Despite five decades of research concerning cardiac arrest/cardiopulmonary resuscitation (CA/CPR), clinical outcome remains poor. Only 5% of individuals who suffer CA are successfully resuscitated to the extent that they return to normal, productive lives, and neuropsychological deficiencies remain prevalent in the remaining 95% of patients. One reason why outcome from CA/CPR remains poor is that mechanisms of cell injury and targets for neuroprotection have been poorly elucidated. Women are at lower risk than men for cardiovascular disease yet cerebral ischemic events occur in both sexes. The role of estrogens in humans is controversial;however, we demonstrated in the past funding period that female mice have better outcome than males after CA/CPR. We now focus on potential transcriptional mechanisms by which estradiol exerts its neuroprotective action in CA/CPR. Using a microarray technique, we identified gene candidates that are induced/suppressed by estrogen under ischemic conditions. One provocative candidate, the neuropeptide cocaine and amphetamine regulated transcript (CART) is strongly induced by cerebral ischemia and provides robust neuroprotection. We propose to determine if CART is an important mechanism by which estradiol reduces neuronal injury after CA/CPR and whether CART exerts its neuroprotective effects via the extracellular regulated kinase (ERK) pathway. While most research has focused on understanding the role of estradiol in ischemia, the role of androgens in ischemic sensitivity is unknown. We propose to study testosterone, a sex steroid with potential to exacerbate brain injury from CA/CPR. Our preliminary data suggests that testosterone increases and castration decreases neuronal injury after CA/CPR, and we hypothesize that androgens signal through their cognate receptor to orchestrate neuronal ischemic death. Thus, this proposal will focus on novel mechanisms by which male and female sex steroids shape brain outcome after CA/CPR.
Aim 1 determines if estradiol enhances CART expression and suppresses ERK activation after CA/CPR in a region-specific manner.
Aim 2 determines if CART protection requires signaling via estrogen receptor beta.
Aim 3 determines if androgens play an important role in neuropathological and functional recovery after CA/CPR. Finally, Aim 4 determines if the androgen receptor is essential to how androgen enhances post arrest brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046072-09
Application #
7755865
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2002-09-30
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$331,793
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Orfila, James E; McKinnon, Nicole; Moreno, Myriam et al. (2018) Cardiac Arrest Induces Ischemic Long-Term Potentiation of Hippocampal CA1 Neurons That Occludes Physiological Long-Term Potentiation. Neural Plast 2018:9275239
Orfila, James E; Grewal, Himmat; Dietz, Robert M et al. (2017) Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke. J Cereb Blood Flow Metab :271678X17750761
Quillinan, Nidia; Herson, Paco S; Traystman, Richard J (2016) Neuropathophysiology of Brain Injury. Anesthesiol Clin 34:453-64
Terry, Peter B; Traystman, Richard J (2016) The Clinical Significance of Collateral Ventilation. Ann Am Thorac Soc 13:2251-2257
Dietz, R M; Deng, G; Orfila, J E et al. (2016) Therapeutic hypothermia protects against ischemia-induced impairment of synaptic plasticity following juvenile cardiac arrest in sex-dependent manner. Neuroscience 325:132-41
Deng, G; Yonchek, J C; Quillinan, N et al. (2014) A novel mouse model of pediatric cardiac arrest and cardiopulmonary resuscitation reveals age-dependent neuronal sensitivities to ischemic injury. J Neurosci Methods 222:34-41
Deng, Guiying; Carter, Jessica; Traystman, Richard J et al. (2014) Pro-inflammatory T-lymphocytes rapidly infiltrate into the brain and contribute to neuronal injury following cardiac arrest and cardiopulmonary resuscitation. J Neuroimmunol 274:132-40
Herson, Paco S; Traystman, Richard J (2014) Animal models of stroke: translational potential at present and in 2050. Future Neurol 9:541-551
Herson, Paco S; Bombardier, Chris G; Parker, Susan M et al. (2013) Experimental pediatric arterial ischemic stroke model reveals sex-specific estrogen signaling. Stroke 44:759-63
Planas, Anna M; Traystman, Richard J (2011) Advances in translational medicine 2010. Stroke 42:283-4

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