Abstract
Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term “oxygen radical disease of prematurity”. Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28–32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.
Highlights
Advances in neonatal intensive care have led to a significant increase in the survival rate of premature infants, but extremely premature infants have a higher risk of dying or suffering permanent and serious damage [1,2]
There are several reasons for the high susceptibility of preterm infants to oxidative damage: (i) birth is associated with a dramatic change of intrauterine hypoxic milieu to a relatively hyperoxic extrauterine environment, and this relative hyperoxia can be enhanced by supplemental oxygen [7,8]; (ii) premature infants are less able to cope with the oxygen-rich environment of extrauterine life because their antioxidant defense system is poorly developed [9]; and (iii) preterm infants have increased susceptibility to infections [5]
Thiobarbituric acid reactive substances (TBARS) were increased in brain tissue of newborn rats exposed to 24 h of hyperoxia to 180% ± 27.4% (p < 0.01) compared to litter control mates kept in atmospheric air (Figure 1A)
Summary
Advances in neonatal intensive care have led to a significant increase in the survival rate of premature infants, but extremely premature infants have a higher risk of dying or suffering permanent and serious damage [1,2]. Up to 50% of surviving extremely preterm infants show cognitive deficits or behavioral problems during the later stages of development [3]. The antioxidative defense system undergoes developmental changes during the neonatal period, resulting in a relevantly lower intracellular defense in preterm infants compared to term infants [10]
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