Identification of altered lipids predictive of anesthetic-induced brain injury

描述(申请人提供)：最近，越来越多的啮齿动物和非人类灵长类动物的临床前证据表明，临床上常用的麻醉剂对发育中的大脑具有神经毒性，并可能导致长期的神经行为异常，这引起了人们对婴儿和儿童麻醉安全性的极大关注。因此，麻醉剂神经毒性的临床相关性以及早期检测麻醉剂所致神经元损伤的生物标志物的开发是公共卫生的当务之急。由于各种神经元脂质在神经系统中发挥着特殊的作用，大脑中的微小干扰都会导致大脑、脑脊液(CSF)、 和血浆。全身麻醉药由于其脂溶性，很容易进入大脑，溶解到细胞膜，穿透细胞器，扰乱神经元脂质体的动力学，并对发育中的神经系统造成深远的影响(神经毒性)。我们假设麻醉药对脑脂类物质的扰动在麻醉性脑损伤早期就存在于脑组织、脑脊液和/或血浆中，这些变化的脂类可以作为早期检测麻醉剂神经毒性的生物标志物(S)。我们相信，通过我们的使能技术-鸟枪式脂质组学，可以在脑损伤的非常早期阶段检测到麻醉剂暴露引起的血脂变化，这是我们最近在NIH资金的支持下开创的。随着阿尔茨海默病脑组织的变化，这项技术的力量已经在发现脑脊液和血浆中的脂质变化方面得到了证明。在应用中，我们将利用现有的一个研究项目的优势，在该项目中，我们在FDA的合作者正在对发育中的猴子模型进行麻醉剂诱导的神经元损伤的研究，这被证明对人类药理学、生理学、毒理学等方面的信息具有非常宝贵的价值。初步研究表明，暴露于麻醉剂的猴子的脑、脑脊液和血浆中的许多脂质类别发生了显著变化，这有力地支持了我们的假设。为了进一步验证我们的假设，我们将(1)确定与神经细胞死亡增加和/或基因表达变化相比，麻醉剂作用下猴子脑组织中脂质含量的变化发生得更早(即持续时间更短)；(2)确定麻醉(S)下猴子脑脊液和血浆中脂质含量的变化与脑组织中脂质含量和/或成分的变化平行；以及(3)验证 麻醉猴(S)脑脊液和血浆中脂质的变化可作为早期检测麻醉剂神经毒性的生物标志物。这些拟议的研究为发现一组特异和敏感的脂质生物标志物以检测麻醉药物早期脑脊液和/或血浆中的神经毒性提供了巨大的希望，可用于未来的翻译研究。这项研究也可能对全麻药神经毒性的生化机制提供深入的了解。

DESCRIPTION (provided by applicant): A big concern has recently arisen regarding the safety of anesthesia in infants and children based on the profoundly increasing preclinical evidences in rodents and nonhuman primates that the commonly used anesthetics in clinic are neurotoxic to the developing brain and may cause long-term neurobehavioral abnormalities. Hence, the clinical relevance of anesthetic neurotoxicity as well as the development of biomarkers for early detection of anesthetic-induced neuronal injury is an urgent matter of public health. Since the diversified neuronal lipids play specific roles in the nervous system, small disturbance in the brain could result in changes of lipids in the brain, cerebrospinal fluid (CSF), and plasma. General anesthetics, due to their lipid solubility, readily enter the brain, dissolve into cellular membranes, penetrate organelle, disturb dynamics of neuronal lipidome, and leave far-reaching effects on the developing nervous system (neurotoxicity). We hypothesized that perturbation of brain lipids with anesthetics is manifest in brain tissues, CSF, and/or plasma of patients at a very early stage of anesthetic-induced brain injury, and these changed lipids can serve as biomarker(s) for early detection of anesthetic neurotoxicity. We believe the changes of lipids induced with anesthetic exposure can be detected at a very early stage of brain injury by our enabling technology, shotgun lipidomics, which we have recently pioneered with the support of NIH funding. The power of this technology has been demonstrated in discovery of altered lipids in CSF and plasma in accompanying the changes in brain tissues of Alzheimer's disease. In the application, we will take the advantages of an existing research project in which our collaborators at the FDA are conducting studies on the anesthetic- induced neuronal injury in the developing monkey model, which has proved to be invaluable for informing aspects of human pharmacology, physiology, toxicology, etc. Our hypothesis is strongly supported by the preliminary studies showing that numerous lipid classes were significantly changed in brain, CSF, and plasma of monkeys exposed to anesthetics. To further test our hypothesis, we will (1) identify that the changes of lipid content in monkey brain tissues occur at a much earlier stage (i.e., shorter duration) of anesthetic exposure in comparison to that revealed from the enhanced neuronal cell death and/or changes in gene expression; (2) determine that altered lipids in both CSF and plasma of monkeys which are exposed to anesthetic(s) occurs at the stage parallel to that detected with the changes of lipid content and/or composition in brain tissues; and (3) verify that the altered lipids manifest in CSF and plasma of monkeys exposed to anesthetic(s) can be served as biomarkers for early detection of anesthetic-induced neurotoxicity. The proposed studies hold tremendous promise for the discovery of a panel of specific and sensitive lipid biomarkers for detection of anesthetic neurotoxicity at its early stage in CSF and/or plasma, which can be used for future translational studies. This study might also provide insight into the biochemical mechanism underlying general anesthetic neurotoxicity.