Intergenerational Postoperative Neurocognitive Disorder in a Rat Model: Initiating Mechanisms and Pharmacological Prevention

Background: Vulnerability to perioperative neurocognitive disorder (PND) and the mechanisms initiating PND, which may serve as targets for prevention, are incompletely understood. This study hypothesized that sevoflurane can induce persistent upregulation of the hypothalamic–pituitary–adrenal axis, inflammation, and behavioral deficits in young adult male rats by stimulating hypothalamic arginine vasopressin (AVP) production via Na + -K + -Cl − (NKCC1) Cl − importer/γ-aminobutyric acid type A receptor signaling. These changes may also result in neurocognitive deficits in the offspring of exposed rats ( i.e. , intergenerational PND). Methods: Sprague Dawley male rats (generation F0) were exposed to 2.1% sevoflurane for 3 h on postnatal days 56, 58, and 60. Before each sevoflurane exposure. they received vehicle (F0M_S group), the NKCC1 inhibitor bumetanide (F0M_BS group), or the glucocorticoid receptor inhibitor RU486 (F0M_RS group). They were mated on postnatal day 90 with treatment-naïve females to generate offspring (generation F1). Results: Consistent with our hypothesis, short-term and sustained changes in F0M_S rats, but not F0M_BS and F0M_RS rats, included increased hypothalamic c-FOS and AVP (but not oxytocin) expression, increased hypothalamic–pituitary–adrenal axis activity, increased levels of systemic and central inflammatory markers, and increased Nkcc1 / K + -2Cl − ( Kcc2 ) Cl − exporter mRNA ratios in the brain. F0M_S males, but not F0M_BS and F0M_RS males, exhibited anxiety-like behavior and deficits in sensorimotor gating and spatial memory. Male offspring of F0M_S sires, but not F0M_BS or F0M_RS sires, exhibited behavioral abnormalities similar to those in F0M_S, as well as alterations in social behavior. The only deficit in F1 females was impaired spatial memory in the offspring of F0M_S. Conclusions: These findings suggest a role for hypothalamic NKCC1/γ-aminobutyric acid type A receptor/AVP signaling in sevoflurane-triggered PND in adult male rats, which also affects their future sevoflurane-unexposed offspring. NKCC1 and glucocorticoid receptors could serve as therapeutic targets for prevention of sevoflurane-induced PND in exposed rats and in their future offspring.