Ju Ling-Sha, Yang Jiao-Jiao, Gravenstein Nikolaus, Seubert Christoph N, Morey Timothy E, Sumners Colin, Vasilopoulos Terrie, Yang Jian-Jun, Martynyuk Anatoly E
Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States.
Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
Psychoneuroendocrinology. 2017 Jul;81:96-104. doi: 10.1016/j.psyneuen.2017.04.001. Epub 2017 Apr 7.
The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure.
Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na-K-2Cl (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3-7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K-2Cl (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects.
Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.
大多数针对早年接受麻醉手术的人类进行神经认知评估的研究发现，尽管根据人类寿命进行标准化后的典型麻醉持续时间比在啮齿动物中显示可诱发发育异常的时间短得多，但仍存在长期缺陷。因此，我们研究了随后的环境应激源是否会导致短暂新生儿依托咪酯暴露所引发的缺陷。
在出生后第4、5或6天，用赋形剂或钠钾氯共转运体1（NKCC1）抑制剂布美他尼预处理的Sprague-Dawley大鼠接受两次依托咪酯注射，导致麻醉2小时。为了模拟麻醉后的应激，在出生后第10天让动物接受单次母鼠分离3小时。在暴露于依托咪酯后3至7天，大鼠下丘脑NKCC1 mRNA和促肾上腺皮质激素释放激素（CRH）mRNA增加，钾氯共转运体2（KCC2）mRNA水平降低，雄性大鼠的变化更大。在新生期同时暴露于依托咪酯和母鼠分离的大鼠中，这些异常持续到成年期。这些动物在受到束缚应激时皮质酮反应延长，雄性大鼠血浆总皮质酮增加更为明显，并且还表现出行为异常。用NKCC1抑制剂预处理可改善这些影响中的大多数。
即使在使用依托咪酯进行相对较短时间的麻醉后，麻醉后的应激源也可能加剧/暴露神经发育异常，导致成年期应激反应系统失调和神经行为缺陷。布美他尼的改善作用表明，依托咪酯增强的γ-氨基丁酸A型受体介导的去极化在引发基因表达的长期改变中起机制性作用，随后的母鼠分离会进一步增强这种改变。
