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.
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2013-ADG
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
00014 HELSINGIN YLIOPISTO
Finland
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