title: Caffeine combined with sedative/anesthetic drugs triggers widespread neuroapoptosis in a mouse model of prematurity.
abstract: OBJECTIVE
  Caffeine (CAF) and sedative/anesthetic drugs (SADs) are often coadministered to premature infants in the neonatal intensive care unit (NICU). While SAD neurotoxicity in the developing brain is well established, it is not fully clear whether CAF interacts with SADs and whether this interaction is detrimental. Using a mouse model of prematurity, we hypothesized that CAF would increase apoptotic neurotoxicity when coadministered with SADs.
  
  
  METHODS
  Postnatal day 3 mice were treated with vehicle or 80 mg/kg CAF prior to challenge with 6 mg/kg midazolam, 40 mg/kg ketamine, or 40 μg/kg fentanyl. Six hours later, pups were sacrificed for activated caspase 3 (AC3) immunohistochemistry, and number of AC3 positive cells per mm3throughout neocortex, hippocampus, caudate, thalamus, and colliculi was analyzed.
  
  
  RESULTS
  CAF caused a statistically significant increase in AC3 positive cells when coadministered with midazolam (p = 0.002), ketamine (p = 0.014), or fentanyl (p < 0.001). Our composite dataset suggests that the addition of CAF to these SADs has a supra-additive effect, causing more neurotoxicity than expected.
  
  
  CONCLUSIONS
  CAF may augment the neurotoxic action of SADs indicated for neonatal sedation/anesthesia in the NICU by triggering widespread apoptosis in the developing brains of premature infants.
authors.affiliation: a Department of Psychological Sciences , University of Missouri - St. Louis , St. Louis , MO , USA.|b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
authors.forename: Omar Hoseá
authors.identifier: http://orcid.org/0000-0002-9501-6720
authors.initials: OH
authors.lastname: Cabrera
authors.affiliation: c Edward Mallinckrodt Department of Pediatrics, Division of Newborn Medicine , Washington University in St. Louis School of Medicine and St. Louis Children's Hospital , St. Louis , MO , USA.
authors.forename: Shawn David
authors.initials: SD
authors.lastname: O'Connor
authors.affiliation: b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
authors.forename: Brant Stephen
authors.initials: BS
authors.lastname: Swiney
authors.affiliation: b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Salinas-Contreras
authors.affiliation: a Department of Psychological Sciences , University of Missouri - St. Louis , St. Louis , MO , USA.|b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Manzella
authors.affiliation: a Department of Psychological Sciences , University of Missouri - St. Louis , St. Louis , MO , USA.
authors.forename: George Townsend
authors.identifier: http://orcid.org/0000-0002-0102-3787
authors.initials: GT
authors.lastname: Taylor
authors.affiliation: b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
authors.forename: Kevin Kiyoshi
authors.identifier: http://orcid.org/0000-0001-5307-161X
authors.initials: KK
authors.lastname: Noguchi
mesh_terms: D000777:Anesthetics / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002110:Caffeine / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000473:pathology; D011247:Pregnancy; D047928:Premature Birth / Q000188:drug therapy / Q000473:pathology* / Q000523:psychology; D011897:Random Allocation
chemical_list: D000777:Anesthetics; D006993:Hypnotics and Sedatives; D002110:Caffeine
keywords: Caffeine; apoptosis; fentanyl; ketamine; midazolam; premature infant