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

BACKGROUND: 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(A)R) signaling. We studied whether E2 synthesis and excitatory GABA(A)R signaling are involved in the mediation of the developmental effects of sevoflurane in male rats. METHODS: Male 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. RESULTS: The 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. CONCLUSION: These results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABA(A)R signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.