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 (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. 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 GABAAR signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.

中文翻译：

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雌二醇合成抑制剂福美坦降低七氟醚诱导雄性大鼠神经发育异常的能力

背景 在啮齿动物中，全身麻醉剂对发育影响的易感性增加的时期与男性大脑中主要雌性激素 17β-雌二醇 (E2) 和兴奋性 GABA A 型的年龄特异性组织（男性化）作用的时期相吻合受体（GABAAR）信号传导。我们研究了 E2 合成和兴奋性 GABAAR 信号是否参与介导七氟醚对雄性大鼠的发育影响。方法 雄性 Sprague-Dawley 大鼠在出生后 (P) 天第 4 天，P5 暴露于七氟醚 6 小时之前，用 E2 合成抑制剂、福美坦或 Na+-K+-2Cl- (NKCC1) Cl- 输入物布美他尼进行预处理，或 P6。我们测试了这些大鼠随后在 P∼10 上暴露于七氟醚是否会导致脑电图 (EEG) 可检测到的癫痫发作。我们还评估了它们在 P∼60 的高架十字迷宫 (EPM) 测试、P∼70 声惊吓反应的前脉冲抑制 (PPI) 和 P∼80 对物理约束的皮质酮分泌期间的行为。结果 新生暴露于七氟醚的大鼠对反复暴露于七氟醚有反应，EEG 可检测到的癫痫发作增加 (F(3,24) = 7.445, P = 0.001) 并在 EPM 期间表现出缺陷 (F(3,55) = 4.397, P = 0.008) 和 PPI (F(3,110) = 5.222, P = 0.003) 检验。他们还对身体约束做出反应，皮质酮分泌增加（F(3,16) = 11.906，P < 0.001）。用福美坦或布美他尼预处理的暴露于七氟醚的大鼠中的这些参数与对照大鼠中的没有不同。结论 这些结果，连同之前公布的数据，