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Arginine vasopressin and ion transporters in the modulation of brain excitability during birth and birth asphyxia seizures

Arginine vasopressin and ion transporters in the modulation of brain excitability during birth and birth asphyxia seizures

Objective

A transient period of asphyxia in the newborn is an obligatory part of normal parturition. A more prolonged disturbance in cerebral blood supply is a major cause of neonatal seizures. Current therapies of birth asphyxia seizures are ineffective and the underlying mechanisms are unknown.
Our recent landmark work on a rat model of birth asphyxia showed that asphyxia is followed by brain alkalosis, which triggers seizures. The brain-confined alkalosis is generated by activation of Na/H exchange in the blood-brain barrier (BBB). Both alkalosis and the consequent seizures can be suppressed by graded restoration of the high CO2 level after asphyxia and with blockers of Na/H exchange.
Our pilot data indicate that arginine vasopressin (AVP) triggers the post-asphyxia seizures by activating the BBB-located luminal V1a receptor-coupled Na/H exchanger. Akin to human infants, a very high level of plasma copeptin (a part of pro-AVP) is seen following asphyxia but, notably, the copeptin levels remain low with graded restoration of normocapnia. Moreover, intravenous AVP V1a receptor antagonists, acting on the BBB, block the generation of seizures. In striking contrast, AVP suppresses network excitability when acting on V1aRs in the neonate hippocampus.
Thus, I hypothesize that AVP acts on the BBB to promote neonatal seizures, and that this effect is paralleled by a central anticonvulsant action. Next to nothing is known about AVP actions on ionic regulation in the brain. Our pilot data indicate that AVP inhibits the Na-K-2Cl cotransporter NKCC1 and activates the K-Cl cotransporter KCC2 in a manner consistent with reduction of excitability.
My laboratory has an internationally leading role in work on neuronal pH and Cl- regulation and on functions of the immature brain. Understanding the mechanisms of AVP actions during normal birth and birth asphyxia will provide novel insights on the control of the excitability of the newborn brain. This work has a high translational impact.

Principal Investigator

Kai Kalervo Kaila (Prof.)

Host institution

HELSINGIN YLIOPISTO

Address

Yliopistonkatu 3
00014 Helsingin Yliopisto

Finland

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 497 419

Principal Investigator

Kai Kalervo Kaila (Prof.)

Administrative Contact

Katri Wegelius (Dr.)

Beneficiaries (1)

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HELSINGIN YLIOPISTO

Finland

EU Contribution

€ 2 497 419

Project information

Grant agreement ID: 341116

Status

Closed project

  • Start date

    1 February 2014

  • End date

    31 January 2019

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 497 419

  • EU contribution

    € 2 497 419

Hosted by:

HELSINGIN YLIOPISTO

Finland