Wang Jie, Yang Baofeng, Ju Lingsha, Yang Jiaojiao, Allen Andrea, Zhang Jiaqiang, Martynyuk Anatoly E
Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China.
Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States.
Front Syst Neurosci. 2020 Sep 4;14:546531. doi: 10.3389/fnsys.2020.546531. eCollection 2020.
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 R) signaling. We studied whether E2 synthesis and excitatory GABA R signaling are involved in the mediation of the developmental effects of sevoflurane in male rats.
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.
The rats neonatally exposed to sevoflurane responded to repeated exposure to sevoflurane with increased EEG-detectable seizures ( , = 7.445, = 0.001) and exhibited deficiencies during the EPM ( , = 4.397, = 0.008) and PPI ( , = 5.222, = 0.003) tests. They also responded to physical restraint with heightened secretion of corticosterone ( , = 11.906, < 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.
These results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABA R signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.
在啮齿动物中，对全身麻醉药发育影响的易感性增加期与主要雌性性激素17β-雌二醇（E2）在雄性大脑中的年龄特异性组织（雄性化）作用期以及兴奋性γ-氨基丁酸A型受体（GABA R）信号传导期相吻合。我们研究了E2合成和兴奋性GABA R信号传导是否参与七氟醚对雄性大鼠发育影响的介导。
在出生后（P）第4、5或6天，对雄性Sprague-Dawley大鼠在暴露于七氟醚6小时之前，先用E2合成抑制剂福美坦或钠-钾-2氯（NKCC1）氯转运体抑制剂布美他尼进行预处理。我们测试了这些大鼠随后在P10时再次暴露于七氟醚是否会导致脑电图（EEG）可检测到的癫痫发作。我们还在P60时的高架十字迷宫（EPM）试验、P70时的听觉惊吓反应的前脉冲抑制（PPI）以及P80时对身体束缚的皮质酮分泌情况评估了它们的行为。
新生期暴露于七氟醚的大鼠在再次暴露于七氟醚时，EEG可检测到的癫痫发作增加（F，df = 7.445，P = 0.001），并且在EPM（F，df = 4.397，P = 0.008）和PPI（F，df = 5.222，P = 0.003）试验中表现出缺陷。它们对身体束缚的反应是皮质酮分泌增加（F，df = 11.906，P < 0.001）。用福美坦或布美他尼预处理的七氟醚暴露大鼠的这些参数与对照大鼠没有差异。
这些结果与先前发表的数据表明，七氟醚麻醉时七氟醚增强的E2合成和兴奋性GABA R信号传导参与了麻醉药对雄性大鼠神经发育影响的介导。
