Anesthesia-induced developmental neurodegeneration

麻醉引起的发育性神经变性

• 批准号: 8889454
• 负责人: Vesna Jevtovic-Todorovic
• 金额: $ 18.92万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-05 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889454
• 关键词: 4 year old; Adult; Age; Anesthesia procedures; Animals; Apoptotic; Behavioral; Brain; Brain region; Caspase; Cessation of life; Child; Childhood; Clinical; Clinical Research; Cytoplasm; DNA Damage; DNA Fragmentation; Development; EUK-134; Etiology; Event; Exposure to; Extravasation; Female; Frequencies; Functional disorder; General Anesthesia; General anesthetic drugs; Grant; Growth; Health; Hormones; Hour; Human Development; Impaired cognition; Impairment; Infant; Intensive Care Units; Intervention; Investigation; Learning; Learning Disabilities; Length of Stay; Life; Manganese Superoxide Dismutase; Mediating; Melatonin; Membrane; Memory; Mitochondria; Nerve Degeneration; Neuronal Injury; Neurons; Outcome; Oxygen; Pathway interactions; Patients; Phenotype; Premature Infant; Production; Proteins; Protocols documentation; Public Health; Rattus; Reactive Oxygen Species; Relative (related person); Reporting; Rodent; Role; Sedation procedure; Sleep; Staging; Superoxide Dismutase; System; Testing; Therapeutic Intervention; Up-Regulation; Visit; Work; caspase-3; caspase-9; catalase; cytochrome c; design; developmental neurotoxicity; functional disability; in vivo; male; mimetics; premature; pup; research study; synaptogenesis; therapeutic target

DESCRIPTION (provided by applicant): This is a resubmission of a competitive renewal of the R01 grant # HD 044517. The proposed experiments are extensions of earlier ones aimed at deciphering the cellular pathways responsible for anesthesia- induced developmental neurodegeneration. In addition to causing widespread apoptotic neurodegeneration in vulnerable brain regions, general anesthesia exposure at the peak of the brain growth spurt causes learning and memory deficiencies later in life. The gap in learning abilities between control and anesthesia- treated animals progressively widens in adulthood. Moreover, retrospective clinical evidence suggests that there is a relationship between the exposure of very young children to general anesthesia and subsequent life-long learning disabilities. Since general anesthesia cannot be avoided, better understanding the key mechanisms of anesthesia-induced developmental neurodegeneration and ways to ameliorate it are critically important to public health. Our in-vivo rodent studies have suggested that activation of the intrinsic (mitochondria-dependent) apoptotic pathway is the earliest warning sign of neuronal damage. Within the very first couple of hours, general anesthesia causes significant decrease in protein levels of bcl-XL which is quickly followed by a massive increase in cytochrome-c release from mitochondria. This leads to activation of caspase-9, and -3, DNA fragmentation, and neuronal death. In addition, our most recent in-vivo studies demonstrate that general anesthesia induces significant up-regulation of reactive oxygen species and both morphological and functional impairment of developing mitochondria in the immature neurons. Therapeutic intervention aimed at scavenging excessive reactive oxygen species using EUK-134, a synthetic superoxide dismutase and catalase mimetic, abolished anesthesia-induced learning impairment and significantly ameliorated anesthesia-induced increases in reactive oxygen species. The exact mechanisms operational in anesthesia-induced up-regulation of reactive oxygen species and mitochondria damage in the developing neurons must be determined so that therapeutic interventions can be devised. This is the main focus of our revised application.

描述（由申请人提供）：这是对R01授予＃HD 044517的竞争更新的重新提交。拟议的实验是旨在破译细胞途径的较早的实验扩展的扩展。除了在脆弱的大脑区域引起广泛的凋亡神经变性外，大脑生长峰值的全身麻醉暴露会导致生活后来的学习和记忆缺乏。在成年期，控制和麻醉动物之间学习能力的差距逐渐扩大。此外，回顾性的临床证据表明，很小的孩子暴露于全身麻醉与随后的终身学习障碍之间存在关系。由于无法避免全身麻醉，因此可以更好地理解麻醉引起的发育神经退行性的关键机制以及改善其对公共卫生至关重要的方法。我们的体内啮齿动物研究表明，固有（线粒体依赖性）凋亡途径的激活是神经元损伤的最早警告信号。在最初的几个小时内，全身麻醉会导致蛋白质水平的BCl-XL水平显着降低，随后迅速增加了线粒体细胞色素-C释放的大量增加。这导致caspase -9和-3，DNA碎片和神经元死亡的激活。此外，我们最近的体内研究表明，全身麻醉诱导活性氧的显着上调，以及未成熟神经元中线粒体发展的形态学和功能障碍。旨在使用EUK-134（一种合成的超氧化物歧化酶和过氧化氢酶模拟物）清除过量活性氧的治疗干预措施，消除了麻醉诱导的学习障碍，并显着改善了麻醉诱导的反应性氧气的增加。必须确定发育中神经元中的活性氧和线粒体损伤的麻醉引起的上调的确切机制，必须确定可以设计治疗干预措施。这是我们修订的应用程序的主要重点。

项目成果

Early Exposure to Ketamine Impairs Axonal Pruning in Developing Mouse Hippocampus.

• DOI: 10.1007/s12035-017-0730-0
• 发表时间: 2018-01
• 期刊: Molecular neurobiology
• 影响因子: 5.1
• 作者: Obradovic AL;Atluri N;Dalla Massara L;Oklopcic A;Todorovic NS;Katta G;Osuru HP;Jevtovic-Todorovic V
• 通讯作者: Jevtovic-Todorovic V

Functional implications of an early exposure to general anesthesia: are we changing the behavior of our children?

• DOI: 10.1007/s12035-013-8488-5
• 发表时间: 2013-10
• 期刊: MOLECULAR NEUROBIOLOGY
• 影响因子: 5.1
• 作者: Jevtovic-Todorovic, Vesna

General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats.

• DOI: 10.1007/s12640-009-9088-z
• 发表时间: 2010-02
• 期刊: NEUROTOXICITY RESEARCH
• 影响因子: 3.7
• 作者: Lunardi, N.;Ori, C.;Erisir, A.;Jevtovic-Todorovic, V.
• 通讯作者: Jevtovic-Todorovic, V.

Special issue on anaesthetic neurotoxicity and neuroplasticity.

• DOI: 10.1093/bja/aet195
• 发表时间: 2013-06
• 期刊: British journal of anaesthesia
• 影响因子: 9.8
• 作者: Hugh C. Hemmings;Vesna Jevtovic-Todorovic

Potential mechanism of cell death in the developing rat brain induced by propofol anesthesia.

• DOI: 10.1016/j.ijdevneu.2008.12.005
• 发表时间: 2009-05
• 期刊: INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE
• 影响因子: 1.8
• 作者: Pesic, Vesna;Milanovic, Desanka;Tanic, Nikola;Popic, Jelena;Kanazir, Selma;Jevtovic-Todorovic, Vesna;Ruzdijic, Sabera
• 通讯作者: Ruzdijic, Sabera