Mechanism of neurological and cognitive side effects of sevoflurane anesthesia at

七氟醚麻醉的神经和认知副作用机制

• 批准号: 8040573
• 负责人: ANATOLY E MARTYNYUK
• 金额: $ 26.95万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040573
• 关键词: Acoustics; Adolescent; Adverse effects; Affect; Age; Aminobutyric Acids; Anesthesia procedures; Anesthetics; Animals; Attenuated; Behavior; Behavioral; Brain; Bumetanide; Caring; Categories; Cells; Childhood; Clinical; Cognitive; Critical Illness; Data; Defect; Depressed mood; Development; Elements; Epidemiologic Studies; Event; Fetus; Frequencies; General Anesthesia; General anesthetic drugs; Glycine; Glycine Receptors; Grooming; Health; Homeostasis; Human; Impairment; Indium; Individual; Infant; Isoflurane; Learning; Link; Literature; Mediating; Membrane; Modern Medicine; Mothers; N-Methylaspartate; Nature; Neonatal; Neurologic; Neurons; Operative Surgical Procedures; Patients; Pattern; Play; Procedures; Rattus; Regimen; Reporting; Risk; Role; Safety; Seizures; Severities; Staging; Strychnine; Synaptic plasticity; Testing; animal data; base; cytotoxic; cytotoxicity; gamma-Aminobutyric Acid; hypnotic; inhibitor/antagonist; neocortical; neonate; nerve stem cell; neurogenesis; postnatal; postsynaptic; pregnant; prepulse inhibition; pup; receptor; receptor-mediated signaling; response; sevoflurane; symporter; voltage

DESCRIPTION (provided by applicant): Cellular mechanisms mediating cytotoxicity and delayed behavioral/cognitive abnormalities associated with neonatal anesthesia are poorly understood. Altered neurogenesis caused by anesthetic-depressed neuronal activity has been a predominant concept. Based on our preliminary results and literature data we hypothesize: 1) anesthetics that enhance GABAA/glycine receptor activity may exacerbate GABA-induced depolarization and Ca2+ influx in immature neurons resulting in immediate (seizures, cytotoxicity) and delayed brain defects (will be studied by evaluating synaptic plasticity, prepulse inhibition (PPI) of acoustic startle, grooming behavior); 2) seizures are not the prerequisite for other defects to occur; 3) distinct delayed defects are differently depend on duration of a given anesthetic; 4) types and severity of the GABAA receptor-mediated side effects caused by a given anesthetic depend on its efficacy to enhance GABAA receptor-mediated signaling; in addition, the GABAA receptor-mediated side effects of this anesthetic can be modified by its direct effects on Na+ and Ca++ influxes; 5) inhibition of NKCC1 activity diminishes side effects caused by these anesthetics in neonatal rats. Using sevoflurane and isoflurane, two general volatile anesthetics that share a GABAA component of action, this proposal aims to test the above hypotheses. The specific aims are as follows: Aim #1: Determine effects of sevoflurane and isoflurane on GABAA/glycine receptor-mediated responses, neuronal firing, spontaneous excitatory postsynaptic currents and voltage-gated Ca++ channels in postnatal day 4-24 (P4-P24) rat pup neocortical neurons. Aim #2: Determine the ability of sevoflurane and isoflurane to induce cortical seizures in P4-P24 rat pups. Aim #3: Determine the cytotoxic and delayed neuronal side effects of sevoflurane and isoflurane anesthesia in neonatal rat pups. The impact of this study on human health is obvious. Care for increasing numbers of preterm and critically ill term neonates and infants often involves both surgical and non-surgical procedures that require short-term or prolonged administration of anesthesia. The results of the current study will help: 1) to determine the mechanisms of the adverse effects of anesthesia with sevoflurane and isoflurane at early stages of brain development; 2) to provide criteria for choosing safer anesthetic agents or regimens for this age category; 3) to provide approaches to increase efficacy and safety of currently available anesthetics with a GABAA/glycine-ergic component of actions by modifying Cl- homeostasis. PUBLIC HEALTH RELEVANCE: Using neonatal rats this study tests the hypothesis that the excitation, generated by anesthetics that enhance GABAA/glycine receptor activity, may affect safety of general anesthesia and may result in long- term neurological and cognitive risks in neonates and small infants. This study also tests the hypothesis that inhibition of NKCC1 activity may diminish these side effects and increase safety of the anesthetics.

描述（由申请人提供）：对介导与新生儿麻醉相关的细胞毒性和迟发性行为/认知异常的细胞机制知之甚少。由麻醉抑制神经元活动引起的神经发生改变一直是一个主要概念。根据我们的初步结果和文献数据，我们假设：1）增强 GABAA/甘氨酸受体活性的麻醉剂可能会加剧未成熟神经元中 GABA 诱导的去极化和 Ca2+ 流入，从而导致立即（癫痫发作、细胞毒性）和延迟性脑缺陷（将由评估突触可塑性、声惊吓的前脉冲抑制 (PPI)、梳理行为； 2) 癫痫发作不是其他缺陷发生的先决条件； 3) 不同的迟发性缺陷取决于给定麻醉的持续时间； 4) 由特定麻醉剂引起的 GABAA 受体介导的副作用的类型和严重程度取决于其增强 GABAA 受体介导的信号传导的功效；此外，这种麻醉剂的 GABAA 受体介导的副作用可以通过其对 Na+ 和 Ca++ 流入的直接影响来改变； 5)抑制NKCC1活性可减少这些麻醉剂对新生大鼠造成的副作用。本提案旨在使用七氟烷和异氟烷这两种具有 GABAA 作用成分的普通挥发性麻醉剂来检验上述假设。具体目标如下： 目标#1：确定七氟醚和异氟醚对产后 4-24 天 (P4-P24) GABAA/甘氨酸受体介导的反应、神经元放电、自发兴奋性突触后电流和电压门控 Ca++ 通道的影响幼鼠新皮质神经元。目标#2：确定七氟烷和异氟烷诱导 P4-P24 幼鼠皮质癫痫发作的能力。目标#3：确定七氟烷和异氟烷麻醉对新生大鼠幼崽的细胞毒性和迟发性神经元副作用。这项研究对人类健康的影响是显而易见的。对越来越多的早产儿和危重新生儿和婴儿的护理通常涉及需要短期或长期麻醉的手术和非手术程序。目前的研究结果将有助于：1）确定七氟烷和异氟烷麻醉在大脑发育早期阶段产生不良影响的机制； 2) 为该年龄组选择更安全的麻醉剂或方案提供标准； 3) 提供通过改变Cl-稳态来提高目前可用的具有GABAA/甘氨酸能成分的麻醉剂的功效和安全性的方法。 公共健康相关性：本研究使用新生大鼠测试了这样的假设：增强 GABAA/甘氨酸受体活性的麻醉剂产生的兴奋可能会影响全身麻醉的安全性，并可能导致新生儿和小婴儿的长期神经和认知风险。这项研究还测试了抑制 NKCC1 活性可能会减少这些副作用并提高麻醉剂安全性的假设。