Community Research and Development Information Service - CORDIS

ERC

PRESSBIRTH Report Summary

Project ID: 341116
Funded under: FP7-IDEAS-ERC
Country: Finland

Periodic Report Summary 2 - PRESSBIRTH (Arginine vasopressin and ion transporters in the modulation of brain excitability during birth and birth asphyxia seizures)

Severe birth asphyxia (BA) is a life-threatening condition of the newborn, with an annual death rate of a million neonates globally. It is typically caused by compromised umbilical/placental functions during complicated delivery which leads to a fall in the oxygen level and increase in the carbon dioxide levels in the neonate. Moderate and mild forms of BA have lifelong deleterious consequences, ranging from cerebral palsy and other neurological manifestations to psychiatric disorders including autism, ADHD and schizophrenia. A conventional view of BA is that it is mainly an energy-metabolic disorder of the neonate brain. Our research project takes another, complementary angle, examining the roles of the pH-regulatory as well as neuroendocrine mechanisms involving the neonatal hypothalamic–pituitary–adrenal (HPA) axis (the “stress axis”). The HPA-axis is strongly activated during normal delivery, and this activation is further enhanced by BA. We aim at identifying the acute and long-term mechanisms and consequences of the BA-induced pH changes as well as the “over-activation” of the HPA-axis, focusing on the hypothalamic neurohormone arginine vasopressin (AVP). The AVP-signaling system is of key importance in the control and pre-adaptation of the organism to promote survival in potentially threatening conditions attributable to both intrinsic and extrinsic causes. The data we have obtained indicate that AVP plays a major role in the protection of the fetal brain during normal and complicated delivery.
Our animal model of birth asphyxia is based on 6-day old rats exposed to a gas mixture of 4-5% or 9% O2 plus 20% CO2 for 45 min. A massive release of peripheral AVP is triggered in response to the experimental asphyxia, which validates our model. The recovery period starts with Graded or Rapid Restoration of Normocapnia (GRN and RRN, respectively). A finding with particularly important therapeutic implications is that using GRN as experimental resuscitation prevents abnormal changes seen in intracranial multiple-site EEG recordings following asphyxia. This effect is attributable to the slower recovery of brain pH during GRN vs. RRN. A direct effect of AVP on neuronal network functions was discovered in experiments on brain slices, where extremely low concentrations of AVP were found to suppress the activity of neuronal networks in the neonate rat hippocampus in a manner which is likely to be neuroprotective. The subsequent identification of the cellular basis (activation of so-called interneurons) and of a specific receptor class (V1a) mediating this response opens the possibility of generating novel drugs targeting the neonatal hypothalamic–pituitary–adrenal (HPA) axis for neuroprotection of the neonate brain during or following BA.
Our work also provides a rational basis for the development of putative prognostic biomarkers to identify those newborns that are at high risk for poor outcome following BA. Indeed, we have found in a retrospective study that plasma levels of copeptin (a chemically stable cleavage product of AVP) measured right after birth show a strong correlation with poor neurological outcome at the age of 2 years.

Reported by

HELSINGIN YLIOPISTO
Finland
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