Faculty Collaboration Database

Ketamine induces toxicity in human neurons differentiated from embryonic stem cells via mitochondrial apoptosis pathway. Curr Drug Saf 2012 Apr;7(2):106-19

Date

08/10/2012

Pubmed ID

22873495

Pubmed Central ID

PMC3684944

DOI

10.2174/157488612802715663

Scopus ID

2-s2.0-84864798841 (requires institutional sign-in at Scopus site)   80 Citations

Abstract

Ketamine is widely used for anesthesia in pediatric patients. Growing evidence indicates that ketamine causes neurotoxicity in a variety of developing animal models. Our understanding of anesthesia neurotoxicity in humans is currently limited by difficulties in obtaining neurons and performing developmental toxicity studies in fetal and pediatric populations. It may be possible to overcome these challenges by obtaining neurons from human embryonic stem cells (hESCs) in vitro. hESCs are able to replicate indefinitely and differentiate into every cell type. In this study, we investigated the toxic effect of ketamine on neurons differentiated from hESCs. Two-week-old neurons were treated with different doses and durations of ketamine with or without the reactive oxygen species (ROS) scavenger, Trolox. Cell viability, ultrastructure, mitochondrial membrane potential (ΔΨm), cytochrome c distribution within cells, apoptosis, and ROS production were evaluated. Here we show that ketamine induced ultrastructural abnormalities and dose- and time-dependently caused cell death. In addition, ketamine decreased ΔΨm and increased cytochrome c release from mitochondria. Ketamine also increased ROS production and induced differential expression of oxidative stress-related genes. Specifically, abnormal ultrastructural and ΔΨm changes occurred earlier than cell death in the ketamine-induced toxicity process. Furthermore, Trolox significantly decreased ROS generation and attenuated cell death caused by ketamine in a dose-dependent manner. In conclusion, this study illustrates that ketamine time- and dose-dependently induces human neurotoxicity at supraclinical concentrations via ROS-mediated mitochondrial apoptosis pathway and that these side effects can be prevented by the antioxidant agent Trolox. Thus, hESC-derived neurons might provide a promising tool for studying anesthetic-induced developmental neurotoxicity and prevention strategies.

Author List

Bosnjak ZJ, Yan Y, Canfield S, Muravyeva MY, Kikuchi C, Wells CW, Corbett JA, Bai X

Authors

Zeljko Bosnjak PhD, MS Emeritus Professor in the Medicine department at Medical College of Wisconsin
John A. Corbett PhD Professor in the Biochemistry department at Medical College of Wisconsin
Maria Y. Muravyeva PhD, MD Assistant Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anesthetics, Dissociative
Antioxidants
Apoptosis
Cell Differentiation
Chromans
Cytochromes c
Dose-Response Relationship, Drug
Embryonic Stem Cells
Humans
In Vitro Techniques
Ketamine
Membrane Potential, Mitochondrial
Mitochondria
Neurons
Neurotoxicity Syndromes
Oxidative Stress
Reactive Oxygen Species
Time Factors