Background
Toll-like receptors (TLRs) are key regulators of innate immunity and mediate induction of a balanced inflammatory response designed to clear cellular debris and induce tissue repair. TLR activation can increase neural injury but can be neuroprotective, as we have recently shown with the TLR7 agonist Gardiquimod (GDQ). Importantly, adult studies show that TLRs can affect vascular function and neuronal excitability. In this study, we examined the effects of GDQ on post-asphyxial cardiovascular and neurophysiological adaption and seizures in preterm fetal sheep.
Methods
Preterm fetal sheep at 0.7 gestation (104 days, term ~147 days) received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 min. Asphyxia groups randomly received either a continuous intracerebroventricular infusion of GDQ (1.8mg/kg) or vehicle from 1-4 h after asphyxia. Mean arterial blood pressure (MAP), fetal heart rate (FHR) and electroencephalographic (EEG) activity were measured from 24 h before, until 72 h after occlusion. Seizures were analysed off-line.
Results
GDQ treatment was associated with sustained moderate hypertension for 72 h (~44.0 vs. 36.0 mmHg, P<0.05), that was only transiently associated with increased FHR. EEG power was similarly suppressed after asphyxia in both groups; however, EEG frequency increased during GDQ infusion (P<0.05). This was associated with higher alpha and beta and lower delta frequencies (P<0.05), but no change in epileptiform transient activity. GDQ infusion was associated with earlier onset of high amplitude stereotypic evolving seizures, and increased seizure number and burden (P<0.05).
Conclusion
These data are of high importance since immunomodulators, such as GDQ, are potential neuroprotective candidates. Our results highlight the potential for TLR7 agonists to cause hypertension, likely through increased vascular resistance, and to modulate seizures and EEG frequency. These are important indices of preterm neonatal wellbeing. Notably, histological neuroprotection was observed despite hypertension and increased seizure activity.