Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.
Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABA(A) receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABA(A) receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.
Jevtovic-Todorovic
Vesna
V
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA. vj3w@virginia.edu
Hartman
Richard E
RE
Izumi
Yukitoshi
Y
Benshoff
Nicholas D
ND
Dikranian
Krikor
K
Zorumski
Charles F
CF
Olney
John W
JW
Wozniak
David F
DF
D000777:Anesthetics / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D002908:Chronic Disease; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005260:Female; D018755:GABA Agonists / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D007530:Isoflurane / Q000633:toxicity; D007859:Learning Disabilities / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D008874:Midazolam / Q000633:toxicity; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D009609:Nitrous Oxide / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D009435:Synaptic Transmission / Q000187:drug effects
D000777:Anesthetics; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D007530:Isoflurane; D009609:Nitrous Oxide; D008874:Midazolam