Neonatal Anesthetic Neurotoxicity

新生儿麻醉神经毒性

基本信息

批准号：
8243616
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/8243616
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剂会产生无毒且可逆的无意识状态。最近的数据表明，新生动物接触麻醉剂会引发广泛的神经退行性变，导致成年期间持续性记忆和学习异常[1]。麻醉神经毒性引起了人们对全身麻醉对人类胎儿、新生儿和婴儿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，并且本质上是细胞凋亡[1,2]。在发育中的大脑中，与适当目标的突触连接对于神经元的生存至关重要，因为神经元依赖于其目标的营养支持[13-15]。突触连接的丧失会导致细胞凋亡。神经营养蛋白 BDNF 有助于神经元存活和突触发生，以及突触的巩固和成熟 [16]。然而，BDNF 也可导致神经元凋亡[17,18]。 BDNF 作为前分子（proBDNF）从突触小泡分泌，并在突触间隙中被纤溶酶进行蛋白水解，生成成熟的 BDNF（mBDNF）[19]。纤溶酶原是纤溶酶的前体，被 tPA（一种从突触前小泡释放的蛋白酶）以蛋白水解方式裂解。 mBDNF 通过 TrkB 受体发出信号以促进神经元存活和突触发生。在缺乏 tPA 的情况下，proBDNF 未被切割，并优先通过 p75NTR 受体发出信号，导致突触发生减少、树突棘撤退和神经元凋亡 [20]。我们实验室的初步数据表明，挥发性麻醉剂异氟烷可减少 tPA 释放；这导致 proBDNF 通过 p75NTR 优先信号传导，导致 JNK 激活、神经元凋亡和树突棘减少。重要的是，异氟烷诱导的神经元死亡可以通过给予外源重组 tPA 来减轻； tPA 通过 TrkB 受体恢复信号传导，从而激活 Akt、增加树突棘形成和神经元存活。基于这些数据，我们提出了这样的假设：麻醉神经毒性是神经元活性降低、突触 tPA 释放减少、proBDNF 信号传导增强、树突棘形成减少和 p75NTR 神经元凋亡的函数。为了检验这一假设，我们建议在三个具体目标内进行研究。首先，通过评估麻醉剂诱导的细胞凋亡、突触发生的抑制和树突棘的减少，在体内和体外表征麻醉剂的毒性。突触和棘的恢复程度也将被评估。此后，将确定 BDNF-TrkB 信号传导和 tPA-纤溶酶系统对上述毒性的作用。最后，将评估新生儿期麻醉剂暴露对成年期认知功能的影响。总的来说，拟议研究的积极成果将为麻醉剂损伤发育中的大脑的机制以及减轻这种毒性的具体机制提供新的见解。重要的是，我们开发了一种新的治疗方法来预防异氟烷神经毒性。因此，拟议的工作具有明确的转化应用。公共健康相关性：最近的数据表明，麻醉药可能会在发育中的大脑中产生广泛的神经退行性变，从而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担忧。拟议的研究将试图描述麻醉剂损伤发育中的大脑的机制以及预防或治疗这种毒性的方法。