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Intergenerational Postoperative Neurocognitive Disorder in a Rat Model: Initiating Mechanisms and Pharmacological
Ling-Sha Ju1, Zeeshan A Khan1, Nikolaus Gravenstein1
1Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida.
Anesthesiology
|May 23, 2025
Summary
Sevoflurane exposure in male rats can cause lasting neuroinflammation and cognitive deficits, impacting their offspring. Inhibiting NKCC1 or glucocorticoid receptors may prevent these effects, offering therapeutic targets for perioperative neurocognitive disorder (PND).
Area of Science:
- Neuroscience
- Anesthesiology
- Endocrinology
Background:
- Perioperative neurocognitive disorder (PND) mechanisms are not fully understood.
- Sevoflurane may trigger PND by altering the hypothalamic-pituitary-adrenal (HPA) axis, inflammation, and behavior.
- These effects might extend to offspring, causing intergenerational PND.
Purpose of the Study:
- To investigate if sevoflurane induces persistent HPA axis upregulation, inflammation, and behavioral deficits in rats.
- To determine if these sevoflurane-induced changes affect offspring neurocognition.
- To explore the role of hypothalamic arginine vasopressin (AVP) and NKCC1 signaling in sevoflurane-induced PND.
Main Methods:
- Male Sprague Dawley rats (F0) received sevoflurane with vehicle, NKCC1 inhibitor (bumetanide), or glucocorticoid receptor inhibitor (RU486).
- Rats were mated to produce offspring (F1).
- Neuroinflammation, HPA axis activity, and behavioral tests were assessed in F0 and F1 generations.
Main Results:
- Sevoflurane exposure increased hypothalamic AVP, HPA axis activity, and inflammatory markers in F0 rats, an effect blocked by bumetanide or RU486.
- F0 rats exposed to sevoflurane exhibited anxiety, sensorimotor gating, and spatial memory deficits.
- Offspring (F1) of sevoflurane-exposed rats showed similar behavioral deficits and altered social behavior; F1 females had impaired spatial memory.
Conclusions:
- Hypothalamic NKCC1/GABA-A receptor/AVP signaling mediates sevoflurane-induced PND in male rats.
- Sevoflurane exposure leads to intergenerational neurocognitive effects in offspring.
- NKCC1 and glucocorticoid receptors are potential therapeutic targets for preventing sevoflurane-induced PND.
