Abstract
BackgroundIn rodents, the period of increased vulnerability to the developmental effects of general anesthetics coincides with the period of age-specific organizing (masculinizing) effects of the major female sex hormone 17β-estradiol (E2) in the male brain and excitatory GABA type A receptor (GABAAR) signaling. We studied whether E2 synthesis and excitatory GABAAR signaling are involved in the mediation of the developmental effects of sevoflurane in male rats.MethodsMale Sprague-Dawley rats were pretreated with the inhibitors of E2 synthesis, formestane, or the Na+-K+-2Cl– (NKCC1) Cl– importer, bumetanide, prior to sevoflurane exposure for 6 h on postnatal (P) day 4, P5, or P6. We tested whether a subsequent exposure of these rats to sevoflurane on P∼10 would cause electroencephalography (EEG)-detectable seizures. We also evaluated their behavior during the elevated plus maze (EPM) test on P∼60, prepulse inhibition (PPI) of acoustic startle responses on P∼70, and corticosterone secretion to physical restraint on P∼80.ResultsThe rats neonatally exposed to sevoflurane responded to repeated exposure to sevoflurane with increased EEG-detectable seizures (F(3,24) = 7.445, P = 0.001) and exhibited deficiencies during the EPM (F(3,55) = 4.397, P = 0.008) and PPI (F(3,110) = 5.222, P = 0.003) tests. They also responded to physical restraint with heightened secretion of corticosterone (F(3,16) = 11.906, P < 0.001). These parameters in the sevoflurane-exposed rats that were pretreated with formestane or bumetanide were not different from those in the control rats.ConclusionThese results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABAAR signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.
Highlights
According to some surveys, 1.5 million children may be exposed to anesthesia during their first 12 months of life each year in the United States (DeFrances et al, 2007; Servick, 2014)
We have previously demonstrated that E2 may exacerbate the acute adverse effects of sevoflurane in neonatal rats through a direct potentiation of excitatory GABA type A receptor (GABAAR) signaling at the time of anesthesia (Zhang et al, 2016)
We studied the ability of sevoflurane to cause EEG-detectable seizures in the P9, P10, or P11 male rats in all four experimental groups, i.e., the control rats and rats that were exposed to sevoflurane for 6 h on postnatal day 4 (P4), P5, or P6 after pretreatment with the vehicle, formestane, or bumetanide
Summary
1.5 million children may be exposed to anesthesia during their first 12 months of life each year in the United States (DeFrances et al, 2007; Servick, 2014). In an attempt to improve the safety of pediatric anesthesia, numerous studies have proposed various mediating mechanisms of the adverse effects of general anesthetics in neonatal animal models, further confirming the mechanistic complexity of this phenomenon (Vutskits and Xie, 2016; Lin et al, 2017) Our approach in this field is based on an assumption that the developing brain is especially vulnerable to the deleterious effects of general anesthetics because, at least in part, the anesthetics exert their adverse effects by affecting mechanisms specific to this age period (Edwards et al, 2010; Tan et al, 2014; Xu et al, 2015; Zhang et al, 2016; Ju et al, 2017, 2018, 2019). We studied whether E2 synthesis and excitatory GABAAR signaling are involved in the mediation of the developmental effects of sevoflurane in male rats
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