The role of neurotrophins in anesthesia-induced developmental neuroapoptosis

神经营养素在麻醉诱导的发育性神经细胞凋亡中的作用

• 批准号: 7278750
• 负责人: Vesna Jevtovic-Todorovic
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278750
• 关键词: Address; Adolescent; Adult; Adverse effects; Air; Anabolism; Anesthesia procedures; Anesthesiology; Anesthetics; Animals; Anus; Apoptosis; Apoptotic; Applications Grants; Award; Barbiturates; Benzodiazepines; Biological Process; Birth; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cavia; Cell Death; Cell membrane; Ceramides; Cerebral cortex; Child; Childhood; Class; Collaborations; Data; Development; Etomidate; Family; Family suidae; General Anesthesia; General anesthetic drugs; Generic Drugs; Glutamate Receptor; Growth; Growth Factor; Halothane; Hippocampus (Brain); Hour; Human; Individual; Infant; Intervention; Intravenous; Intravenous Anesthetics; Isoflurane; Ketamine; Laboratories; Learning; Life; Mediating; Memory impairment; Mental Depression; Midazolam; Molecular Neurobiology; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neonatal; Nerve Degeneration; Nerve Growth Factors; Neurobiology; Neurons; Nitrous Oxide; Operative Surgical Procedures; Pathologic Processes; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiological; Pilot Projects; Play; Pregnancy; Premature Infant; Principal Investigator; Propofol; Prosencephalon; Protein-Serine-Threonine Kinases; Proteins; Protocols documentation; Rate; Rattus; Receptor Activation; Reporting; Role; Signal Transduction; Silicon Dioxide; Support of Research; Sus scrofa; Synaptic plasticity; System; Testing; Thalamic structure; Time; Transcriptional Activation; Tropomyosin; Universities; Up-Regulation; Virginia; Week; Yugoslavia; accomplished suicide; barbiturate receptor; barbituric acid salt; clinically relevant; day; fetal; improved; in utero; in vivo; infancy; interest; neonate; neuronal survival; neurotoxic; neurotransmission; neurotrophic factor; parent grant; prevent; programs; receptor; sevoflurane; synaptogenesis; transcriptional coactivator p75

DESCRIPTION (provided by applicant): This is the FIRCA Award application for the support of the research that will be done primarily in Serbia and Montenegro, in Laboratory for Molecular Neurobiology, the Department of Neurobiology at the University of Belgrade, Belgrade in collaboration with Vesna Jevtovic-Todorovic, Department of Anesthesiology, University of Virginia, as an extension of NIH/NICHD parent grant #R01 HD 044517. Premature infants, neonates and very young children are frequently exposed to general anesthesia. However, some recent findings indicate that anesthetic drugs, by transiently suppressing neuronal activity in the developing mammalian brain, disturb normal brain development (e.g. synaptogenesis) thus promoting apoptotic cell death of the immature neurons. Anesthesia-induced apoptotic neurodegeneration in the immature rats, a species of interest for this proposal, was manifested not only as a severe widespread apoptotic neurodegeneration (e.g. neuroapoptosis) in the developing brain but also as a significant and persistent learning/memory deficits detected latter on in life. The neurotrophins, a family of growth factors, support neuronal survival, differentiation and several forms of synaptic plasticity and therefore play an important role in synaptogenesis of the mammalian brain. Consequently, extensive depression of neuronal activity can impair survival-promoting signals that are regulated by neurotrophins. To investigate the potential relevance of neurotrophin-mediated anesthesia-induced developmental neuroapoptosis we conducted a pilot study on infant rats (at the peak of their synaptogenesis-7 days old) that were exposed to an inhalational anesthetic, isoflurane, at clinically relevant concentration (1.5-vol% in air), for a period of 2, 4 or 6 hrs. We found that isoflurane modulates the key steps in neurotrophin-modulated apoptotic cascade in two most vulnerable brain regions - the cerebral cortex and the thalamus. Namely, the protein levels of activated Akt, a key component in blocking apoptotic cascade, were significantly decreased in both the cortex and the thalamus. However, the BDNF (brain derived neurotrophic factor) protein levels were differentially modulated in the cortex; they were significantly increased, wherein in the thalamus there was a rapid and significant decrease in BDNF levels. In addition, while there was an up-regulation of the activated ceramide in the cortex there were no changes in ceramide activation in the thalamus: These findings suggest that isoflurane not only activates Akt-regulated apoptotic pathways, but does so in differential fashion in different brain regions most likely by activating both Trk dependent and Trk independent, p75NTR dependent neurotrophic survival pathways. In this grant application, the applicants plan to extend the studies of the mechanism of anesthesia-induced developmental apoptosis proposed in the parent grant by performing detailed studies of the mechanism(s) of neurotrophin-modulated anesthesia-induced neuroapoptosis. By expanding our understanding of all the crucial steps in the anesthesia-induced apoptotic cascade we hope to improve our chances of preventing potentially detrimental neurotoxic effects of general anesthetics to the developing mammalian brain.

