Journal Article

Acid extrusion via blood–brain barrier causes brain alkalosis and seizures after neonatal asphyxia

Mohamed M. Helmy, Eva Ruusuvuori, Paul V. Watkins, Juha Voipio, Patrick O. Kanold and Kai Kaila

in Brain

Published on behalf of The Guarantors of Brain

Volume 135, issue 11, pages 3311-3319
Published in print November 2012 | ISSN: 0006-8950
Published online November 2012 | e-ISSN: 1460-2156 | DOI: https://dx.doi.org/10.1093/brain/aws257

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Birth asphyxia is often associated with a high seizure burden that is predictive of poor neurodevelopmental outcome. The mechanisms underlying birth asphyxia seizures are unknown. Using an animal model of birth asphyxia based on 6-day-old rat pups, we have recently shown that the seizure burden is linked to an increase in brain extracellular pH that consists of the recovery from the asphyxia-induced acidosis, and of a subsequent plateau level well above normal extracellular pH. In the present study, two-photon imaging of intracellular pH in neocortical neurons in vivo showed that pH changes also underwent a biphasic acid–alkaline response, resulting in an alkaline plateau level. The mean alkaline overshoot was strongly suppressed by a graded restoration of normocapnia after asphyxia. The parallel post-asphyxia increase in extra- and intracellular pH levels indicated a net loss of acid equivalents from brain tissue that was not attributable to a disruption of the blood–brain barrier, as demonstrated by a lack of increased sodium fluorescein extravasation into the brain, and by the electrophysiological characteristics of the blood–brain barrier. Indeed, electrode recordings of pH in the brain and trunk demonstrated a net efflux of acid equivalents from the brain across the blood–brain barrier, which was abolished by the Na/H exchange inhibitor, N-methyl-isobutyl amiloride. Pharmacological inhibition of Na/H exchange also suppressed the seizure activity associated with the brain-specific alkalosis. Our findings show that the post-asphyxia seizures are attributable to an enhanced Na/H exchange-dependent net extrusion of acid equivalents across the blood–brain barrier and to consequent brain alkalosis. These results suggest targeting of blood–brain barrier-mediated pH regulation as a novel approach in the prevention and therapy of neonatal seizures.

Keywords: birth asphyxia; neonatal seizures; resuscitation; pH; Na/H exchange

Journal Article.  6436 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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