title: Impact of daily high-dose caffeine exposure on developing white matter of the immature ovine brain.
abstract: BACKGROUND
  Caffeine is widely used to treat apnea of prematurity, but the standard dosing regimen is not always sufficient to prevent apnea. Before higher doses of caffeine can be used, their effects on the immature brain need to be carefully evaluated. Our aim was to determine the impact of daily high-dose caffeine administration on the developing white matter of the immature ovine brain.
  
  
  METHODS
  High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) were administered to pregnant sheep from 0.7 to 0.8 of term, equivalent to approximately 27-34 wk in humans. At 0.8 of term, the white and gray matter were assessed histologically and immunohistochemically.
  
  
  RESULTS
  Daily caffeine administration led to peak caffeine concentration of 32 mg/l in fetal plasma at 1 h, followed by a gradual decline, with no effects on mean arterial pressure and heart rate. Initial caffeine exposure led to transient, mild alkalosis in the fetus but did not alter oxygenation. At necropsy, there was no effect of daily high-dose caffeine on brain weight, oligodendrocyte density, myelination, axonal integrity, microgliosis, astrogliosis, apoptosis, or neuronal density.
  
  
  CONCLUSIONS
  Daily high-dose caffeine administration does not appear to adversely affect the developing white matter at the microstructural level.
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Anzari
authors.initials: A
authors.lastname: Atik
authors.affiliation: 1] Department of Neonatal Services, Royal Women's Hospital, Victorian Infant Brain Studies, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia [2] Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jeanie
authors.initials: J
authors.lastname: Cheong
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Harding
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rees
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: De Matteo
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute of Medical Research and Monash University, Clayton, Victoria, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Tolcos
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000196:embryology*; D002110:Caffeine / Q000009:adverse effects* / Q000097:blood; D005260:Female; D005911:Gliosis / Q000473:pathology; D018811:Maternal Exposure / Q000009:adverse effects*; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D009836:Oligodendroglia / Q000166:cytology; D011247:Pregnancy; D011270:Pregnancy, Animal; D012756:Sheep; D013997:Time Factors
chemical_list: D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D002110:Caffeine