Role of the limbic-hypothalamic-pituitary-adrenal axis and gamma-aminobutyric acid type A receptor-mediated excitation in the developmental central and systemic effects of neonatal anesthesia

 描述(申请人提供)：边缘-下丘脑-垂体-肾上腺轴和伽马-氨基丁酸A型受体介导的兴奋在新生儿麻醉对发育、中枢和全身影响中的作用超过1/4的儿童在其出生的第一年就接触到全身麻醉。尽管在动物实验中提出了安全问题，并得到了人类流行病学研究的支持，但新生儿麻醉诱导的发育异常的机制和谱系仍知之甚少。本研究旨在研究七氟醚(SEVO)、异丙酚(PF)和依托咪酯(ET)对发育的影响。七氟醚是儿科麻醉中应用最广泛的麻醉剂，其多价作用包括增强伽马氨基丁酸A型受体(GABAAR)的活性，异丙酚(PF)是最常用的静脉麻醉剂，具有选择性GABA介导的作用，依托咪酯(ET)的作用机制类似于PF，与PF相比，依托咪酯干扰肾上腺皮质类固醇的合成。这些麻醉剂的性别和年龄效应将通过让SD大鼠在出生后4、5或6天(P4-P6)和P17、P18或P19(P17-P19)接受麻醉来评估。根据我们的实验结果和文献中的数据，我们假设：1)麻醉增强的持续边缘-下丘脑-垂体-肾上腺(LHPA)轴活动和GABA能兴奋(由于两个系统之间的正反馈循环实现了可持续性)在随后的性别依赖性内分泌和神经行为异常中起关键作用；2)生命后期的应激经历加剧了新生儿早期暴露于全身麻醉下的异常，即使麻醉时间不够长，本身也不足以引起显著的异常；3)LHPA轴活动的负性调节剂和/或Na+-K+-2Cl-共转运体抑制可减轻麻醉剂的发育效应。具体目标如下：目的1.确定新生儿暴露于SEVO、PF和ET的发育内分泌和神经行为的影响，以及麻醉时间和随后的应激暴露对其的调节作用。目的2.确定麻醉诱导的LHPA轴改变和兴奋性GABA能活动导致性别和年龄依赖性发育异常的机制。目的3.测定麻醉时麻醉增强LHPA轴活动正常化和GABAAR介导的兴奋的治疗效果。长期目标是开发翻译策略来研究和减轻新生儿麻醉对人类的不良影响。

 DESCRIPTION (provided by applicant): Role of the limbic-hypothalamic-pituitary-adrenal axis and gamma-aminobutyric acid type A receptor-mediated excitation in the developmental central and systemic effects of neonatal anesthesia More than 1 in 4 children are exposed to general anesthesia in their first year of life. Despite safety concerns raised in animal experiments and supported by human epidemiological studies, the mechanisms and spectrum of neonatal anesthesia-induced developmental abnormalities are poorly understood. This study is designed to investigate the developmental effects of sevoflurane (SEVO), the most widely used anesthetic in pediatric anesthesia, whose polyvalent actions include enhancement of gamma- aminobutyric acid type A receptor (GABAAR) activity, propofol (PF), the most frequently used intravenous anesthetic with a selective GABAAR-mediated action, and etomidate (ET), an anesthetic with a GABAergic mechanism of action similar to PF that, in contrast to PF, disrupts the adrenal synthesis of corticosteroids. The sex- and age-dependent effects of these anesthetics will be assessed by exposing Sprague-Dawley rats to anesthesia at postnatal days (P) 4, 5 or 6 (P4-P6) and P17, P18 or P19 (P17-P19). Based on our experimental findings and data in the literarture, we hypothesize that: 1) anesthetic- enhanced sustained limbic-hypothalamic-pituitary-adrenal (LHPA) axis activity and GABAergic excitation (the sustainability is achieved due to a positive feedback loop between the two systems) play a critical role in the subsequent long-term gender-dependent endocrine and neurobehavioral abnormalities; 2) stressful experiences later in life exacerbate the abnormalities programmed earlier by neonatal exposure to general anesthesia, even if the exposure to anesthesia is not long enough to induce prominent abnormalities by itself; 3) negative modulators of LHPA axis activity, and/or Na+-K+-2Cl- cotransporter inhibition, alleviate the observed developmental effects of the anesthetics. The specific aims are as follows: Aim 1. Determine the developmental endocrine and neurobehavioral effects of neonatal exposure to SEVO, PF, and ET and their modulation by anesthesia duration and subsequent stress exposure. Aim 2. Determine the mechanisms of anesthetic-induced alterations in the LHPA axis and excitatory GABAergic activities that contribute to the gender- and age-dependent developmental abnormalities. Aim 3. Determine the therapeutic effects of normalization of anesthetic-augmented LHPA axis activity and GABAAR-mediated excitation at the time of anesthesia. The long-term goal is to develop translational strategies to study and mitigate adverse effects of neonatal anesthesia in humans.