Mechanisms of anesthesia mediaited neurotoxicity

麻醉介导的神经毒性机制

基本信息

批准号：
8113131
负责人：
HUAFENG WEI
金额：
$ 27.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-22 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113131
关键词：
Alzheimer&apos s Disease Anesthesia procedures Anesthetics Animal Model Apoptosis Apoptotic Brain Breathing Calcium Calcium Channel Cause of Death Cell Culture Techniques Cell Death Cells Cerebrum Cessation of life Cultured Cells Dose Endoplasmic Reticulum Functional disorder GRP78 gene General Anesthesia Goals Heat shock proteins Heat-Shock Proteins 70 Homeostasis Huntington Disease Impaired cognition In Vitro Injection of therapeutic agent Inositol Intervention Investigation Isoflurane Knock-out Knowledge Lead Learning Learning Disabilities Measures Mediating Membrane Memory Memory Loss Mutation Neonatal Neurons Operative Surgical Procedures Patients Rattus Research Ryanodine Receptor Calcium Release Channel Small Interfering RNA Testing Time Translating XeC compound cell type desflurane endoplasmic reticulum stress expectation genetic regulatory protein in vivo neuron apoptosis neuroprotection neurotoxic neurotoxicity preconditioning presenilin-1 prevent public health relevance receptor receptor expression sevoflurane stress protein

项目摘要

DESCRIPTION (provided by applicant): Increasing evidence suggests that commonly used inhaled anesthetics, especially isoflurane, cause neuronal apoptosis in the developing brain, which is associated with memory loss and learning disabilities. The long term goal of this research is to understand the mechanisms of anesthesia-mediated neurotoxicity, with an expectation that this knowledge will eventually lead to more efficacious and safer use of inhaled anesthetics. The immediate goal of the study is to test our central hypothesis that inhaled anesthetics induce cell death by apoptosis in a dose- and time-dependent manner by causing excessive calcium release from the endoplasmic reticulum (ER) via over activation of a calcium channel (IP3 receptor) on the ER membrane. An additional goal of this project is to study and better understand the double features of isoflurane's neurotoxic and neuroprotective effects in both cell culture and animal models. We will test these hypotheses via the following specific aims: (1). Aim 1 will test whether prolonged exposure of isoflurane induces apoptosis by causing excessive calcium release from the ER and depletion of ER calcium via over activation of IP3 receptor. We will examine whether these effects lead to neuronal death by apoptosis, especially in neurons with elevated IP3 receptor activity such as cells with Alzheimer's presenilin-1 mutation or Huntington's Q111 mutation. (2). Aim 2 will test whether prolonged exposure of Isoflurane induces neuronal apoptosis, subsequent memory and learning disabilities in developing rat brains by over activation of IP3 receptors. We will also test whether these effects can be inhibited by the IP3 receptor antagonist xestospongin C. (3). Aim 3 will examine whether a short exposure of isoflurane in cell culture and animal models provides neuroprotection by preconditioning neurons with a moderate calcium release from the ER via activation of IP3 receptors. Aim 3 will further examine whether these induced endogenous neuroprotective mechanisms occur by over expression of some ER stress proteins (e.g. GRP78, HSP70) or changes of apoptotic regulatory proteins (e.g. Bcl-2/Bax). Our preliminary studies have suggested that sevoflurane and desflurane, at equipotent concentrations, have much less potency than isoflurane to cause apoptosis, as well as abnormal calcium release from the ER. We will further compare the neurotoxic effects of isoflurane, sevoflurane and desflurane in both cell culture and animal models. PUBLIC HEALTH RELEVANCE: Our preliminary studies suggest that commonly used inhaled anesthetics, especially isoflurane, induce apoptotic neuronal death by causing excessive calcium release from the endoplasmic reticulum via over activation of a calcium channel (IP3 receptor) on the ER membrane. We therefore intend to study the mechanisms through which inhaled anesthetics induce neuronal apoptosis via disruption of intracellular calcium homeostasis. Ultimately we hope to develop a strategy to prevent these harmful effects. This research will increase our understanding of general anesthesia-mediated neurotoxicity and make a safer use of inhaled anesthetics to surgical patients.

描述（由申请人提供）：越来越多的证据表明，通常使用吸入的麻醉药，尤其是异氟烷，引起发育中的大脑中神经元凋亡，这与记忆丧失和学习障碍有关。这项研究的长期目标是了解麻醉介导的神经毒性的机制，并期望这种知识最终会导致对吸入麻醉药的更有效，更安全的使用。该研究的直接目的是测试我们的中心假设，即吸入麻醉药以剂量和时间依赖性的方式通过钙网状（ER）过量钙释放而导致内质网（ER）过量释放，从而引起细胞凋亡的细胞死亡。该项目的另一个目标是研究并更好地了解在细胞培养和动物模型中异氟烷神经毒性和神经保护作用的双重特征。我们将通过以下特定目的检验这些假设：（1）。 AIM 1将测试异氟烷长期暴露是否会通过导致ER释放过多的钙释放和通过IP3受体的过度激活而导致ER钙的耗竭来诱导细胞凋亡。我们将检查这些作用是否导致细胞凋亡导致神经元死亡，尤其是在IP3受体活性升高的神经元中，例如具有阿尔茨海默氏症的Presenilin-1突变或亨廷顿Q111突变的细胞。（2）。 AIM 2将测试异氟烷长期暴露是否会通过过度激活IP3受体的激活来诱导神经元凋亡，随后的记忆和学习障碍。我们还将测试IP3受体拮抗剂XestosponginC是否可以抑制这些作用。（3）。 AIM 3将检查在细胞培养物和动物模型中，异氟烷在细胞培养和动物模型中是否通过激活IP3受体的激活来从ER释放中等钙释放来提供神经保护作用。 AIM 3将进一步检查这些诱导的内源性神经保护机制是通过过度表达某些ER应激蛋白（例如GRP78，HSP70）或凋亡调节蛋白（例如Bcl-2/Bax）的变化而发生的。我们的初步研究表明，在等式浓度下，七氟醚和去氟烷的效力远低于引起凋亡以及从ER中钙释放的异常钙释放的效力。我们将进一步比较细胞培养和动物模型中异氟烷，七氟烷和去氟烷的神经毒性作用。公共卫生相关性：我们的初步研究表明，通常使用吸入的麻醉剂，尤其是异氟烷，通过过度激活钙通道（IP3受体）在ER膜上引起内质网的过度释放，从而诱导凋亡神经元死亡。因此，我们打算研究吸入麻醉药通过破坏细胞内钙稳态而诱导神经元凋亡的机制。最终，我们希望制定一种防止这些有害影响的策略。这项研究将增加我们对全身麻醉介导的神经毒性的理解，并对手术患者更安全地使用吸入麻醉药。