Abstract
Fetal brain hypoxic injury remains a concern in high-risk delivery. There is significant clinical interest in agents that may diminish neuronal damage during birth asphyxia, such as in allopurinol, an inhibitor of the prooxidant enzyme xanthine oxidase. Here, we established in a rodent model the capacity of allopurinol to be taken up by the mother, cross the placenta, rise to therapeutic levels, and suppress xanthine oxidase activity in the fetus. On day 20 of pregnancy, Wistar dams were given 30 or 100 mg kg−1 allopurinol orally. Maternal and fetal plasma allopurinol and oxypurinol concentrations were measured, and xanthine oxidase activity in the placenta and maternal and fetal tissues determined. There were significant strong positive correlations between maternal and fetal plasma allopurinol (r = 0.97, P < 0.05) and oxypurinol (r = 0.88, P < 0.05) levels. Under baseline conditions, maternal heart (2.18 ± 0.62 mU mg−1), maternal liver (0.29 ± 0.08 mU mg−1), placenta (1.36 ± 0.42 mU mg−1), fetal heart (1.64 ± 0.59 mU mg−1), and fetal liver (0.14 ± 0.08 mU mg−1) samples all showed significant xanthine oxidase activity. This activity was suppressed in all tissues 2 h after allopurinol administration and remained suppressed 24 h later (P < 0.05), despite allopurinol and oxypurinol levels returning toward baseline. The data establish a mammalian model of xanthine oxidase inhibition in the mother, placenta, and fetus, allowing investigation of the role of xanthine oxidase–derived reactive oxygen species in the maternal, placental, and fetal physiology during healthy and complicated pregnancy.
Highlights
Despite advances in obstetric practice, acute intrapartum fetal hypoxia remains one of the most common forms of fetal stress, with substantial morbidity and mortality (Low 2004)
There has been growing clinical and scientific interest in establishing whether perinatal outcome may be improved in complicated labor if the window of treatment with allopurinol could be initiated before birth, for instance, via maternal treatment to cover the actual period of fetal hypoxia and reperfusion (Derks et al 2010; Kaandorp et al 2010)
The aims of this study were to investigate in rodent pregnancy: (1) whether xanthine oxidase is active in the placenta, maternal, and fetal tissues in late gestation; (2) if maternal oral administration of allopurinol could increase maternal plasma levels of allopurinol and its active metabolite oxypurinol; (3) if maternal allopurinol and oxypurinol could cross the placenta, yielding therapeutic levels in the fetal circulation; and (4) whether elevations in maternal and fetal plasma levels of allopurinol and oxypurinol resulted in suppression of xanthine oxidase activity in the placenta, maternal, and fetal tissues
Summary
Despite advances in obstetric practice, acute intrapartum fetal hypoxia remains one of the most common forms of fetal stress, with substantial morbidity and mortality (Low 2004). Xanthine Oxidase Inhibition in the Pregnant Rat pregnancy complicated by intrapartum hypoxia in order to protect the infant from excessive generation of ROS (Peeters-Scholte et al 2003; Benders et al 2006; Chaudhari and McGuire 2008; Torrance et al 2009; Kaandorp et al 2010, 2011b, 2012) This clinical interest in antenatal maternal administration of allopurinol follows previous studies which reported that allopurinol treatment in the asphyxiated neonate improved neonatal outcome (Van Bel et al 1998), but if the time interval between hypoxia and treatment had been too long, or when fetal hypoxia had been too severe, no reduction in serious morbidity or mortality was observed (Benders et al 2006). There has been growing clinical and scientific interest in establishing whether perinatal outcome may be improved in complicated labor if the window of treatment with allopurinol could be initiated before birth, for instance, via maternal treatment to cover the actual period of fetal hypoxia and reperfusion (Derks et al 2010; Kaandorp et al 2010)
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