Acid extrusion via blood–brain barrier causes brain alkalosis and seizures after neonatal asphyxia
| العنوان: | Acid extrusion via blood–brain barrier causes brain alkalosis and seizures after neonatal asphyxia |
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| المؤلفون: | Mohamed M. Helmy, Patrick O. Kanold, Paul V. Watkins, Juha Voipio, Eva Ruusuvuori, Kai Kaila |
| المصدر: | Brain |
| بيانات النشر: | Oxford University Press (OUP), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Sodium-Hydrogen Exchangers, Alkalosis, Intracellular pH, resuscitation, neonatal seizures, Na/H exchange, birth asphyxia, Blood–brain barrier, Membrane Potentials, Amiloride, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Seizures, Internal medicine, medicine, Extracellular, Animals, Humans, Normocapnia, 030304 developmental biology, Acidosis, Acid-Base Equilibrium, Neurons, Asphyxia, Asphyxia Neonatorum, 0303 health sciences, pH, Chemistry, Infant, Newborn, Brain, Original Articles, Hydrogen-Ion Concentration, medicine.disease, Rats, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, Animals, Newborn, Blood-Brain Barrier, Anesthesia, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1460-2156 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1e44da3c9de3b059ce1cfaacee38ac1fTest https://doi.org/10.1093/brain/aws257Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1e44da3c9de3b059ce1cfaacee38ac1f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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