title: Caffeine protects neuronal cells against injury caused by hyperoxia in the immature brain.
abstract: Caffeine administered to preterm infants has been shown to reduce rates of cerebral palsy and cognitive delay, compared to placebo. We investigated the neuroprotective potential of caffeine for the developing brain in a neonatal rat model featuring transient systemic hyperoxia. Using 6-day-old rat pups, we found that after 24 and 48h of 80% oxygen exposure, apoptotic (TUNEL(+)) cell numbers increased in the cortex, hippocampus, and central gray matter, but not in the hippocampus or dentate gyrus. In the dentate gyrus, high oxygen exposure led to a decrease in the number of proliferating (Ki67(+)) cells and the number of Ki67(+) cells double staining for nestin (immature neurons), doublecortin (progenitors), and NeuN (mature neurons). Absolute numbers of nestin(+), doublecortin(+), and NeuN(+) cells also decreased after hyperoxia. This was mirrored in a decline of transcription factors expressed in immature neurons (Pax6, Sox2), progenitors (Tbr2), and mature neurons (Prox1, Tbr1). Administration of a single dose of caffeine (10mg/kg) before high oxygen exposure almost completely prevented these effects. Our findings suggest that caffeine exerts protection for neonatal neurons exposed to high oxygen, possibly via its antioxidant capacity.
authors.affiliation: Department of Neonatology, Charité University Medical Center, D-13353 Berlin, Germany. Electronic address: stefanie.endesfelder@charite.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Endesfelder
authors.affiliation: Department of Neonatology, Charité University Medical Center, D-13353 Berlin, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Zaak
authors.affiliation: Department of Neonatology, Charité University Medical Center, D-13353 Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Weichelt
authors.affiliation: Department of Neonatology, Charité University Medical Center, D-13353 Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
authors.affiliation: Department of Neonatology, Charité University Medical Center, D-13353 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology*; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D066128:Gray Matter / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D034961:Antigens, Nuclear; D015415:Biomarkers; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005136:Eye Proteins; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D009479:Neuropeptides; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605733:Pax6 protein, rat; C546339:Rbfox3 protein, rat; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C527784:Sox2 protein, rat; D020825:T-Box Domain Proteins; C540454:Tbr1 protein, rat; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D002110:Caffeine
keywords: Developmental brain; Free radicals; Hyperoxia; Methylxanthine; Oxidative stress; Postnatal neurogenesis; Preterm infants