Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia

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起到神经毒素的作用，并导致长期的 婴儿期暴露后的神经行为变化。反复接触对人体尤其有害。 发育中的神经系统，以及4岁前接受一次以上全身麻醉的儿童 在情感和认知方面发生重大变化的风险增加。因此，至关重要的是，预防性 可以找到治疗方法。在动物模型中的研究表明，持续麻醉剂引起的变化 由于神经毒性、神经胶质毒性、突触丢失和线粒体结构的改变可能导致长期 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： 全麻药产生自由基对线粒体氧化应激的保护作用 消除啮齿动物成年后的认知障碍。我们已经建立了一种非人类的灵长类 早期麻醉暴露的模型。在之前的一个奖项中，我们展示了幼年恒河猴 多次接触吸入麻醉剂七氟醚，儿科麻醉中常用的，显示 在发育后期进行测试时，社会情绪和认知发展的长期变化。在这个新的 提案中，我们将使用该模型来检验新生儿麻醉暴露与 灵长类动物脑内突触和线粒体结构的长期变化及其保护作用 麻醉时氧化应激产生的线粒体可减轻或防止随后的变化 在认知和社会情感发展方面。具体地说，在这个项目的目标1中，线粒体和突触 将在电子显微镜水平上检查成年后制备和储存的组织的结构 上一次获奖的那些主题。对于目标2，幼年恒河猴将暴露在七氟醚中(3 在线粒体保护剂R()普拉克索存在的情况下)或接受治疗 并将进行为期2年的行为跟踪，以评估患者神经行为变化的严重性 治疗组。我们将确定R()普拉克索治疗是否也对突触和 这些猴子体内线粒体的变化。总之，这些研究的结果可以提供一个因果联系 麻醉暴露，线粒体功能障碍，改变猴子的情绪和认知行为。他们 还将向改进麻醉方案和预防性治疗迈出第一步，这将使 儿童接受安全的手术，同时将对大脑和行为的意外长期影响降至最低。

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.