Abstract
Background: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic–ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control. Methods: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia. Results: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery (p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery (p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus (r2 = 0.61, p < 0.05) and CA1/2 hippocampal region (r2 = 0.66, p < 0.05). Conclusion: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions.
Highlights
Hypoxic–ischemic encephalopathy (HIE) is more frequent in preterm infants than at term [1] and is highly associated with increased risk of adverse outcomes, such as subcortical brain injury and life-long neurodevelopmental disabilities [2,3]
We previously reported that central infusion of the synthetic TLR7 agonist Gardiquimod (GDQ) from 1 to 4 h after asphyxia in preterm fetal sheep reduced white and grey matter damage after 3 days recovery [13]
We examined the hypothesis that this apparent transient histological neuroprotection after an early TLR7 agonist infusion after asphyxia, in preterm fetal sheep at 0.7 gestation [15], is associated with modulation of seizure-genic processes and hemodynamic control
Summary
Hypoxic–ischemic encephalopathy (HIE) is more frequent in preterm infants than at term [1] and is highly associated with increased risk of adverse outcomes, such as subcortical brain injury and life-long neurodevelopmental disabilities [2,3]. We previously reported that central infusion of the synthetic TLR7 agonist Gardiquimod (GDQ) from 1 to 4 h after asphyxia in preterm fetal sheep reduced white and grey matter damage after 3 days recovery [13]. In this cohort, central GDQ administration was associated with hypertension and transiently improved recovery of spectral edge frequency (SEF), and suppression of epileptiform transients [14]. In that study, GDQ was associated with increased neuronal survival in the CA4 region of the hippocampus but greater neuronal loss in the caudate nucleus
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