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

Brain. 2012 Nov;135(Pt 11):3311-9. doi: 10.1093/brain/aws257. Epub 2012 Nov 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid-Base Equilibrium / drug effects
  • Alkalosis / complications
  • Alkalosis / drug therapy
  • Alkalosis / metabolism*
  • Alkalosis / physiopathology
  • Amiloride / analogs & derivatives
  • Amiloride / pharmacology
  • Amiloride / therapeutic use
  • Animals
  • Animals, Newborn
  • Asphyxia Neonatorum / complications
  • Asphyxia Neonatorum / drug therapy*
  • Asphyxia Neonatorum / metabolism*
  • Asphyxia Neonatorum / physiopathology
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / physiopathology
  • Brain / drug effects
  • Brain / metabolism
  • Disease Models, Animal
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • Infant, Newborn
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / complications
  • Seizures / drug therapy
  • Seizures / metabolism*
  • Seizures / physiopathology
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors

Substances

  • Sodium-Hydrogen Exchangers
  • Amiloride
  • 5-(N-methyl-N-isobutyl)amiloride