? Exposure of premature infants, neonates and very young children to general anesthesia is a frequent occurrence in modern medicine. The anesthetic agents that are presently available have important mechanistic features in common: either they promote GABAergic inhibitory neurotransmission (e.g. volatile anesthetics, barbiturates, benzodiazepines), or they suppress NMDA glutamatergic excitatory transmission (e.g., ketamine, nitrous oxide, xenon). This poses a potential conundrum in view of recent evidence that drugs which act by either of these two mechanisms can trigger widespread apoptotic neurodegeneration in the developing rat brain. The developing brain is most vulnerable to this neurotoxic action during the period of synaptogenesis, also known as the brain growth spurt period, which occurs at different times in different species. In humans, it is both pre- and postnatal phenomenon (from beginning of third trimester of pregnancy to a couple of years after birth). In rats, guinea pigs and piglets, three species of interest for this proposal, synaptogenesis occurs postnatally (first 2 weeks after birth in rats), prenatally (about 10 weeks of in utero life in guinea pigs) or both prenatally and postnatally (last 5 weeks of in utero life and first 15 weeks of life in piglets). In general, it appears that drugs that transiently suppress neuronal activity to an unphysiological degree, and thereby disrupt synaptogenesis, cause immature neurons to receive an internal signal to commit suicide (i.e. die by apoptosis). To investigate the potential relevance of this neurotoxic mechanism to clinical anesthesia, the applicants conducted a pilot study on infant rats and pregnant guinea pigs (for studying fetal brains) in which clinically relevant concentrations of volatile anesthetic isoflurane were used to induce and maintain anesthesia for a period of 6 hrs. This anesthesia protocol did not cause hypoxia, changes in cortical cerebral blood flow (in infant rats), or shift blood chemistries in an abnormal direction, but it did cause significant apoptotic neurodegeneration in the developing rat brains of both infant rats and guinea pig's fetuses. In addition, our preliminary work with infant rats suggests that isoflurane anesthesia activates the intrinsic apoptotic cascade. In the revised grant application, the applicant proposes to perform detailed studies of the mechanisms of anesthesia-induced neuro-apoptosis and to identify early steps in the apoptotic cascade, prior to the point of cell death commitment, which may be amenable to intervention. In addition we propose to study the correlation between the rate of synaptogenesis (by using three different species) and the duration of anesthesia necessary to induce significant neuronal apoptosis in the developing brain. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD044517-01A2
Application #
6873549
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Giacoia, George
Project Start
2005-03-05
Project End
2009-12-31
Budget Start
2005-03-05
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$270,081
Indirect Cost
Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Dalla Massara, Lorenza; Osuru, Hari Prasad; Oklopcic, Azra et al. (2016) General Anesthesia Causes Epigenetic Histone Modulation of c-Fos and Brain-derived Neurotrophic Factor, Target Genes Important for Neuronal Development in the Immature Rat Hippocampus. Anesthesiology 124:1311-1327
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Jevtovic-Todorovic, Vesna (2014) Good gas, bad gas: isoflurane, carbon monoxide, and which is which? Anesth Analg 118:1160-2
Milanovi?, Desanka; Peši?, Vesna; Popi?, Jelena et al. (2014) Propofol anesthesia induces proapoptotic tumor necrosis factor-? and pro-nerve growth factor signaling and prosurvival Akt and XIAP expression in neonatal rat brain. J Neurosci Res 92:1362-73
Jevtovic-Todorovic, V; Absalom, A R; Blomgren, K et al. (2013) Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. Br J Anaesth 111:143-51

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