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: 10400934
• 负责人: MARIA C ALVARADO
• 金额: $ 41.88万
• 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 2022-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400934
• 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.

项目摘要 全身麻醉药可能在发育中的哺乳动物神经系统中充当神经毒素，并引起长期的 婴儿期暴露后的神经行为变化。反复接触对人体特别有害， 发育中的神经系统，以及在4岁之前接受过一次以上全身麻醉的儿童 会增加情绪和认知变化的风险因此，至关重要的是， 在动物模型中的研究表明，持续的麻醉诱导的变化， 由于神经毒性、神经胶质毒性、突触丢失和线粒体结构变化可能导致长期的 行为障碍麻醉对线粒体的早期影响可能是长期损害的关键： 保护线粒体免受由全身麻醉药产生的自由基引起的氧化应激 消除了啮齿动物成年后的认知障碍。我们建立了一种非人类灵长类动物 早期麻醉剂暴露模型。在之前的一个奖项中，我们发现， 多次暴露于常用于儿科麻醉的吸入麻醉剂七氟烷，显示 在社会情感和认知发展的长期变化时，在后来的发展测试。在这个新 建议，我们将使用该模型来检验假设，即新生儿麻醉暴露与 灵长类动物大脑中突触和线粒体结构的长期变化，以及 在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作用具体来说，在本项目的目标1中，线粒体和突触 成年期的结构将在电子显微镜水平上在组织中进行检查，这些组织是从 这是上一个奖项的主题。对于目标2，将恒河猴幼崽暴露于七氟烷（3 在存在R（+）普拉克索（一种线粒体保护剂）或经治疗的情况下， 并将在行为上随访2年，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保护突触和 线粒体的变化。总之，这些研究的结果可以提供一个因果关系， 麻醉剂暴露，线粒体功能障碍，以及猴子的情绪和认知行为改变。他们 还将为改进麻醉方案和预防性治疗迈出第一步， 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。