Mechanisms of anesthesia mediaited neurotoxicity

麻醉介导的神经毒性机制

基本信息

批准号：
8306165
负责人：
HUAFENG WEI
金额：
$ 27.01万
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/8306165
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 Health 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 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，常用的吸入麻醉剂，尤其是异氟烷，会导致发育中的大脑神经元凋亡，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，期望这些知识最终将导致更有效、更安全地使用吸入麻醉剂。这项研究的直接目标是检验我们的中心假设，即吸入麻醉剂通过钙通道（IP3）过度激活，导致内质网（ER）过量钙释放，从而以剂量和时间依赖性方式诱导细胞凋亡而死亡。受体）在内质网膜上。该项目的另一个目标是研究和更好地了解异氟烷在细胞培养和动物模型中的神经毒性和神经保护作用的双重特征。我们将通过以下具体目标来检验这些假设：（1）。目标 1 将测试长期暴露于异氟烷是否会通过导致 ER 中钙释放过多以及 IP3 受体过度激活导致 ER 钙消耗来诱导细胞凋亡。我们将检查这些效应是否会导致神经元因细胞凋亡而死亡，特别是在 IP3 受体活性升高的神经元中，例如具有阿尔茨海默病 presenilin-1 突变或亨廷顿氏 Q111 突变的细胞。（2）。目标 2 将测试长期暴露于异氟烷是否会因 IP3 受体过度激活而导致发育中的大鼠大脑中的神经元凋亡、随后的记忆和学习障碍。我们还将测试 IP3 受体拮抗剂 xestospongin C 是否可以抑制这些作用。(3)。目标 3 将检查细胞培养物和动物模型中短暂暴露于异氟醚是否可以通过激活 IP3 受体，通过内质网适度释放钙来预处理神经元，从而提供神经保护作用。目标 3 将进一步检查这些诱导的内源性神经保护机制是否是通过某些 ER 应激蛋白（例如 GRP78、HSP70）的过度表达或凋亡调节蛋白（例如 Bcl-2/Bax）的变化而发生的。我们的初步研究表明，等浓度的七氟醚和地氟醚引起细胞凋亡以及内质网异常钙释放的效力远低于异氟醚。我们将进一步比较异氟醚、七氟醚和地氟醚在细胞培养和动物模型中的神经毒性作用。公共健康相关性：我们的初步研究表明，常用的吸入麻醉剂，尤其是异氟烷，通过过度激活内质网钙通道（IP3 受体），导致内质网钙释放过多，从而诱导细胞凋亡。因此，我们打算研究吸入麻醉剂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项策略来防止这些有害影响。这项研究将增加我们对全身麻醉介导的神经毒性的了解，并使手术患者更安全地使用吸入麻醉剂。