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Updated: Oct 31, 2025
Continuous Video Electroencephalogram during Hypoxia-Ischemia in Neonatal Mice
Published on: June 11, 2020
Carbonic anhydrase inhibitors suppress seizures in a rat model of birth asphyxia
Alexey S Pospelov1,2, Tommi Ala-Kurikka1,2, Samu Kurki1,2
1Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.
Insights
Carbonic anhydrase inhibitors effectively block seizures in newborn rats after birth asphyxia by inducing acidosis. Acetazolamide may be repurposed for neonatal seizure treatment.
Area of Science:
- Neuroscience
- Neonatal Medicine
- Pharmacology
Background:
- Neonatal seizures following birth asphyxia are common.
- Current antiseizure drug therapies are suboptimal.
- Novel treatments are urgently needed for neonatal seizures.
Purpose of the Study:
- To investigate if carbonic anhydrase inhibitors (CAIs) can prevent post-asphyxia seizures.
- To determine if CAIs, by inducing systemic acidosis, block seizures triggered by pH recovery after asphyxia.
Main Methods:
- Administered acetazolamide (AZA), benzolamide (BZA), and ethoxzolamide (EZA) to 11-day-old rats.
- Exposed rats to intermittent asphyxia (30 min).
- Measured brain pH, Po2, and local field potentials (LFPs); examined seizures and acid-base parameters.
Main Results:
- All three CAIs decreased brain pH and suppressed electrographic seizures.
- CAIs induced a modest increase in brain Po2 with no effect on LFPs.
- Acetazolamide reduced convulsive seizure incidence in freely behaving rats.
Conclusions:
- Carbonic anhydrase inhibitors effectively block post-asphyxia seizures in a rat model.
- The antiseizure effect is attributed to respiratory acidosis from CAI action.
- Acetazolamide shows potential for repurposing in neonatal seizure treatment.
Objective:
Seizures are common in neonates recovering from birth asphyxia but there is general consensus that current pharmacotherapy is suboptimal and that novel antiseizure drugs are needed. We recently showed in a rat model of birth asphyxia that seizures are triggered by the post-asphyxia recovery of brain pH. Here our aim was to investigate whether carbonic anhydrase inhibitors (CAIs), which induce systemic acidosis, block the post-asphyxia seizures.
Methods:
The CAIs acetazolamide (AZA), benzolamide (BZA), and ethoxzolamide (EZA) were administered intraperitoneally or intravenously to 11-day-old rats exposed to intermittent asphyxia (30 min; three 7+3 min cycles of 9% and 5% O2 at 20% CO2 ). Electrode measurements of intracortical pH, Po2 , and local field potentials (LFPs) were made under urethane anesthesia. Convulsive seizures and blood acid-base parameters were examined in freely behaving animals.
Results:
The three CAIs decreased brain pH by 0.14-0.17 pH units and suppressed electrographic post-asphyxia seizures. AZA, BZA, and EZA differ greatly in their lipid solubility (EZA > AZA > BZA) and pharmacokinetics. However, there were only minor differences in the delay (range 0.8-3.7 min) from intraperitoneal application to their action on brain pH. The CAIs induced a modest post-asphyxia elevation of brain Po2 that had no effect on LFP activity. AZA was tested in freely behaving rats, in which it induced a respiratory acidosis and decreased the incidence of convulsive seizures from 9 of 20 to 2 of 17 animals.
Significance:
AZA, BZA, and EZA effectively block post-asphyxia seizures. Despite the differences in their pharmacokinetics, they had similar effects on brain pH, which indicates that their antiseizure mode of action was based on respiratory (hypercapnic) acidosis resulting from inhibition of blood-borne and extracellular vascular carbonic anhydrases. AZA has been used for several indications in neonates, suggesting that it can be safely repurposed for the treatment of neonatal seizures as an add-on to the current treatment regimen.
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