The Effect of Long Term Caffeine Treatment on Hypoxic-Ischemic Brain Damage in the Neonate

Abstract

There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion + exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A, and A,, receptors, A, mRNA and A, , mRNA, were examined by receptor autoradiography and in situ hybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 rt 3.2% in controls to 29.8 ? 4.0% (p < 0.05) in low dose and 33.7 2 3.9% (NS) in the high dose group. The A, receptor density measured as [3~]-1,3-dipropyl-8-cyclopentyl xanthine ([?HI-DPCPX) bindCaffeine is widely consumed by women during pregnancy and immediately thereafter (1) and it is used, together with its metabolite theophylline, in the treatment of premature apnea (2). Furthermore, the fetus and the newborn become exposed because caffeine crosses the placenta (3,4) and diffuses into the breast milk (5). Caffeine affects several systems in the body, e.g. the renal, respiratory, cardiovascular (6), gastrointestinal, and the C N S (7,8). Caffeine is metabolized in the liver (9), and the metabolites are then excreted in the urine. The metabolism is much slower in neonates than in adults: tl12 in infants is 50-103 h (7,10, 11) and tIl2 in adults is 2-6 h (7, 12). Several recent reports have raised concern about the safety of caffeine use during and after pregnancy (13). Caffeine is a receptor antagonist for the endogenous nucleoside adenosine. Adenosine influences various transmitter systems in the CNS: noradrenaline, dopamine, serotonin, acetylcholine, y-aminobutyrate, and glutamate (14). Adenosine also has neuroprotective actions during ischemia (15)(16)(17)(18)(19)(20). The extracellular concentration of adenosine increases rapidly during ischemia (21,22), and the number of adenosine receptors decreases promptly (23,24). In the adult brain, chronic caffeine treatment, which leads to up-regulation of adenosine receptors, reduces ischemic damage (25), whereas acute exposure (receptor antagonistic effect) increases ischemic damage (26). The purpose of this study was to extend present knowledge to the neonatal setting, considering the common situation of fetal and neonatal caffeine exposure (1). Adenosine receptors appear and are functional at an early ontogenetic age (27,28). There are four types of adenosine receptors, A,, A,,, A,,, and A,, all of which are expressed in the brain (29). A , and A,, receptors are the most likely targets for caffeine actions. Exposure of neonatal rats to high amounts of caffeine given by gavage during postnatal d 2-6 incre...

Adenosine receptors and caffeine in retinopathy of prematurity

“…This raises an exciting possibility that caffeine, the ubiquitous trimethylxanthine that is widely used in premature infants with apnea of prematurity (Abdel-Hady et al, 2015) may protect against pathological neovascularization in ROP. The protection against ROP by caffeine is in general agreement with the finding that caffeine treatment reduced the vulnerability of the immature brain to hypoxic ischemia (Bona et al, 1995), reduced the effects of NMDA on e.g. seizure susceptibility (Georgiev et al, 1993) in neonates.…”

Perinatal Caffeine, Acting on Maternal Adenosine A1 Receptors, Causes Long-Lasting Behavioral Changes in Mouse Offspring

“…The dose of caffeine given produced blood levels in dams comparable to those obtained in humans after consumption of 3–4 cups of coffee [13]. Together with offspring of untreated WT dams, caffeine pre-treated male and female mice were tested for motor balance and coordination on the rotarod on Day 1 of the evaluation protocol (Figure 1).…”

Perinatal brain injury: From pathogenesis to neuroprotection

“…Although in some perinatal models adenosine agonists have been beneficial, the available data do not show clearly consistent effects [Bona et al, 1995[Bona et al, , 1997Gidday et al, 1995;Halle et al, 1997]. Although in some perinatal models adenosine agonists have been beneficial, the available data do not show clearly consistent effects [Bona et al, 1995[Bona et al, , 1997Gidday et al, 1995;Halle et al, 1997].…”