Author: Maciver MB, et al.
Anesthesia & Analgesia 141(2):412-421, August 2025. doi:10.1213/ANE.0000000000007178
This preclinical study compared the electroencephalography (EEG) effects of propofol, a broad-spectrum GABAAR agonist, with a newly developed selective GABAAR-slow agonist, KSEB 01-S2. Male rats were implanted with subcranial EEG electrodes and given either propofol or KSEB 01-S2. EEG recordings were analyzed around the time of loss of consciousness (LOC).
Propofol increased delta power (0.1–4 Hz) and reduced high-frequency activity (>30 Hz), consistent with prior findings. KSEB 01-S2, by contrast, produced a distinct EEG signature, with a significant increase in theta frequency power and a marked reduction in low gamma power at LOC. Both drugs produced flattening of chaotic attractor plots, a marker of reduced brain responsiveness, but their frequency-specific effects differed substantially.
The findings suggest that anesthetic modulation of EEG activity may be closely linked to GABAAR subtype specificity. KSEB 01-S2’s unique profile — boosting theta while suppressing gamma — supports models proposing that slow GABAAR synapses underlie theta oscillations, while fast synapses drive gamma activity. These results highlight the potential for receptor-selective anesthetics to produce distinct neurophysiological states and inform future anesthetic development.
Things to Know
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Propofol and KSEB 01-S2 produce different EEG signatures despite both inducing unconsciousness.
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KSEB 01-S2 selectively enhances theta power and suppresses gamma activity.
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Distinct EEG changes appear linked to receptor subtype targeting (slow vs. fast GABAAR synapses).
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Findings support the concept that receptor-specific anesthetics may create unique brain states and open the door to more precise drug design.
Thank you to Anesthesia & Analgesia for publishing this important work on receptor subtype selectivity and EEG signatures under anesthesia.
KEY POINTS
- Questions: What are the electroencephalographic and physiologic profiles of a new anesthetic and anticonvulsant that is selective for the gamma amino butyric acid type A receptor subtypes (GABAAR) slow receptor subtype as compared to that of propofol?
- Findings: Compared to propofol, KSEB 01-S2 produces a different set of electroencephalography (EEG) frequency band signatures, has a similar chaos attractor measure of anesthetic effect as well as a similar ability to produce the anesthetic phenotype, but contrastingly spares cardiorespiratory depression in the rat.
- Meaning: Our new class of agents are unique in their activities at the GABAAR-slow receptor functional subtype while producing effective Chaos Attractor measures of anesthesia, suggesting a possible mechanistic link between receptor subtype specificity, EEG frequency band signatures, and improved cardiorespiratory stabilities.
Thank you to Anesthesia & Analgesia for publishing this important work on receptor subtype selectivity and EEG signatures under anesthesia.