Combination Drug Therapy Reduces Iron Accumulation and Microglia-Mediated Pathologies in Neonatal Intraventricular Hemorrhage: A Biochemical and Transcriptomic Analysis
This study describes the distribution of non-reactive brain-resident microglia densely populated along the borders of the lateral ventricles and choroid plexus in premature rabbit pups during early forebrain development. Following intraventricular hemorrhage (IVH), microglia become activated, proliferate, and migrate deeper into parenchymal regions. During this process, activated microglia exhibit a global expansion with a disproportionally elevated proinflammatory M1 nomenclature phenotype from 25% to 50% of the total; that shift was reduced by sulforaphane (SFN; Nrf2-antioxidant response element [ARE] activator of anti-inflammatory pathways) plus deferoxamine (DFN; iron chelator) treatment. Transcriptome analysis identified over expression of pro-inflammatory calcium-binding proteins S100A8 and S100A12 (intracellular damage signals), as well as chemokines CXCL8 and CXCL10 by neurons and microglia. The combination treatment of SFN-DFN mitigated M1 infiltration, suppressed the magnitude of inflammation and reduced ferroptosis after IVH in the developing postnatal brain. Moreover, SFN-DFN treatment reversed most dysregulated genes in inflammation and iron homeostasis networks, revealing potential molecular targets for additional pharmacologic interventions after IVH. We propose that reducing the toxic microcellular environment will attenuate both the injurious inflammatory responses and improve recovery of the trajectory toward normal brain development. Additionally, suppression of proinflammatory molecules and iron toxicity should promote better survival as well as salutary effects of "living stem cell therapy" as we have previously shown.