Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia.

BMC Neuroscience (Impact Factor: 2.85). 05/2014; 15(1):67.
Source: PubMed

ABSTRACT Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates.Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adverse cognitive and educational outcomes are often ascribed to perinatal hypoxia without good evidence. To investigate neurocognitive and behavioural outcomes after neonatal encephalopathy. Sixty five children with neonatal encephalopathy, identified using the Trent Neonatal Survey database for 1992-1994, were followed up at the age of 7 years. They were examined at school, with a classmate for those in mainstream school, by a paediatrician and a psychologist. Neonatal encephalopathy was graded as moderate or severe using published definitions.Findings: Fifteen children had major disability, all with cerebral palsy; eight were in special school with severe cognitive impairment (IQ<55). Disability was present in 6% of the moderate and 42% of the severe encephalopathy group. Of the 50 children without motor disability, cognitive scores were lowest in the severe group (mean IQ difference from peers -11.3 points (95% confidence interval (CI) -19.0 to -3.6) and with similar scores for the moderate group compared with classmates (mean difference -1.7 points (95% CI -7.3 to +3.9). Neuropsychological testing showed similar findings in all domains. In particular, memory and attention/executive functions were impaired in the severe group. Despite relatively small differences in performance of the moderate group, special educational needs were identified more often in both encephalopathy groups, associated with lower achievement on national curriculum attainment targets. After neonatal encephalopathy, subtle cognitive impairments are found in the absence of neuromotor impairment. Subtle impairments are found more commonly after a more severe clinical course. Studies of brain protection strategies require long term follow up to study effects on cognitive outcome.
    Archives of Disease in Childhood - Fetal and Neonatal Edition 09/2005; 90(5):F380-7. · 3.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.
    PEDIATRICS 11/2008; 122(4):e791-8. · 5.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We aimed to develop a model of fetal hypoxia-ischemia (HI) preconditioning that reflects the pathophysiological conditions of perinatal asphyxia more closely than the existing neonatal stroke models. Fetal asphyxia (FA) was induced by clamping the uterine vasculature on embryonic day E17. At birth (P0), severe perinatal asphyxia (SPA) was induced during cesarean section. At P4, carotid arteries were studied in a wire myograph and at P8 brains were analyzed for apoptotic cell death in the prefrontal cortex and striatum. The contraction induced by K+ was significantly reduced in the carotid arteries from the SPA group and endothelium-dependent relaxation (mediated by acetylcholine) was augmented in the FA group. These changes in vascular responsiveness were not present in the animals exposed to both insults (FA + SPA). Additionally, FA+SPA animals showed lower numbers of apoptotic cells compared to SPA animals in both the prefrontal cortex and striatum. Exposure to a global fetal asphyctic insult seems to protect against the vascular alterations and the increase of apoptosis in striatum and prefrontal cortex induced by severe asphyxia at birth.
    Frontiers in bioscience (Scholar edition) 01/2010; 2:781-90.

Full-text (3 Sources)

Available from
Aug 28, 2014