Neurological injury after resuscitation from cardiac arrest is a major impediment to improving survival for victims who experience sudden cardiopulmonary collapse. Induction of hypothermia after restoration of circulation improves neurological recovery and is being advanced clinically. However, mild hypothermia does not completely reverse brain injury and a rational approach to improve this intervention is required. This project will employ a rat model of cardiac arrest that mimics the whole-brain injury, and that replicates the beneficial effects of post-resuscitation hypothermia. Preliminary studies indicate that hypothermia increases intracellular signaling in the brain via the extracellular signal regulated kinase, ERK (a mitogen activated protein kinase), and also increases brain tissue levels of brain-derived neurotrophic factor (BDNF). The time course of ERK and BDNF activation as well as the time window during which induction of hypothermia is beneficial suggest that induced hypothermia may affect new gene expression via these signaling systems. This proposal will expand our understanding of the beneficial effects of induced hypothermia and the by examining the relationship between BDNF, ERK and new gene expression in brain after cardiac arrest and resuscitation. This project will be divided into three specific aims: (1) The first aim will determine the role of neurotrophic factors in the control of ERK signaling after resuscitation and hypothermia. To accomplish this aim, we will employ neutralizing antibodies or antisense oligonucleotides or administration of exogenous neurotrophic factors after ischemia and hypothermic reperfusion. We will determine the localization and time-course of increased levels of particular neurotrophic factors in brain during hypothermic reperfusion. (2) The second aim will be to determine the participation of the downstream effectors of the ERK signaling pathway after resuscitation and hypothermia. We hypothesize that hypothermic reperfusion will increase activation of ERK-regulated transcription factors and expression of particular ERK-regulated gene products. Conversely, blockade of ERK activation is hypothesized to decrease expression of these same genes. (3) The final aim of the project will determine the participation of ERK and BDNF signaling in the hypothermia-induced improvement of neuronal survival and behavioral recovery after resuscitation. These pathways will be blocked and stimulated during hypothermic reperfusion, and behavioral and histological outcome for cardiac arrest will be measured.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046073-02
Application #
6666680
Study Section
Special Emphasis Panel (ZHL1-CSR-M (S1))
Project Start
2002-09-30
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$176,838
Indirect Cost
Name
University of Pittsburgh
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Callaway, Clifton W; Rittenberger, Jon C; Logue, Eric S et al. (2008) Hypothermia after cardiac arrest does not alter serum inflammatory markers. Crit Care Med 36:2607-12
Callaway, Clifton W; Ramos, Ramiro; Logue, Eric S et al. (2008) Brain-derived neurotrophic factor does not improve recovery after cardiac arrest in rats. Neurosci Lett :
Ho, Y; Logue, E; Callaway, C W et al. (2007) Different mechanisms account for extracellular-signal regulated kinase activation in distinct brain regions following global ischemia and reperfusion. Neuroscience 145:248-55
Logue, Eric S; McMichael, Melissa J; Callaway, Clifton W (2007) Comparison of the effects of hypothermia at 33 degrees C or 35 degrees C after cardiac arrest in rats. Acad Emerg Med 14:293-300
D'Cruz, Brian J; Logue, Eric S; Falke, Eric et al. (2005) Hypothermia and ERK activation after cardiac arrest. Brain Res 1064:108-18
Vosler, Peter S; Logue, Eric S; Repine, Melissa J et al. (2005) Delayed hypothermia preferentially increases expression of brain-derived neurotrophic factor exon III in rat hippocampus after asphyxial cardiac arrest. Brain Res Mol Brain Res 135:21-9
Schmidt, Katherine M; Repine, Melissa J; Hicks, Shawn D et al. (2004) Regional changes in glial cell line-derived neurotrophic factor after cardiac arrest and hypothermia in rats. Neurosci Lett 368:135-9