%A Wang,Jie %A Yang,Baofeng %A Ju,Lingsha %A Yang,Jiaojiao %A Allen,Andrea %A Zhang,Jiaqiang %A Martynyuk,Anatoly E. %D 2020 %J Frontiers in Systems Neuroscience %C %F %G English %K sevoflurane,EEG seizures,Behavioral abnormalities,Corticosterone,Estradiol,Excitatory GABAA receptor signaling %Q %R 10.3389/fnsys.2020.546531 %W %L %M %P %7 %8 2020-September-04 %9 Original Research %# %! Estradiol in sevoflurane's developmental effects %* %< %T The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats %U https://www.frontiersin.org/articles/10.3389/fnsys.2020.546531 %V 14 %0 JOURNAL ARTICLE %@ 1662-5137 %X 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.