Anesthetic-Induced Oxidative Stress and Potential Protection

Cheng Wang,Merle G Paule,Fang Liu,William Slikker, Jr,Xuan Zhang

doi:10.1100/tsw.2010.118

Abstract

Prolonged exposure of developing mammals to general anesthetics affects the N-methyl-D-aspartate (NMDA)–type glutamate or γ-aminobutyric acid (GABA) receptor systems and enhances neuronal toxicity. Stimulation of immature neurons by NMDA antagonists or GABA agonists is thought to increase overall nervous system excitability and may contribute to abnormal neuronal cell death during development. Although the precise mechanisms by which NMDA antagonists or GABA agonists cause neuronal cell death are still not completely understood, up-regulation of the NMDA receptor subunit NR1 may be an initiative factor in neuronal cell death. It is increasingly apparent that mitochondria lie at the center of the cell death regulation process. Evidence for the role of oxidative stress in anesthetic-induced neurotoxicity has been generated in studies that apply oxidative stress blockers. Prevention of neuronal death by catalase and superoxide dismutase in vitro, or by M40403 (superoxide dismutase mimetic) in vivo, supports the contention that the involvement of reactive oxygen species (ROS) and the nature of neuronal cell death in rodents is mainly apoptotic. However, more evidence is necessary to in order verify the role of the NMDA receptor subunit NR1 and ROS in anesthetic-induced neurodegeneration.

Highlights

Lines of evidence have indicated that activation of N-methyl-D-aspartate (NMDA) or γ-aminobutyric acid (GABA) receptors caused neuronal cell death[1,2,3,4,5,6]
Neuronal apoptosis can be the final result of anesthetic-induced toxicity, the pathways leading to apoptosis are not completely understood
Excessive activation of up-regulated NMDA receptors results in a calcium overload that exceeds the buffering capacity of the mitochondria and interferes with electron transport in a manner that results in an elevated production of reactive oxygen species (ROS), and the dissociation of some transcription proteins, such as NF-κB, and their transport into the nucleus

Summary

INTRODUCTION

Lines of evidence have indicated that activation of N-methyl-D-aspartate (NMDA) or γ-aminobutyric acid (GABA) receptors caused neuronal cell death[1,2,3,4,5,6]. Repeated ketamine injections produced the most severe neuronal damage (~10-fold increase) in the frontal cortex vs a threefold increase (or less) in the striatum, hippocampus, thalamus, and amygdala These data suggest that the frontal cortex is the brain region most vulnerable to ketamine-induced neurotoxicity during development. Observations may imply that the frontal cortex is the brain region most vulnerable to ketamine-induced neurotoxicity during development, and the neuronal survival in the early phases of the apoptotic cascades mostly depends on the balance between the pro- and antiapoptotic factors of the apoptosis-related genes. In previous in vitro studies, general anesthetics, such as ketamine administration, caused a significant upregulation of nitrotyrosine expression accompanied by enhanced neuronal apoptosis as indicated by cell death detection ELISA and decreased PSA-NCAM expression[26].

31 Rassf5

Findings

SUMMARY