Neonatal Anesthetic Neurotoxicity

新生儿麻醉神经毒性

基本信息

批准号：
8068322
负责人：
Piyush M Patel
金额：
$ 28.74万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068322
关键词：
Adult Alteplase Anesthesia procedures Anesthetics Apoptosis Apoptotic Behavioral Biochemical Genetics Brain Brain Injuries Brain-Derived Neurotrophic Factor Cessation of life Cleaved cell Data Dendritic Spines Elements Evaluation Fetus General Anesthesia Hippocampus (Brain)Human Impaired cognition In Vitro Infant Injury Isoflurane Laboratories Lead Learning MAPK8 gene Memory Modality Molecular Mus N-Methyl-D-Aspartate Receptors NGFR Protein Nature Neonatal Nerve Degeneration Neurons Newborn Animals Outcome Peptide Hydrolases Plasmin Plasminogen Prevention approach Protein Tyrosine Kinase Receptor Inhibition Receptor Protein-Tyrosine Kinases Receptor Signaling Recombinants Recovery Research Role Signal Transduction Spinal Cord Synapses Synaptic Cleft Synaptic Vesicles System Testing Toxic effect Unconscious State Vertebral column Withdrawal Work base cognitive function efficacy testing in vivo injured insight neonate neuron apoptosis neuronal survival neurotoxicity neurotrophic factor novel novel therapeutic intervention novel therapeutics prevent public health relevance receptor research study synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): A premise of general anesthesia is that anesthetics produce a non-toxic and reversible state of unconsciousness. Recent data indicate that exposure of neonatal animals to anesthetics triggers widespread neurodegeneration leading to persistent memory and learning abnormalities during adulthood [1]. Anesthetic neurotoxicity has raised concerns about the potential adverse impact of general anesthesia in the human fetus, neonate and infant. Although the precise mechanism is not clear, the toxicity occurs during synaptogenesis and is apoptotic in nature [1,2]. In the developing brain, synaptic connections with appropriate targets are essential for neuronal survival as neurons are dependent upon trophic support from their targets [13-15]. Loss of synaptic connection leads to apoptosis. The neurotrophin BDNF contributes to neuronal survival and synaptogenesis, and to the consolidation and maturation of synapses [16]. BDNF can, however, also result in neuronal apoptosis [17,18]. BDNF is secreted from synaptic vesicles as a pro molecule (proBDNF) and undergoes proteolytic cleavage in the synaptic cleft by plasmin to generate mature BDNF (mBDNF) [19]. Plasminogen, the precursor to plasmin, is proteolytically cleaved by tPA, a protease released from pre-synaptic vesicles. The mBDNF signals through TrkB receptors to promote neuronal survival and synaptogenesis. In the absence of tPA, proBDNF is uncleaved and preferentially signals through p75NTR receptors, resulting in reduced synaptogenesis, withdrawal of dendritic spines and neuronal apoptosis [20]. Preliminary data from our laboratory indicate that the volatile anesthetic, isoflurane, reduces tPA release; this results in the preferential signaling of proBDNF through p75NTR, leading to JNK activation, neuronal apoptosis and reduction in dendritic spines. Importantly, isoflurane-induced neuronal death can be mitigated by administration of exogenous recombinant tPA; tPA restores signaling through TrkB receptors, leading to the activation of Akt, increased dendritic spine formation and neuronal survival. Based on these data, we advance the hypothesis that anesthetic neurotoxicity is a function of reduced neuronal activity, decreased synaptic tPA release, enhanced proBDNF signaling, reduced dendritic spine formation and neuronal apoptosis via p75NTR. To test this hypothesis, we propose studies that will be conducted within three specific aims. First, the toxicity of anesthetics will be characterized in vivo and in vitro with the evaluation of anesthetic induced apoptosis, suppression of synaptogenesis and reduction in dendritic spines. The extent of recovery of synapses and spines will also be evaluated. Thereafter, the role of BDNF-TrkB signaling and of the tPA-plasmin system on the aforementioned mentioned toxicity will be determined. Finally, the effects of anesthetic exposure during the neonatal period on cognitive function during adulthood will be evaluated. Collectively, the positive outcome of the proposed studies will provide novel insights into the mechanisms by which anesthetic agents injure the developing brain and into specific mechanisms by which this toxicity can be mitigated. Importantly, we have developed a novel therapeutic approach to the prevention of isoflurane neurotoxicity. As such, the proposed work has clear translational application. PUBLIC HEALTH RELEVANCE: Recent data have indicated that anesthetics can produce widespread neurodegeneration in the developing brain and this leads to cognitive dysfunction during adulthood. This has provoked concern about the possibility that anesthesia in neonates might lead to brain injury. The proposed research will attempt to characterize the mechanisms by which anesthetics injure the developing brain and the means by which this toxicity can be prevented or treated.

