AUTHOR=Wang Jie , Yang Baofeng , Ju Lingsha , Yang Jiaojiao , Allen Andrea , Zhang Jiaqiang , Martynyuk Anatoly E. 

TITLE=The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats

JOURNAL=Frontiers in Systems Neuroscience

VOLUME=14

YEAR=2020

URL=https://www.frontiersin.org/journals/systems-neuroscience/articles/10.3389/fnsys.2020.546531

DOI=10.3389/fnsys.2020.546531

ISSN=1662-5137

ABSTRACT=<sec><title>Background</title><p>In 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 (GABA<sub><italic>A</italic></sub>R) signaling. We studied whether E2 synthesis and excitatory GABA<sub><italic>A</italic></sub>R signaling are involved in the mediation of the developmental effects of sevoflurane in male rats.</p></sec><sec><title>Methods</title><p>Male Sprague-Dawley rats were pretreated with the inhibitors of E2 synthesis, formestane, or the Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>–</sup> (NKCC1) Cl<sup>–</sup> 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.</p></sec><sec><title>Results</title><p>The rats neonatally exposed to sevoflurane responded to repeated exposure to sevoflurane with increased EEG-detectable seizures (<italic>F</italic><sub>(</sub><sub>3</sub>,<sub>24</sub><sub>)</sub> = 7.445, <italic>P</italic> = 0.001) and exhibited deficiencies during the EPM (<italic>F</italic><sub>(</sub><sub>3</sub>,<sub>55</sub><sub>)</sub> = 4.397, <italic>P</italic> = 0.008) and PPI (<italic>F</italic><sub>(</sub><sub>3</sub>,<sub>110</sub><sub>)</sub> = 5.222, <italic>P</italic> = 0.003) tests. They also responded to physical restraint with heightened secretion of corticosterone (<italic>F</italic><sub>(</sub><sub>3</sub>,<sub>16</sub><sub>)</sub> = 11.906, <italic>P</italic> &lt; 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.</p></sec><sec><title>Conclusion</title><p>These results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABA<sub><italic>A</italic></sub>R signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.</p></sec>