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

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.

Brain alkalosis causes birth asphyxia seizures, suggesting therapeutic strategy.

OBJECTIVE: The mechanisms whereby birth asphyxia leads to generation of seizures remain unidentified. To study the possible role of brain pH changes, we used a rodent model that mimics the alterations in systemic CO(2) and O(2) levels during and after intrapartum birth asphyxia. METHODS: Neonatal rat pups were exposed for 1 hour to hypercapnia (20% CO(2) in the inhaled gas), hypoxia (9% O(2)), or both (asphyxic conditions). CO(2) levels of 10% and 5% were used for graded restoration of normocapnia. Seizures were characterized behaviorally and utilizing intracranial electroencephalography. Brain pH and oxygen were measured with intracortical microelectrodes, and blood pH, ionized calcium, carbon dioxide, oxygen, and lactate with a clinical device. The impact of the postexposure changes in brain pH on seizure burden was assessed during 2 hours after restoration of normoxia and normocapnia. N-methyl-isobutyl-amiloride, an inhibitor of Na(+) /H(+) exchange, was given intraperitoneally. RESULTS: Whereas hypercapnia or hypoxia alone did not result in an appreciable postexposure seizure burden, recovery from asphyxic conditions was followed by a large seizure burden that was tightly paralleled by a rise in brain pH, but no change in brain oxygenation. By graded restoration of normocapnia after asphyxia, the alkaline shift in brain pH and the seizure burden were strongly suppressed. The seizures were virtually blocked by preapplication of N-methyl-isobutyl-amiloride. INTERPRETATION: Our data indicate that brain alkalosis after recovery from birth asphyxia plays a key role in the triggering of seizures. We question the current practice of rapid restoration of normocapnia in the immediate postasphyxic period, and suggest a novel therapeutic strategy based on graded restoration of normocapnia.

Stripping the boss: the powerful role of humor in the Egyptian Revolution 2011.

The Egyptian Revolution 2011 has shaken the Arab world and stirred up Middle-East politics. Moreover, it caused a rush in political science and the neighboring disciplines, which had not predicted an event like this and now have troubles explaining it. While many things can be learned from the popular uprising, and from the limitations of previous scholarship, our focus will be on a moral resource, which has occasionally been noticed, but not sufficiently explored: the role of humor in keeping up the spirit of the Revolution. For 18 days, protestors persevered at Liberation Square in Central Cairo, the epicenter of resistance; at times a few dozens, at times hundreds of thousands. What they did was to fight the terror of the regime, which reached absurd peaks during those days, with humor-successfully. We offer a social-functionalist account of the uprising, which includes behavioral as well as cultural levels of analysis, and illuminates how humorous means helped to achieve deadly serious goals. By reconstructing how Egyptians laughed themselves into democracy, we outline a social psychology of resistance, which uses humor both as a sword and a shield.