Ischemic stroke is the major cause of vascular dementia. Epidemiological studies have suggested a progressive course of dementia after ischemia stroke. Consistently, the preliminary study presented in this application indicates that, following a transient focal cerebral ischemia, rats exhibit a delayed significant decline of cognitive function. Furthermore, a delayed synaptic alternation was indicated in the hippocampus remote to the primary ischemic area. The relatively slow onset of cognitive dysfunction and synaptic alternation in the hippocampus suggest that therapeutic interventions applied after ischemic stroke could prevent progression of vascular cognitive impairment. In this application, we propose to further determine the long-term effects of transient focal cerebral ischemia on various sensorimotor and cognitive functions of rats, and to delineate the neuropathological mechanisms underlying the vascular cognitive impairment in this model with a focus on the hippocampus synaptic alternation, using behavioral, molecular biochemical, and electrophysiological approaches. In addition, the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue will be tested in this experimental model. To achieve this objective, the following aims will be addressed:
Specific Aim 1. To characterize vascular cognitive impairment after transient focal cerebral ischemia. In the proposed studies, an extensive behavioral battery will be employed to determine the impact of transient focal cerebral ischemia on long-term sensorimotor functions, cognitive functions, and anxiety-related behavior in a transient middle cerebral artery occlusion model in rats.
Specific Aim 2. To determine the mechanisms contributing to the progressive decline of cognitive function after transient focal cerebral ischemia. We will focus on the neuropathological change in hippocampus, which plays a critical role in cognitive function, since delayed synaptic alternation has been identified in this area remote to the primary infarct area after transient middle cerebral artery occlusion in rats.
Specific Aim 3. To determine the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue on the progression of vascular cognitive impairment induced by transient focal cerebral ischemia, using behavioral, biochemical, and electrophysiological approaches. Collectively, the studies proposed will provide new insight in the mechanism of vascular dementia and identify potential therapeutic target for the prevention of cognitive decline following cerebral ischemia.

Public Health Relevance

In this application, we propose to determine the long-term effects of transient focal cerebral ischemia on various sensorimotor and cognitive functions of rats, and to determine the neuropathological mechanisms underlying the vascular cognitive impairment in this model with a focus on the hippocampus synaptic alternation, using behavioral, molecular biochemical, and electrophysiological approaches. In addition, the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue will be tested in this experimental model. The studies proposed will provide new insight on the mechanism of vascular dementia and identify potential therapeutic target for the prevention of cognitive decline following cerebral ischemia. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS054651-01A2
Application #
7460059
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Refolo, Lorenzo
Project Start
2008-02-15
Project End
2013-01-31
Budget Start
2008-02-15
Budget End
2009-01-31
Support Year
1
Fiscal Year
2008
Total Cost
$315,000
Indirect Cost
Name
University of North Texas
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Yang, Shao-Hua; Li, Wenjun; Sumien, Nathalie et al. (2017) Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots. Prog Neurobiol 157:273-291
Cai, Bin; Li, Wenjun; Mao, XiaoOu et al. (2016) Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism. Mol Neurobiol 53:1254-65
Roy Choudhury, Gourav; Winters, Ali; Rich, Ryan M et al. (2015) Methylene blue protects astrocytes against glucose oxygen deprivation by improving cellular respiration. PLoS One 10:e0123096
Xie, Luokun; Choudhury, Gourav Roy; Winters, Ali et al. (2015) Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol 45:180-91
Xie, Luokun; Yang, Shao-Hua (2015) Interaction of astrocytes and T cells in physiological and pathological conditions. