Cardiac arrest remains one of the leading causes of death and disability in the U.S.A. This proposal is a competitive renewal application. In the previous funding cycle, we defined the pathophysiological mechanisms impairing functional recovery following asphyxia cardiac arrest (ACA). Because CA promotes significant cognitive deficits, our central emphasis in the previous cycle was to understand the mechanisms behind ACA induced synaptic deficits and to establish novel, mitigating therapies against these deficits. Furthermore, new evidence in heart failure (HF) patients indicate that brain alterations in these patients are similar to regions affected by Alzheimer's disease (AD), suggesting that HF may be a major risk factor for AD. We discovered, in our previous studies, that physical exercise (PE) following ACA significantly enhances cognitive recovery. To require ailing, elderly CA patients, however, to adhere to a chronic exercise regimen presents a major obstacle. Therefore, we focus this competitive renewal on defining the mechanisms by which PE ameliorates cognitive deficits following ACA, and specifically defining potential post-ACA neurotherapeutics to act synergistically, with mild, beneficial PE. These goals will be achieved in the following specific aims: 1) To determine the effect of post-ACA PE on synaptic function, cognitive outcomes, and AD-like pathology of young female and male rats; 2) To identify molecular factors mediating the ameliorating effects of PE on cognitive deficits following ACA; and 3) To determine whether the combination of PE with pharmacological agents mitigates cognitive deficits and improves functional recovery after ACA in aged animals of both sexes.

Public Health Relevance

Cerebral ischemia in the form of cardiopulmonary arrest remains one of the leading causes of death and disability in the USA. A major pathological consequence of cardiac arrest is cognitive deficits. This proposal examines the molecular mechanisms by which physical exercise and its potential downstream pathways can ameliorate cognitive deficits following cardiac arrest. The goal is to find novel therapeutic agents that act synergistically with physical exercise that may benefit patients that undergo acute myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS045676-10A1
Application #
10069485
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koenig, James I
Project Start
2004-06-01
Project End
2025-07-31
Budget Start
2020-08-15
Budget End
2021-07-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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Koronowski, Kevin B; Dave, Kunjan R; Saul, Isabel et al. (2015) Resveratrol Preconditioning Induces a Novel Extended Window of Ischemic Tolerance in the Mouse Brain. Stroke 46:2293-8
Cohan, Charles H; Neumann, Jake T; Dave, Kunjan R et al. (2015) Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS One 10:e0124918
Narayanan, Srinivasan V; Dave, Kunjan R; Saul, Isa et al. (2015) Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2-Related Factor 2. Stroke 46:1626-32
Neumann, Jake T; Thompson, John W; Raval, Ami P et al. (2015) Increased BDNF protein expression after ischemic or PKC epsilon preconditioning promotes electrophysiologic changes that lead to neuroprotection. J Cereb Blood Flow Metab 35:121-30
Koronowski, Kevin B; Perez-Pinzon, Miguel A (2015) Sirt1 in cerebral ischemia. Brain Circ 1:69-78

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