Abstract
In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1–4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.
Highlights
Preterm birth is closely associated with long-term neurodevelopmental disability[1]
We have previously shown that pre-conditioning with the inflammatory mediator lipopolysaccharide (LPS) before an hypoxic-ischemic (HI) insult in the preterm fetal sheep reduced preterm brain injury, in association with upregulation of TLR7 gene expression and both central and peripheral induction of interferon-β (IFN-β)[19]
In the two occlusion groups, Umbilical cord occlusion (UCO) was associated with a significant reduction in both fetal mean arterial pressure (MAP) and fetal heart rate (FHR) compared to sham asphyxia, which was not significantly different from each other (p > 0.05)
Summary
Preterm birth is closely associated with long-term neurodevelopmental disability[1]. While survival rates among preterm infants have significantly improved, rates of neonatal morbidity remain high with 50% of extremely preterm infants displaying cognitive and behavioural difficulties[2,3,4]. The etiology of preterm brain injury is multifactorial[5], a key contributing factor is the greater occurrence of acute hypoxic ischemic encephalopathy (HIE) in moderately preterm infants compared to term[6]. We have previously shown that pre-conditioning with the inflammatory mediator lipopolysaccharide (LPS) before an hypoxic-ischemic (HI) insult in the preterm fetal sheep reduced preterm brain injury, in association with upregulation of TLR7 gene expression and both central and peripheral induction of interferon-β (IFN-β)[19]. The purpose of this study was to evaluate the effect of delayed GDQ administration on cerebral white and grey matter 7 days after an acute HI insult in utero in 0.7 gestation preterm fetal sheep. Neural development of the preterm fetal sheep at this gestational age is broadly equivalent to human brain development at 28–32 weeks gestation[26]
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