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

基本信息

批准号：
7465488
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
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7465488
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

项目摘要

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.

描述（由申请人提供）：这是 FIRCA 奖申请，用于支持将主要在塞尔维亚和黑山、贝尔格莱德大学神经生物学系分子神经生物学实验室与 Vesna 合作进行的研究Jevtovic-Todorovic，弗吉尼亚大学麻醉学系，作为 NIH/NICHD 家长补助金 #R01 HD 044517 的延伸。婴儿、新生儿和幼儿经常接受全身麻醉。然而，最近的一些发现表明，麻醉药物通过暂时抑制发育中的哺乳动物大脑中的神经元活动，扰乱正常的大脑发育（例如突触发生），从而促进未成熟神经元的凋亡细胞死亡。未成熟大鼠中麻醉诱导的细胞凋亡性神经变性（本提案感兴趣的一个物种）不仅表现为发育中大脑中严重广泛的细胞凋亡性神经变性（例如神经细胞凋亡），而且表现为后期检测到的显着且持续的学习/记忆缺陷在生活中。神经营养蛋白是生长因子家族，支持神经元存活、分化和多种形式的突触可塑性，因此在哺乳动物大脑的突触发生中发挥重要作用。因此，神经元活动的广泛抑制会损害由神经营养素调节的促进生存的信号。为了研究神经营养蛋白介导的麻醉诱导的发育性神经细胞凋亡的潜在相关性，我们对幼年大鼠（在突触发生高峰期 - 7 天大）进行了一项初步研究，这些大鼠暴露于临床相关浓度（1.5 -空气中的vol%），持续2、4或6小时。我们发现异氟烷调节两个最脆弱的大脑区域（大脑皮层和丘脑）中神经营养蛋白调节的细胞凋亡级联的关键步骤。也就是说，激活的 Akt（阻止细胞凋亡级联的关键成分）的蛋白质水平在皮层和丘脑中均显着降低。然而，BDNF（脑源性神经营养因子）蛋白水平在皮质中受到差异调节；它们显着增加，其中丘脑中 BDNF 水平快速显着下降。此外，虽然皮质中的激活神经酰胺上调，但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激活 Akt 调节的细胞凋亡途径，而且在不同的细胞中以不同的方式发挥作用。大脑区域最有可能通过激活 Trk 依赖性和 Trk 独立性、p75NTR 依赖性神经营养存活途径。在本拨款申请中，申请人计划通过对神经营养蛋白调节的麻醉诱导的神经细胞凋亡的机制进行详细研究，来扩展母基金中提出的麻醉诱导的发育细胞凋亡机制的研究。通过扩大我们对麻醉诱导的细胞凋亡级联中所有关键步骤的理解，我们希望提高预防全身麻醉药对发育中的哺乳动物大脑产生潜在有害神经毒性作用的机会。