Current options for clinical treatment of ischemic strokes are currently very limited and there is a great need for interventions that can be safely administered during a period of several hours following the onset of a stroke and minimize neuronal loss. It has long been known that repetitive waves of spreading depolarizations (SD) (analogous to cortical spreading depression) occur in animal stroke models, but only recently has it been convincingly shown that SDs are very prevalent following human ischemic brain injuries. SDs produce massive ionic redistributions in neurons and glia, requiring the expenditure of metabolic energy to restore homeostasis. The repetitive SDs following ischemia place a severe additional metabolic demand on brain tissue that is already compromised by reductions in local blood flow. Thus approaches to prevent the onset and progression of these post-ischemic SD events, or even to limit their deleterious consequences, are likely to have substantial positive outcomes in clinical medicine. We have discovered that Zn2+ can play an important role in initiation of SD, and that Zn2+ release from synapses is substantial following each SD event. Zn2+ has previously been demonstrated to be toxic to both neurons and glia, and our overall hypothesis is that Zn2+ increases associated with SD make a significant contribution to injury following ischemia. We propose that this is due to Zn2+ accumulation in both neurons and astrocytes, which in turn 1) lowers the threshold for initiation of SD events and 2) serves as an upstream trigger for Ca2+ excitotoxicity. Studies in Aim 1 utilize hippocampal slice preparations from mice to evaluate the mechanisms of Zn2+ release and accumulation in single neurons and populations of astrocytes.
Aim 2 examines mechanisms by which Zn2+ can facilitate the onset of SD in hippocampal slices, including inhibition of astrocyte uptake function and up-regulation of neuronal NMDA receptor function.
Aim 3 tests the hypothesis that Zn2+ is upstream of Ca2+ deregulation following SD, and tests whether interventions that disrupt the processes identified in Aims 1&2 provide significant improvements in neuronal viability in brain slice and in vivo. Slice studies of synaptic structure and function will be complemented by in vivo studies of focal ischemia in mice.
Each aim should independently provide significant new information for the field, and when taken together, these mechanistic studies should suggest novel approaches to limit the consolidation and spread of ischemic brain injury.

Public Health Relevance

This project is designed to identify new approaches to limit the deleterious consequences of a stroke. Following a stroke, aberrant waves of brain activation contribute to the spread of injury. This project is designed to identify new approaches to limit the onset, or consequences, of these spreading waves of activation and thereby improve functional recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051288-09
Application #
8672694
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2005-04-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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Santos, Edgar; León, Fiorella; Silos, Humberto et al. (2016) Incidence, hemodynamic, and electrical characteristics of spreading depolarization in a swine model are affected by local but not by intravenous application of magnesium. J Cereb Blood Flow Metab 36:2051-2057
Seidel, Jessica L; Escartin, Carole; Ayata, Cenk et al. (2016) Multifaceted roles for astrocytes in spreading depolarization: A target for limiting spreading depolarization in acute brain injury? Glia 64:5-20
Poddar, Ranjana; Rajagopal, Sathyanarayanan; Shuttleworth, C William et al. (2016) Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP: MOLECULAR BASIS FOR ZN2+-INDUCED ERK MAPK ACTIVATION. J Biol Chem 291:813-25
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Seidel, Jessica L; Faideau, Mathilde; Aiba, Isamu et al. (2015) Ciliary neurotrophic factor (CNTF) activation of astrocytes decreases spreading depolarization susceptibility and increases potassium clearance. Glia 63:91-103
Li, Lu; Candelario, Kate M; Thomas, Kelsey et al. (2014) Hypoxia inducible factor-1α (HIF-1α) is required for neural stem cell maintenance and vascular stability in the adult mouse SVZ. J Neurosci 34:16713-9
Aiba, Isamu; Shuttleworth, C William (2014) Characterization of inhibitory GABA-A receptor activation during spreading depolarization in brain slice. PLoS One 9:e110849

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