The risk for ischemic stroke increases drastically with age. Although this has been attributed to vascular factors, aging could result in changes such that the central nervous system (CNS) itself has an increased vulnerability to ischemic injury. White matter (WM) is injured in most strokes and axonal injury and dysfunction are responsible for much of the disability associated with clinical deficits. We suggest that failure to protect WM is one of the primary reasons contributing to the lack of successful stroke therapy. The long term goal is to determine if aging WM function can be improved in a model of ischemic injury by attenuating oxidative injury and by preserving mitochondrial integrity through blockade of age-specific excitotoxic pathways. Recently, we reported that CNS WM is intrinsically more vulnerable to ischemic injury in older animals. In young WM, the damage from ischemic injury involves the sequence of energy depletion (ionic pathway), excessive glutamate release (excitotoxicity), generation of reactive oxygen species and oxidative stress (oxidative pathway). Overactivation of either AMPA or kainate receptors in optic nerve but activation of Ca2+permeable AMPA receptors in corpus callosum mediate injury, suggesting a region specific mechanism of ischemic injury in young WM. In older WM, the injury is mediated by Ca2+independent excitotoxicity and an earlier and more robust glutamate release associated with upregulation of glutamate transporter GLT1. Our preliminary studies suggest that excitotoxicity leads to oxidative stress in aging WM associated with alterations in axonal mitochondrial dynamics. It is not known whether manipulating excitotoxicity in an age-specific manner can rescue axon function, reducing oxidative stress and maintaining mitochondrial dynamics. This proposal combines electrophysiology, immunohistochemistry, confocal imaging, biochemical measurements, and genetically modified mice to test the hypothesis that increased excitotoxicity is due to multiple release sites and release mechanisms of glutamate, activating age-specific glutamate receptors in a cell-specific manner, and that, this is responsible for increased vulnerability of aging WM to ischemia by disrupting mitochondrial dynamics and aggravating oxidative injury. The three specific aims of this proposal are designed to better understand the cellular sites and mechanisms that link excitotoxicity to oxidative injury and mitochondrial dysfunction during ischemia in aging WM. Acutely isolated optic nerve and corpus callosum slices will be used to ascertain quantitative measurements of WM function and structure. Our focus is to define appropriate age-specific therapeutic targets for stroke and other neurodegenerative diseases involving WM.

Public Health Relevance

Stroke is the third leading cause of death in the US with an enormous cost to national health resources. This proposal is critically designed to include and explore axon injury (white matter) during stroke, considering age as the main risk factor. Our study will suggest age-specific therapeutic approaches to stroke victims, thus reducing social and economical burden on society.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG033720-06
Application #
8690720
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Baltan, Selva (2015) Can lactate serve as an energy substrate for axons in good times and in bad, in sickness and in health? Metab Brain Dis 30:25-30
Murphy, Sean P; Lee, Rona J; McClean, Megan E et al. (2014) MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury. J Neurochem 129:509-15
Baltan, Selva; Morrison, Richard S; Murphy, Sean P (2013) Novel protective effects of histone deacetylase inhibition on stroke and white matter ischemic injury. Neurotherapeutics 10:798-807
Baltan, Selva; Murphy, Sean P; Danilov, Camelia A et al. (2011) Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. J Neurosci 31:3990-9
Baltan, Selva; Bachleda, Amelia; Morrison, Richard S et al. (2011) Expression of Histone Deacetylases in Cellular Compartments of the Mouse Brain and the Effects of Ischemia. Transl Stroke Res 2:411-423