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) injury, activated microglia expand by proliferation, and migrate deeper into parenchymal regions. During this process, activated microglia exhibit a disproportionate elevation of the proinflammatory microglia phenotype (M1 nomenclature) from the total IBA-1+ microglia cell population along with tissue iron accumulation; this shift was reduced by sulforaphane (SFN; Nrf2-antioxidant response element [ARE] activator of anti-inflammatory pathways) plus deferoxamine (DFN; iron chelator) treatment. A separate DFN monotherapy 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 microglia and other cells, along with upregulated ferroptosis interactive network genes in IVH including: HMOX1, CTSB, FTL, PRM2, LPCAT1, and CDK1. Importantly, the expression of multiple key genes involved in iron metabolism and transport function included: ACSL4, TFRC, SLC7A11 and ABCA4 which were all downregulated in IVH and this trend was reversed after DFN treatment. Taken together, in the developing postnatal brain, the combination treatment of SFN-DFN mitigated M1 infiltration, reduced iron deposition in the tissue and in the CSF, suppressed the magnitude of inflammation and reduced cell death after IVH. Moreover, DFN monotreatment reversed most dysregulated genes in inflammation and iron homeostasis networks, revealing potential molecular targets for additional pharmacologic interventions after IVH. We speculate that reducing the toxic microcellular environment will attenuate injurious inflammatory responses and improve recovery of the trajectory toward normal brain development.