Abstract
BackgroundPerinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. The molecular mechanisms of this protection have, however, not been elucidated. Evidence implicates that inflammatory cytokines play a protective role in the induction of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult.MethodsIn rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global PA was induced by placing the uterine horns, containing the pups, in a saline bath for 19 min. We assessed, at different time points after FA and PA, mRNA and protein expression of several cytokines and related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally, we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines.ResultsPrenatally, FA induced acute downregulation in IL-1β, TNF-α and IL-10 mRNA levels. At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3 levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6 mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and IL-6 mRNA levels were comparable to those in controls.ConclusionsFA leads to prenatal changes in the neuroinflammatory response. This modulation of the cytokine response probably results in the protective inflammatory phenotype seen when combining FA and PA and may have significant implications for preventing post-asphyctic perinatal encephalopathy.
Highlights
Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants
Acute downregulation of IL-1β, tumor necrosis factor (TNF)-α and IL-10 mRNA levels but increased IL-6 mRNA and IL-10 protein expression occurred 96 h after fetal asphyxia Prenatally, FA induced an acute downregulation of IL-1β at 2 h (Figure 2A; p = 0.008) and TNF-α at 6 h (Figure 2B; p = 0.05) compared with respective controls
The antiinflammatory cytokine IL-10 followed the same pattern as the acute inflammatory response of IL-1β and TNF-α, with decreased IL-10 mRNA levels at 12 h after FA (Figure 2C; p = 0.02)
Summary
Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. We hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult. Irrespective of the prevalence of PA, there is no effective treatment for term infants having post-asphyctic encephalopathy, except for hypothermia for Several studies suggest that inflammation has a key role in perinatal brain injury, including cerebral hypoxia/. Inflammatory cells, such as neutrophils and macrophages, and resident brain cells, such as astrocytes and microglia, have been found to be activated by cerebral ischemia These cells produce inflammatory mediators, including reactive oxygen species and cytokines [8]. We found that FA induces time-dependent cytokine changes, probably resulting in a protective inflammatory phenotype when followed by PA
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