DESCRIPTION (provided by applicant): This is the FIRCA Award application for the support of the research that will be done primarily in Serbia and Montenegro, in Laboratory for Molecular Neurobiology, the Department of Neurobiology at the University of Belgrade, Belgrade in collaboration with Vesna Jevtovic-Todorovic, Department of Anesthesiology, University of Virginia, as an extension of NIH/NICHD parent grant #R01 HD 044517。早产婴儿，新生儿和非常小的孩子经常暴露于全身麻醉。然而，最近的一些发现表明，通过瞬时抑制发育中的哺乳动物大脑中的神经元活性，干扰正常的大脑发育（例如突触发生），从而促进未成熟神经元的凋亡细胞死亡。麻醉诱导的未成熟大鼠的凋亡神经退行性是该提案的一种感兴趣的物种，不仅表现为发育中大脑中严重的广泛凋亡神经退行性变化（例如，神经吞噬作用），而且还表现为重要的，并且在生命中持续检测到了一个很大的学习/记忆缺陷。神经营养蛋白是一种生长因子家族，支持神经元的生存，分化和几种突触可塑性，因此在哺乳动物大脑的突触发生中起着重要作用。因此，神经元活性的广泛抑郁会损害由神经营养蛋白调节的促进生存信号。 To investigate the potential relevance of neurotrophin-mediated anesthesia-induced developmental neuroapoptosis we conducted a pilot study on infant rats (at the peak of their synaptogenesis-7 days old) that were exposed to an inhalational anesthetic, isoflurane, at clinically relevant concentration (1.5-vol% in air), for a period of 2, 4 or 6 hrs.我们发现，异氟烷调节了两个最脆弱的大脑区域中神经营养蛋白调节的凋亡级联反应的关键步骤 - 大脑皮层和丘脑。也就是说，在皮质和丘脑中，激活的Akt的蛋白质水平是阻断凋亡级联反应的关键成分。然而，在皮质中对BDNF（脑衍生的神经营养因子）蛋白水平有差异调节。它们显着增加，其中丘脑中的BDNF水平迅速而显着下降。此外，虽然皮质中活化神经酰胺的上调虽然丘脑中的神经酰胺激活没有变化：这些发现表明，异氟烷不仅可以激活Akt调节的凋亡途径，而且在不同的大脑区域在不同的大脑区域中却在TRK依赖性和TRK Indepents Ippertion intk Ippertion content和p75n中都以差异性来激活这种方式。在此赠款应用中，申请人计划通过对神经营养蛋白修饰的麻醉诱导的神经凋亡的机制进行详细研究，扩大父母赠款中麻醉诱导的发育凋亡机制的研究。通过扩展我们对麻醉诱导的凋亡级联的所有关键步骤的理解，我们希望提高我们预防普通麻醉剂对发育中的哺乳动物大脑的潜在有害神经毒性作用的机会。