Mechanisms of anesthesia mediaited neurotoxicity

麻醉介导的神经毒性机制

• 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
• 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' 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

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，特别是异氟醚，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，并期望这些知识最终将导致更有效和更安全地使用吸入麻醉剂。本研究的直接目标是验证我们的中心假设，即吸入麻醉剂通过内质网（ER）上的钙通道（IP3受体）的过度激活，导致过量的钙释放，从而以剂量和时间依赖性的方式诱导细胞凋亡。该项目的另一个目标是研究和更好地了解异氟醚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)。目的1将测试长时间暴露于异氟醚是否通过IP3受体的过度激活引起内质网钙的过度释放和内质网钙的消耗而诱导细胞凋亡。我们将研究这些影响是否会通过细胞凋亡导致神经元死亡，特别是IP3受体活性升高的神经元，如阿尔茨海默氏早老素-1突变或亨廷顿Q111突变的细胞。（2）. 目的2将测试长时间暴露于异氟醚是否通过IP3受体的过度激活诱导发育中的大鼠大脑神经元凋亡、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)。目的3将研究在细胞培养和动物模型中，短时间暴露于异氟醚是否通过IP3受体的激活，使神经元从内质网释放适度的钙，从而提供神经保护。Aim 3将进一步研究这些诱导的内源性神经保护机制是否通过一些内质网应激蛋白（如GRP78、HSP70）的过度表达或凋亡调节蛋白（如Bcl-2/Bax）的改变而发生。我们的初步研究表明，在等效浓度下，七氟醚和地氟醚引起细胞凋亡和内质网钙释放异常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。