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

边缘-下丘脑-垂体-肾上腺轴和γ-氨基丁酸A型受体介导的兴奋在新生儿麻醉发育中枢和全身效应中的作用

• 批准号: 9323607
• 负责人: ANATOLY E MARTYNYUK
• 金额: $ 32.81万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323607
• 关键词: Acute; Adrenal Cortex Hormones; Adrenal Glands; Adverse effects; Affect; Age; Anesthesia procedures; Anesthetics; Animal Experiments; Animals; Brain; Cardiovascular Abnormalities; Child; Childhood; Cognitive; Corticotropin-Releasing Hormone; Data; Development; Endocrine; Etomidate; Exposure to; Feedback; Female; Frequencies; Gender; General Anesthesia; Goals; Hippocampus (Brain); Human; Hyperactive behavior; Hypothalamic structure; Intravenous Anesthetics; Life; Life Experience; Literature; Manuscripts; Mediating; Memory impairment; Neonatal; Neurologic; Neurons; Pituitary Gland; Play; Propofol; Publishing; Rattus; Role; Safety; Sprague-Dawley Rats; Steroids; Stress; Synapses; System; Testing; Therapeutic Effect; Time; Up-Regulation; Update; age related; base; body system; design; epidemiology study; experience; experimental study; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; male; maternal separation; neonatal exposure; neurobehavioral; neurosteroids; paraventricular nucleus; pediatric patients; postnatal; prepulse inhibition; public health relevance; receptor; receptor-mediated signaling; sevoflurane; sex; sodium-potassium-chloride cotransporter 1 protein; stressor; translational approach

 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.

 描述（由申请人提供）：边缘-下丘脑-垂体-肾上腺轴和γ-氨基丁酸A型受体介导的兴奋在新生儿麻醉的发育中枢和全身效应中的作用超过四分之一的儿童在出生第一年接受全身麻醉。尽管动物实验提出了安全问题，并得到了人类流行病学研究的支持，但对新生儿麻醉引起的发育异常的机制和范围仍知之甚少。 本研究旨在研究七氟烷 (SEVO)（儿科麻醉中最广泛使用的麻醉剂，其多价作用包括增强 γ-氨基丁酸 A 型受体 (GABAAR) 活性）、丙泊酚 (PF)（最常用的具有选择性 GABAAR 介导作用的静脉麻醉剂）和依托咪酯 (ET)（一种 具有与 PF 类似的 GABA 作用机制的麻醉剂，与 PF 不同的是，它会破坏肾上腺皮质类固醇的合成。这些麻醉剂的性别和年龄依赖性效应将通过在出生后第 4、5 或 6 天 (P4-P6) 和 P17、P18 或 P19 (P17-P19) 将 Sprague-Dawley 大鼠暴露于麻醉来评估。 根据我们的实验结果和文献数据，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（可持续性是由于两个系统之间的正反馈回路实现的）在随后的长期性别依赖性内分泌和神经行为中发挥着关键作用 异常； 2) 晚年的压力经历会加剧早期因新生儿接受全身麻醉而导致的异常，即使麻醉时间不足以引起明显的异常； 3) LHPA轴活性的负调节剂和/或Na+-K+-2Cl-协同转运蛋白抑制，减轻观察到的麻醉剂的发育效应。 具体目标如下： 目标 1. 确定新生儿暴露于 SEVO、PF 和 ET 对发育内分泌和神经行为的影响及其通过麻醉持续时间和随后的应激暴露的调节。目标 2. 确定麻醉诱导的 LHPA 轴改变和兴奋性 GABA 活性改变的机制，这些改变导致性别和年龄依赖性发育异常。目标 3. 确定麻醉时麻醉剂增强的 LHPA 轴活性和 GABAAR 介导的兴奋正常化的治疗效果。长期目标是制定转化策略来研究和减轻新生儿麻醉对人类的不利影响。