Propofol-Induced Electroencephalographic Seizures in Neonatal Rats

Abstract

Background An imbalance between excitation and inhibition in the developing central nervous system may result in a pathophysiological outcome. We investigated he mechanistic roles of endocrine activity and gamma-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 h before and 1 h after intraperitoneal administration of propofol (40 mg kg−1). Various treatments were administered 15 min 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 h after propofol administration in animals that underwent experimental manipulations identical to those used to study electroencephalographic activity. Pretreatment with bumetanide, the Na+–K+–2Cl– co-transporter 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.

Anesthesia with sevoflurane in neonatal rats: Developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl− importer antagonists

“…In order to control for the injections in groups 4 and 5, groups 1 and 2 received equal volumes of intraperitoneal saline or DMSO. Previously we have shown that neither saline nor DMSO at these volumes caused any obvious physiological responses (Tan et al, 2014; Willis et al, 2015). The effects of bumetanide and RU28318 (groups 4 and 5) were studied in male rats only because our previous study of propofol (Tan et al, 2014) and preliminary data on the side effects of sevoflurane indicate that female rats are relatively resistant to the long-term developmental effects of the anesthetics, at least based on physiological and behavioral parameters that we measured.…”

“…Bumetanide in this concentration/dose range is widely used as most selective of currently available inhibitors of NKCC1 (Dzhala et al, 2005; Tyzio et al, 2014). We previously demonstrated that bumetanide at this dose alleviated the developmental effects of sevoflurane and propofol in neonatal rats (Edwards et al, 2010; Cao et al, 2012; Seubert et al, 2013; Tan et al, 2014; Willis et al, 2015). The dose for RU28318 was originally chosen based on its depressant effect of acute stress in rats (Yuen et al, 2009).…”

“…Previously we have shown that exogenous corticosterone, administered to P4–P6 rats, induced an increase in GABAergic activity, similar to one observed in the sevoflurane exposed rats (Tan et al, 2014), suggesting that corticosterone may act through mechanisms that do not involve activation of the mineralocorticoid receptors to induce the observed alterations in GABAergic activity. Although, bumetanide and RU28318 at doses that were investigated in this study are widely used as selective inhibitors of the respective mechanisms in rats (Dzhala et al, 2005; Tyzio et al, 2014; Yuen et al, 2009; Willis et al, 2015), the fact that we tested the effects of these agents only at a single dose limits interpretation of the obtained results.…”

“…Recently, we reported that propofol, an intravenous general anesthetic, which is considered a relatively selective GABA A R enhancer, initiated similar acute and long-term developmental abnormalities when administered to neonatal rats (Tan et al, 2014; Willis et al, 2015) suggesting that similar mechanisms may be involved in initiation of the developmental effects of all general anesthetics that positively modulate GABA-ergic signaling.…”

“…The dose for RU28318 was originally chosen based on its depressant effect of acute stress in rats (Yuen et al, 2009). Subsequently, we demonstrated that bumetanide and RU28318 at these doses depressed propofol-induced electroencephalographic seizures in neonatal rats (Willis et al, 2015). In order to control for the injections in groups 4 and 5, groups 1 and 2 received equal volumes of intraperitoneal saline or DMSO.…”