A decade ago, the applicant and colleagues discovered that drugs that have either NMDA antagonist or GABAA agonist properties, a description that fits alcohol and all general anesthetics, trigger widespread death of nerve cells in the developing animal brain. In order to maximize the translational significance of our anesthesia toxicity studies, we applied for and were awarded a grant (start date Jan 2007) to study this phenomenon in the developing non-human primate (NHP) brain. The present application is a request for renewal of funding for ongoing studies pertaining to the apoptogenic properties of anesthetic drugs in the developing NHP brain. This work is being performed in collaboration with colleagues at Washington University and Oregon Health &Science University and Oregon National Primate Research Center. In the first 4 years of the grant period we have developed a valuable data base documenting susceptibility of the developing fetal and neonatal NHP brain to apoptotic death of brain cells (both neurons and oligodendrocytes) induced by clinically relevant exposure to each of three anesthetic drugs (isoflurane, ketamine, propofol). In this renewal application we are proposing to conduct additional NHP studies to further clarify the potential neurotoxicity of anesthetic drugs for the developing NHP brain and explore ways of modifying anesthesia protocols to enhance their safety for the developing brain. We have already developed a valuable data base, and now want to build upon that base toward the goal of achieving improved safety in the clinical application of anesthetic drugs in pediatric and obstetric medicine.
The aims of the proposed research are to determine: 1) If there is a significant positive correlation between duration of anesthesia exposure and the number of neurons and/or oligodendrocytes that undergo apoptotic cell death;2) How anesthesia without surgery compares in toxic impact with anesthesia with surgery;3) How long into the post natal period does the brain remain vulnerable to significant neuronal or glial loss following clinically relevant exposure to anesthesia;and 4) Can the apoptotic response to anesthesia be prevented or significantly mitigated by adjunctive administration of neuroprotective drugs.

Public Health Relevance

Researchers from Washington University will collaborate with colleagues from Oregon Health &Science University and the Oregon National Primate Research Center to study the potential neurotoxic effects of anesthetic drugs in the developing non-human primate brain. A major goal of the proposed research is to develop methods for achieving improved safety in the clinical application of anesthetic drugs in pediatric and obstetric medicine.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD052664-07
Application #
8440300
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Oster-Granite, Mary Lou
Project Start
2007-02-05
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
7
Fiscal Year
2013
Total Cost
$389,947
Indirect Cost
$87,961
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Creeley, Catherine E; Dikranian, Krikor T; Dissen, Gregory A et al. (2014) Isoflurane-induced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology 120:626-38
Creeley, C; Dikranian, K; Dissen, G et al. (2013) Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth 110 Suppl 1:i29-38
Olsen, Emily A; Brambrink, Ansgar M (2013) Anesthesia for the young child undergoing ambulatory procedures: current concerns regarding harm to the developing brain. Curr Opin Anaesthesiol 26:677-84
Brambrink, Ansgar M; Evers, Alex S; Avidan, Michael S et al. (2012) Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 116:372-84
Brambrink, Ansgar M; Evers, Alex S; Avidan, Michael S et al. (2010) Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 112:834-41
Straiko, Megan M W; Young, Chainllie; Cattano, Davide et al. (2009) Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology 110:862-8