Adverse and protective influences of adenosine on the newborn and embryo: clinical implications

Adenosine is a nucleoside present in all cells and is a component of nucleic acids and energy-carrying molecules. According to current knowledge, few signaling molecules have the potential to influence the developing mammal as adenosine.
The receptors that transduce adenosine action are the A1, A2a, A2b, and A3 adenosine receptors (ARs). Although several of the different AR subtypes are likely playing important and possibly protective roles during development, the role of A1ARs in this regard has been elucidated in more detail than the role of other receptors. A1AR is expressed in the brain when neural tissue first appears, and A1ARs are one of the earliest expressed receptors in the fetal heart. In addition, A1ARs are expressed in the nervous system during periods of neuronal birth, migration, and axon sprouting.
Of note, increased A1AR action at stages equivalent to the last trimester of pregnancy perturbs the development of oligodendrocytes, thus resulting in hypomyelination and a periventricular white matter injury (PWMI) phenotype. Caffeine is an adenosine antagonist widely used to stimulate respiration in preterm infants. In addition, animal models suggest that caffeine treatment results in more normally arranged myelinated axon orientation than that observed in hypoxemic controls. The results of recent clinical studies support the notion the beneficial effects of caffeine in the premature infants. Preterm infants randomized to be treated with caffeine or placebo in the caffeine for apnea of prematurity (CAP) study had reduced rates of bronchopulmonary dysplasia and patent ductus arterious when treated with caffeine. In addition, caffeine-treated infants had significantly lower rates of cerebral palsy than the control group. This effect was most prominent in infants with respiratory distress. This neuroprotective effect may be attributed, at least in part, to the blockade of adenosine activity on oligodendrocytes.
Moreover, it is likely that caffeine involves action at ARs other than A1ARs. In particular, A2a and A2bARs are located on capillaries and their activation can induce capillary leak, thus raising the possibility that adenosine contributes to intraventricular hemorrhage (IVH). Because IVH occurs shortly after birth, potential preventative effects of caffeine on IVH may only be detected with early intervention. Interestingly, the CAP study showed lower IVH rates in the caffeine-treated infants than the placebo group. This finding may reflect the effects of caffeine on blood-brain barrier function of the infant.
Another cause of perinatal brain injury is hypoxic-ischemic encephalopathy (HIE). Some studies revealed that caffeine reduced brain injury in mice after HIE. However, to date, it appears that the protective caffeine effects on HIE are either AR independent or mediated by two or more receptor subtypes.
In contrast to the neonatal period, reduced A1AR action during embryogenesis leads to embryo loss, acute growth retardation, and hearts with thinner ventricular walls. Adenosine thus exerts dramatic protective effects during embryogenesis. These embryo protective effects are blocked by caffeine, and therefore caffeine intake during early pregnancy increases the risk of miscarriage and fetal growth retardation.
In conclusion, adenosine plays important modulatory roles in mammalian development, conferring protective or deleterious effects depending on the timing of exposure and site of action. As such, adenosine antagonists, including caffeine, may be an unwelcome exposure for the embryo but a welcome therapeutic option for the preterm infant.

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