title: Acid extrusion via blood-brain barrier causes brain alkalosis and seizures after neonatal asphyxia.
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.
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Helmy
authors.forename: Eva
authors.initials: E
authors.lastname: Ruusuvuori
authors.forename: Paul V
authors.initials: PV
authors.lastname: Watkins
authors.forename: Juha
authors.initials: J
authors.lastname: Voipio
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Kanold
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000471:Alkalosis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007231:Infant, Newborn; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors
chemical_list: D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; C056369:5-(N-methyl-N-isobutyl)amiloride