描述（由申请人提供）：全身麻醉的前提是麻醉药会产生无毒和可逆的无意识状态。最近的数据表明，新生动物暴露于麻醉剂中，触发了广泛的神经变性，导致了持续的记忆和学习异常[1]。麻醉神经毒性引起了人们对人类胎儿，新生儿和婴儿的潜在不利影响的担忧。尽管确切的机制尚不清楚，但毒性发生在突触发生过程中，本质上是凋亡的[1,2]。在发展中的大脑中，具有适当靶标的突触连接对于神经元存活至关重要，因为神经元取决于其靶标的营养支持[13-15]。突触连接的丧失导致凋亡。神经营养蛋白BDNF有助于神经元的存活和突触发生，以及突触的巩固和成熟[16]。但是，BDNF也可能导致神经元细胞凋亡[17,18]。 BDNF从突触囊泡中分泌为促分子（probDNF），并通过纤溶酶在突触裂隙中进行蛋白水解裂解以产生成熟的BDNF（MBDNF）[19]。纤溶酶原是纤溶酶的前体，被TPA蛋白水解裂解，TPA是从突触前囊泡中释放的蛋白酶。通过TRKB受体的MBDNF信号促进神经元存活和突触发生。在不存在TPA的情况下，ProbDNF被未溶解并优先通过P75NTR受体信号，从而导致突触发生降低，树突状棘的戒断和神经元细胞凋亡[20]。我们实验室的初步数据表明，挥发性麻醉，异氟烷可减少TPA释放。这导致通过p75ntr对probDNF的优先信号传导，从而导致JNK激活，神经元细胞凋亡和树突状棘的减少。重要的是，通过给予外源性重组TPA来减轻异氟烷诱导的神经元死亡。 TPA通过TRKB受体恢复信号传导，导致Akt激活，增加树突状脊柱形成和神经元存活。基于这些数据，我们推进了一个假设，即麻醉神经毒性是神经元活性降低，突触TPA释放降低，增强的探针信号传导，树突状脊柱形成减少和通过P75NTR的神经元凋亡的函数。为了检验这一假设，我们提出的研究将在三个特定目标中进行。首先，通过评估麻醉诱导的细胞凋亡，突触发生的抑制和树突状棘的减少，在体内和体外表征麻醉剂的毒性。突触和刺的恢复程度也将得到评估。此后，将确定BDNF-TRKB信号传导和TPA-质蛋白系统在上述毒性上的作用。最后，将评估新生儿期间麻醉暴露对成年期间认知功能的影响。总的来说，拟议的研究的积极结果将为麻醉药物损害发育中的大脑的机制提供新颖的见解，并将这种毒性受到降低的特定机制。重要的是，我们已经开发了一种新型的治疗方法来预防异氟其腺神经毒性。因此，拟议的工作具有明确的翻译应用。公共卫生相关性：最近的数据表明，麻醉药可以在发育中的大脑中产生广泛的神经变性，这会导致成年期的认知功能障碍。这引起了人们对新生儿麻醉可能导致脑损伤的可能性的关注。拟议的研究将试图表征麻醉剂会损害发育中大脑的机制以及可以预防或治疗这种毒性的手段。