This is a resubmission of a competitive renewal of the R01 grant # HD 044517. The proposed experiments are extensions of earlier ones aimed at deciphering the cellular pathways responsible for anesthesia- induced developmental neurodegeneration. In addition to causing widespread apoptotic neurodegeneration in vulnerable brain regions, general anesthesia exposure at the peak of the brain growth spurt causes learning and memory deficiencies later in life. The gap in learning abilities between control and anesthesia- treated animals progressively widens in adulthood. Moreover, retrospective clinical evidence suggests that there is a relationship between the exposure of very young children to general anesthesia and subsequent life-long learning disabilities. Since general anesthesia cannot be avoided, better understanding the key mechanisms of anesthesia-induced developmental neurodegeneration and ways to ameliorate it are critically important to public health. Our in-vivo rodent studies have suggested that activation of the intrinsic (mitochondria-dependent) apoptotic pathway is the earliest warning sign of neuronal damage. Within the very first couple of hours, general anesthesia causes significant decrease in protein levels of bcl-XL which is quickly followed by a massive increase in cytochrome-c release from mitochondria. This leads to activation of caspase-9, and -3, DNA fragmentation, and neuronal death. In addition, our most recent in-vivo studies demonstrate that general anesthesia induces significant up-regulation of reactive oxygen species and both morphological and functional impairment of developing mitochondria in the immature neurons. Therapeutic intervention aimed at scavenging excessive reactive oxygen species using EUK-134, a synthetic superoxide dismutase and catalase mimetic, abolished anesthesia-induced learning impairment and significantly ameliorated anesthesia-induced increases in reactive oxygen species. The exact mechanisms operational in anesthesia-induced up-regulation of reactive oxygen species and mitochondria damage in the developing neurons must be determined so that therapeutic interventions can be devised. This is the main focus of our revised application.

Public Health Relevance

Clinically used general anesthetics are damaging to developing mammalian brain. Since general anesthetics are a necessity that often cannot be avoided, better understanding of the key mechanisms of anesthesia-induced developmental neurotoxicity and ways to ameliorate their effects are of great importance. Using in-vivo and ex-vitro systems, this proposal aims to investigate the mechanisms involved in anesthesia-induced reactive oxygen-mediated neurodegeneration during developmental synaptogenesis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044517-09
Application #
8605203
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Giacoia, George
Project Start
2003-07-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2014
Total Cost
$290,002
Indirect Cost
$90,773
Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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 124:1311-27
Lunardi, N; Oklopcic, A; Prillaman, M et al. (2015) Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum. Mol Neurobiol 52:942-51
Joksovic, Pavle M; Lunardi, Nadia; Jevtovic-Todorovic, Vesna et al. (2015) Early Exposure to General Anesthesia with Isoflurane Downregulates Inhibitory Synaptic Neurotransmission in the Rat Thalamus. Mol Neurobiol 52:952-8
DiGruccio, Michael R; Joksimovic, Srdjan; Joksovic, Pavle M et al. (2015) Hyperexcitability of rat thalamocortical networks after exposure to general anesthesia during brain development. J Neurosci 35:1481-92
Jevtovic-Todorovic, Vesna (2014) Good gas, bad gas: isoflurane, carbon monoxide, and which is which? Anesth Analg 118:1160-2
Milanović, Desanka; Pešić, Vesna; Popić, Jelena et al. (2014) Propofol anesthesia induces proapoptotic tumor necrosis factor-α 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
Jevtovic-Todorovic, Vesna (2013) Functional implications of an early exposure to general anesthesia: are we changing the behavior of our children? Mol Neurobiol 48:288-93
Boscolo, Annalisa; Milanovic, Desanka; Starr, John A et al. (2013) Early exposure to general anesthesia disturbs mitochondrial fission and fusion in the developing rat brain. Anesthesiology 118:1086-97
Hemmings Jr, H C; Jevtovic-Todorovic, V (2013) Special issue on anaesthetic neurotoxicity and neuroplasticity. Br J Anaesth 110 Suppl 1:i1-2

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