Propofol-induced electroencephalographic seizures in neonatal rats: the role of corticosteroids and γ-aminobutyric acid type A receptor-mediated excitation.
BACKGROUND
An imbalance between excitation and inhibition in the developing central nervous system may result in a pathophysiological outcome. We investigated the mechanistic roles of endocrine activity and γ-aminobutyric acid type A receptor (GABAAR)-mediated excitation in electroencephalographic seizures caused by the GABAAR-selective anesthetic propofol in neonatal rats.


METHODS
Postnatal day 4-6 Sprague Dawley rats underwent a minor surgical procedure to implant electrodes to measure electroencephalographic activity for 1 hour before and 1 hour after intraperitoneal administration of propofol (40 mg·kg). Various treatments were administered 15 minutes before administration of propofol.


RESULTS
Episodes of electroencephalographic seizures and persistent low-amplitude spikes occurred during propofol anesthesia. Multifold increases in serum levels of corticosterone (t(10) = -5.062; P = 0.0005) and aldosterone (t(10) = -5.069; P = 0.0005) were detected 1 hour after propofol administration in animals that underwent experimental manipulations identical to those used to study electroencephalographic activity. Pretreatment with bumetanide, the Na-K-2Cl cotransporter inhibitor, which diminishes GABAAR-mediated excitation, eliminated both seizure and spike electroencephalographic activities caused by propofol. Mineralocorticoid and glucocorticoid receptor antagonists, RU 28318 and RU486, depressed electroencephalographic seizures but did not affect the spike electroencephalographic effects of propofol. Etomidate, at a dose sufficient to induce loss of righting reflex, was weak at increasing serum corticosteroid levels and eliciting electroencephalographic seizures. Etomidate given to corticosterone-pretreated rat pups further increased the total duration of electroencephalographic seizures caused by administration of exogenous corticosterone (t(21) = -2.512, P = 0.0203).


CONCLUSIONS
Propofol increases systemic corticosteroid levels in neonatal rats, which along with GABAAR-mediated excitation appear to be required for propofol-induced neonatal electroencephalographic seizures. Enhancement of GABAAR activity alone may not be sufficient to elicit neonatal electroencephalographic seizures.
From the *Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida; †Lake Erie College of Osteopathic Medicine, Bradenton, Florida; and ‡McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida.
Jesse
J
Willis
Wanting
W
Zhu
Julio
J
Perez-Downes
Sijie
S
Tan
Changqing
C
Xu
Christoph
C
Seubert
Nikolaus
N
Gravenstein
Anatoly
A
Martynyuk
D000305:Adrenal Cortex Hormones / Q000502:physiology*; D000450:Aldosterone / Q000097:blood; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D003345:Corticosterone / Q000097:blood; D004569:Electroencephalography / Q000187:drug effects*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology
D000305:Adrenal Cortex Hormones; D018686:Anesthetics, Intravenous; D000451:Mineralocorticoid Receptor Antagonists; D011963:Receptors, GABA-A; D011965:Receptors, Glucocorticoid; D000450:Aldosterone; D003345:Corticosterone; D015742:Propofol