Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia

线粒体保护以防止产后麻醉后神经行为的变化

• 批准号: 10170393
• 负责人: MARIA C ALVARADO
• 金额: $ 67.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170393
• 关键词: 3 year old; Address; Adolescent; Adult; Adverse effects; Age; Anesthesia procedures; Anesthetics; Animal Model; Apoptosis; Attenuated; Award; Behavior; Behavioral; Brain; Child; Childhood; Clinical; Clinical Research; Cognitive; Development; Dopamine Agonists; Dopamine Receptor; Electrons; Elements; Emotional; Euthanasia; Exposure to; Free Radicals; General Anesthesia; General anesthetic drugs; Generations; Goals; Hippocampus (Brain); Hour; Human; Impaired cognition; Impairment; Infant; Inhalant dose form; Inhalation Anesthetics; Injections; Lead; Life; Link; Long-Term Effects; Macaca mulatta; Microscopic; Mitochondria; Modeling; Monkeys; Morphology; Neonatal; Nervous system structure; Neuraxis; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurons; Neurotoxins; Observational Study; Operative Surgical Procedures; Outcome; Oxidative Stress; Pharmaceutical Preparations; Physiology; Prefrontal Cortex; Preventive treatment; Primates; Prospective Studies; Protocols documentation; Research; Risk; Rodent; Stereoisomer; Structure; Synapses; Testing; Time; Tissues; Visual impairment; anxiety-related behavior; behavioral impairment; brain behavior; clinically relevant; cognitive change; cognitive development; density; early childhood; enantiomer; experimental study; improved; infancy; memory recognition; mitochondrial dysfunction; neurobehavioral; neurotoxicity; nonhuman primate; postnatal; pramipexol; preclinical study; presynaptic; prevent; programs; relating to nervous system; sedative; sevoflurane; sex

Project Summary General anesthetics may act as neurotoxins in the developing mammalian nervous system and cause long-term neurobehavioral changes after exposure in infancy. Repeated exposure is particularly deleterious to the developing nervous system, and children who undergo more than one general anesthesia before the age of 4 are at an increased risk for substantial emotional and cognitive changes. It is therefore critical that preventative treatments be found. Studies in animal models have suggested that persistent anesthetic-induced changes such as neurotoxicity, gliotoxicity, loss of synapses and changes in mitochondrial structure may lead to long-term behavioral impairments. Early effects of anesthesia on mitochondria may be key to long-term impairments: protection of mitochondria from oxidative stress caused by free radical generation from general anesthetics eliminates subsequent cognitive impairment in adulthood in rodents. We have established a nonhuman primate model of early anesthetic exposure. In a previous award, we showed that infant rhesus monkeys that received multiple exposures of to the inhalation anesthetic sevoflurane, commonly used in pediatric anesthesia, showed long-term changes in socioemotional and cognitive development when tested later in development. In this new proposal, we will use that model to test the hypothesis that neonatal anesthesia exposure is associated with long-term changes in synaptic and mitochondrial structure in the primate brain, and that protection of mitochondria from oxidative stress at the time of anesthesia exposure mitigates or prevents subsequent changes in cognitive and socioemotional development. Specifically, in Aim 1 of this project, mitochondrial and synaptic structure in adulthood will be examined at the electron microscopic level in tissue prepared and banked from those subjects from the previous award. For Aim 2, infant rhesus macaques will be exposed to sevoflurane (3 exposures in the six weeks of life) in the presence of R(+)pramipexole, a mitochondrial protectant, or treated with vehicle and will be followed behaviorally for 2 years to assess sparing of neurobehavioral changes in the treated group. We will determine whether R(+)pramipexole treatment also protects against synaptic and mitochondrial changes in these monkeys. Together, results from these studies can provide a causal link between anesthetic exposure, mitochondrial dysfunction, and altered emotional and cognitive behavior in monkeys. They will also provide a first step towards improved anesthetic protocols and preventative treatments that will allow children to undergo safe surgery while minimizing unintended long-term effects on the brain and behavior.

项目概要 全身麻醉剂可能在发育中的哺乳动物神经系统中充当神经毒素，并导致长期 婴儿期暴露后神经行为的变化。反复接触对身体尤其有害 神经系统正在发育中，以及 4 岁之前接受过一次以上全身麻醉的儿童 发生重大情绪和认知变化的风险增加。因此，预防性措施至关重要 找到治疗方法。动物模型研究表明，持续麻醉引起的变化，例如 因为神经毒性、胶质毒性、突触损失和线粒体结构的变化可能导致长期 行为障碍。麻醉对线粒体的早期影响可能是长期损伤的关键： 保护线粒体免受全身麻醉剂产生自由基引起的氧化应激 消除啮齿类动物成年后的认知障碍。我们已经建立了一种非人类灵长类动物 早期麻醉暴露模型。在之前的一个奖项中，我们展示了获得的幼年恒河猴 多次暴露于小儿麻醉中常用的吸入麻醉剂七氟醚，表明 在发育后期进行测试时，会发现社会情感和认知发展的长期变化。在这个新 建议，我们将使用该模型来检验新生儿麻醉暴露与 灵长类动物大脑中突触和线粒体结构的长期变化，以及对 麻醉暴露时线粒体免受氧化应激，减轻或防止随后的变化 在认知和社会情感发展中。具体来说，在该项目的目标 1 中，线粒体和突触 成年期的结构将在电子显微镜水平上检查从以下组织中制备和储存的组织 以前获奖的那些科目。对于目标 2，幼年恒河猴将暴露于七氟醚（3 生命六周内的暴露）在存在 R(+)普拉克索（一种线粒体保护剂）或经过治疗的情况下 与车辆一起进行为期 2 年的行为跟踪，以评估神经行为变化的保留情况 治疗组。我们将确定 R(+)普拉克索治疗是否也能预防突触和 这些猴子的线粒体变化。总之，这些研究的结果可以提供之间的因果关系 麻醉剂暴露、线粒体功能障碍以及猴子情绪和认知行为的改变。他们 还将为改进麻醉方案和预防性治疗迈出第一步，使 儿童接受安全的手术，同时尽量减少对大脑和行为的意外长期影响。