Recent evidence in heart and brain suggest that mild ischemic episodes may limit the damage from subsequent ischemic insults. This program of research is directed toward understanding the mechanisms of such ischemic preconditioning. Understanding these mechanisms may allow pharmacological access to this protective state during surgical procedures. This understanding may also offer unique new insights into the basic mechanisms of ischemic injury and into potential therapeutic interventions that may ameliorate the consequences of cerebral ischemia. Goals of this research are to test four broad hypotheses. First we propose that a sub-lethal period of ischemia followed by a brief referfusion period will protect against a subsequent global ischemic insult. This hypothesis will be tested in an in vivo model of transient forebrain global ischemia in rats. The intensity of ischemic neuronal damage will be assessed different times. The second hypothesis relates to the mechanism of neuroprotection afforded by IPC. Concentration will be upon derangements produced by global ischemia that are functional (changes in ion homeostasis as indicated by extracellular potassium ion activity, evoked potentials; and metabolic activities as signalled by local blood flow, and neurotransmitter releases). The third hypothesis relates to the role of adenosine during IPC. In vivo studies will determine whether adenosine plays a key role during IPC, as has been established in cardiac ischemia. These studies will determine the neuroprotective role of adenosine on ion homeostasis, electrical activity, blood flow, neurotransmitter release and histopathology. Finally, IPC will be studied by emphasizing intracellular mechanisms. The hypothesis is that IPC promotes a better maintenance of neuronal energy charge by inhibiting electrical activity. Intracellular studies will determine effect of IPC on different conductances of the pyramid cells of the Ca1 hippocampal slices. Definition of IPC will likely provide an important step toward understanding mechanisms of ischemic damage and tolerance. It is toward this goal that the present research is proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
3R29NS034773-02S1
Application #
6071672
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Jacobs, Tom P
Project Start
1997-05-01
Project End
2002-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Narayanan, Srinivasan V; Dave, Kunjan R; Perez-Pinzon, Miguel A (2018) Ischemic Preconditioning Protects Astrocytes against Oxygen Glucose Deprivation Via the Nuclear Erythroid 2-Related Factor 2 Pathway. Transl Stroke Res 9:99-109
Xu, Jing; Jackson, Charlie W; Khoury, Nathalie et al. (2018) Brain SIRT1 Mediates Metabolic Homeostasis and Neuroprotection. Front Endocrinol (Lausanne) 9:702
Koronowski, Kevin B; Khoury, Nathalie; Saul, Isabel et al. (2017) Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance. Stroke 48:3117-3125
Morris-Blanco, Kahlilia C; Dave, Kunjan R; Saul, Isabel et al. (2016) Protein Kinase C Epsilon Promotes Cerebral Ischemic Tolerance Via Modulation of Mitochondrial Sirt5. Sci Rep 6:29790
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
Thompson, John W; Narayanan, Srinivasan V; Koronowski, Kevin B et al. (2015) Signaling pathways leading to ischemic mitochondrial neuroprotection. J Bioenerg Biomembr 47:101-10
Morris-Blanco, Kahlilia C; Cohan, Charles H; Neumann, Jake T et al. (2014) Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. J Cereb Blood Flow Metab 34:1024-32

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