Abstract
Caffeine is one of the few treatments available for infants with apnea of prematurity. As the recommended dosing regimen is not always sufficient to prevent apnea, higher doses may be prescribed. However, little is currently known about the impact of high-dose caffeine on the developing brain; thus, our aim was to investigate the consequences of a high-dose regimen on the immature ovine brain. High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) was administered to pregnant sheep from 105 to 118 days of gestation (DG; term = 147 days); this is broadly equivalent to 28–33 weeks of human gestation. At 119DG, the cerebral cortex, striatum, and cerebellum were assessed histologically and by immunohistochemistry. Compared with controls, caffeine-exposed fetuses showed (i) an increase in the density of Ctip2-positive layers V–VI projection neurons (p = 0.02), Tbr1-positive layers V–VI projection neurons (p < 0.0001), astrocytes (p = 0.03), and oligodendrocytes (p = 0.02) in the cerebral cortex, (ii) a decrease in the density of Cux1-positive layers II–IV projection neurons (p = 0.01) in the cerebral cortex, and (iii) a reduction in the area of Purkinje cell bodies in the cerebellum (p = 0.03). Comparing high-dose caffeine-exposed fetuses with controls, there was no difference (p > 0.05) in: (i) the volume of the cerebral cortex or striatum, (ii) the density of neurons (total and output projection neurons) in the striatum, (iii) dendritic spine density of layer V pyramidal cells, (iv) the density of cortical GABAergic interneurons, microglia, mature oligodendrocytes or proliferating cells, (v) total cerebellar area or dimensions of cerebellar layers, or (vi) the density of cerebellar white matter microglia, astrocytes, oligodendrocytes, or myelin. Daily exposure of the developing brain to high-dose caffeine affects some aspects of neuronal and glial development in the cerebral cortex and cerebellum in the short-term; the long-term structural and functional consequences of these alterations need to be investigated.
Highlights
Caffeine therapy has become an integral part of management of apnea of prematurity in very preterm infants
In addition we identified projection neurons in the upper layers with antibodies to cut-like homeobox 1 (Cux1), a transcription factor which regulates several genes involved in cellular proliferation and differentiation (Nepveu, 2001)
We found that caffeine treatment resulted in an increase in the density of COUP-TF interacting protein 2 (Ctip2)-IR and T-box brain 1 (Tbr1)-IR neurons in the deeper cortical layers and a decrease in Cux1-IR neurons in the upper layers
Summary
Caffeine therapy has become an integral part of management of apnea of prematurity in very preterm infants. We have previously reported that daily high-dose caffeine had no detectable effects on the cerebral white matter (WM) of the immature ovine brain (Atik et al, 2014). We report the effects of high-dose caffeine on the developing cerebral cortex, striatum, and cerebellum in a clinically appropriate animal model. Reported beneficial effects of high-dose caffeine exposure include increased total dendritic length and arborization of layer III pyramidal neurons of the prefrontal cortex of rats (JuarezMendez et al, 2006) and reduced seizure susceptibility to some chemo-convulsants in both juvenile and adult rats (Guillet and Dunham, 1995). Highdose caffeine treatment during the first 24 h of life increases the incidence of cerebellar hemorrhage compared with infants treated with standard doses of caffeine, with no apparent injury to the cerebellar white or gray matter (McPherson et al, 2015)
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