Abstract
Preterm brain injury is highly associated with inflammation, which is likely related in part to sterile responses to hypoxia-ischemia. We have recently shown that neuroprotection with inflammatory pre-conditioning in the immature brain is associated with induction of toll-like receptor 7 (TLR7). We therefore tested the hypothesis that central administration of a synthetic TLR7 agonist, gardiquimod (GDQ), after severe hypoxia-ischemia in preterm-equivalent fetal sheep would improve white and gray matter recovery. Fetal sheep at 0.7 of gestation received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 minutes, followed by a continuous intracerebroventricular infusion of GDQ or vehicle from 1 to 4 hours (total dose 1.8 mg/kg). Sheep were killed 72 hours after asphyxia for histology. GDQ significantly improved survival of immature and mature oligodendrocytes (2′,3′-cyclic-nucleotide 3′-phosphodiesterase, CNPase) and total oligodendrocytes (oligodendrocyte transcription factor 2, Olig-2) within the periventricular and intragyral white matter. There were reduced numbers of cells showing cleaved caspase-3 positive apoptosis and astrogliosis (glial fibrillary acidic protein, GFAP) in both white matter regions. Neuronal survival was increased in the dentate gyrus, caudate and medial thalamic nucleus. Central infusion of GDQ was associated with a robust increase in fetal plasma concentrations of the anti-inflammatory cytokines, interferon-β (IFN-β) and interleukin-10 (IL-10), with no significant change in the concentration of the pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α). In conclusion, delayed administration of the TLR7 agonist, GDQ, after severe hypoxia-ischemia in the developing brain markedly ameliorated white and gray matter damage, in association with upregulation of anti-inflammatory cytokines. These data strongly support the hypothesis that modulation of secondary inflammation may be a viable therapeutic target for injury of the preterm brain.
Highlights
Preterm infants continue to have a very high risk of adverse neurodevelopmental outcomes[1]
We have recently shown in preterm fetal sheep that lipopolysaccharide (LPS)-induced preconditioning before hypoxia-ischemia attenuates cellular apoptosis, microglial activation and reactive astrogliosis
We examined the hypothesis that central (intracerebroventricular (ICV)) infusion of the toll-like receptor 7 (TLR7) agonist, GDQ, after acute profound umbilical cord occlusion would reduce white and gray matter damage in 0.7 gestation preterm fetal sheep
Summary
Preterm infants continue to have a very high risk of adverse neurodevelopmental outcomes[1]. The link between inflammation and neural injury is complex, but at least in part it is highly likely that inflammation is a sterile response to hypoxia-ischemia[7]. Following hypoxia-ischemia, dead and dying cells release danger associated molecular patterns (DAMPs), which initiate a downstream pro-inflammatory immune response through activation of pattern recognition receptors (PPRS), such as toll-like receptors (TLRs), on the surface of microglia, astrocytes, brain endothelial cells, and perivascular macrophages[4,8,9]. We have recently shown in preterm fetal sheep that lipopolysaccharide (LPS)-induced preconditioning before hypoxia-ischemia attenuates cellular apoptosis, microglial activation and reactive astrogliosis. These protective responses were associated with up regulation of TLR7 gene expression and central and peripheral upregulation of IFN-β23. TLR7 signaling is protective against experimental autoimmune encephalomyelitis through IFN-β production and stimulation of IL-10 production and IL-10-inducing cytokines[25,26,27]
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