kinases; transforming growth factor-β; white matter injury.
© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.