This is an application for competing renewal of an RO1 grant which was funded for 3 years (11/1/98 - 10/31/01) to support studies aimed at clarfying the role(s) of excitotoxic and/or apoptotic cell death mechanisms in developmental (perinatal) brain injury associated with head trauma and hypoxia/ischemia. In addition to addressing these aims during the grant period, the PI has made the unanticipated discovery that during the synaptogenesis period of development transient ethanol intoxication triggers a massive wave of apoptotic neurodegeneration, deleting millions of neurons from many different regions of the developing rat, mouse or guinea pig brain. Our findings document that ethanol triggers apoptosis by a dual mechanism - blockade of NMDA glutamate receptors and excessive activation of GABAA receptors. We propose that our findings can help explain the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). Significance of this discovery is broadened by accompanying evidence that ethanol's neurotoxic properties are shared by numerous other agents that either block NMDA glutamate receptors or activate GABA^ receptors, and many of these agents are drugs of abuse and/or are used regularly in obstetric and pediatric medicine. An important feature of our findings is that within the synaptogenesis period (first 2 weeks after birth for rats and mice, but third trimester and first several years after birth for humans) different neuronal populations have different temporal patterns for responding to the apoptosis-inducing effects of these drugs. Thus, depending on the timing of exposure, different combinations of neuronal groups will be deleted, which signifies that this is a neurodevelopmental mechanism that can contribute to a wide spectrum of neuropsychiatric disturbances. Consistent with this interpretation is evidence that victims of FAS manifest not only childhood hyperactivity/attention deficit and learning disorders, but have a high incidence of adult onset psychiatric disturbances, including major depressive disorder and psychosis.
The aims of this competing renewal proposal are threefold, the first being to continue exploring the role of excitotoxic and apoptotic mechanisms in ischemic neurodegeneration, and the second and third being to more fully characterize molecular, neuropathological and neurobehavioral aspects of the apoptotic neurodegenerative syndrome we have found can be induced in the developing mouse brain by transient exposure to ethanol during synaptogenesis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Nitkin, Ralph M
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Washington University
Schools of Medicine
Saint Louis
United States
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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
Yuede, Carla M; Olney, John W; Creeley, Catherine E (2013) Developmental neurotoxicity of alcohol and anesthetic drugs is augmented by co-exposure to caffeine. Brain Sci 3:1128-52
Creeley, Catherine E; Olney, John W (2013) Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development. Brain Sci 3:1153-81
Brambrink, Ansgar M; Back, Stephen A; Riddle, Art et al. (2012) Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol 72:525-35
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
Christensen, Heather M; Dikranian, Krikor; Li, Aimin et al. (2010) A highly toxic cellular prion protein induces a novel, nonapoptotic form of neuronal death. Am J Pathol 176:2695-706
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
Farber, Nuri B; Creeley, Catherine E; Olney, John W (2010) Alcohol-induced neuroapoptosis in the fetal macaque brain. Neurobiol Dis 40:200-6
Creeley, Catherine E; Olney, John W (2010) The young: neuroapoptosis induced by anesthetics and what to do about it. Anesth Analg 110:442-8

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