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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084979-05
Application #
8306165
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Cole, Alison E
Project Start
2008-09-22
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$270,141
Indirect Cost
$98,623
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Joseph, J Donald; Peng, Yi; Mak, Don-On Daniel et al. (2014) General anesthetic isoflurane modulates inositol 1,4,5-trisphosphate receptor calcium channel opening. Anesthesiology 121:528-37
Yang, Bin; Liang, Ge; Khojasteh, Soorena et al. (2014) Comparison of neurodegeneration and cognitive impairment in neonatal mice exposed to propofol or isoflurane. PLoS One 9:e99171
Peng, Jun; Drobish, Julie K; Liang, Ge et al. (2014) Anesthetic preconditioning inhibits isoflurane-mediated apoptosis in the developing rat brain. Anesth Analg 119:939-46
Zhao, Xuli; Yang, Zeyong; Liang, Ge et al. (2013) Dual effects of isoflurane on proliferation, differentiation, and survival in human neuroprogenitor cells. Anesthesiology 118:537-49
Wei, Huafeng; Inan, Saadet (2013) Dual effects of neuroprotection and neurotoxicity by general anesthetics: role of intracellular calcium homeostasis. Prog Neuropsychopharmacol Biol Psychiatry 47:156-61
Peng, Jun; Liang, Ge; Inan, Saddet et al. (2012) Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 516:274-9
Wei, Huafeng (2011) The role of calcium dysregulation in anesthetic-mediated neurotoxicity. Anesth Analg 113:972-4
Wang, Qiujun; Liang, Ge; Yang, Hui et al. (2011) The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease. Toxicol Appl Pharmacol 250:291-8
Liang, Ge; Ward, Christopher; Peng, Jun et al. (2010) Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology 112:1325-34
Zhao, Yifan; Liang, Ge; Chen, Qianru et al. (2010) Anesthetic-induced neurodegeneration mediated via inositol 1,4,5-trisphosphate receptors. J Pharmacol Exp Ther 333:14-22

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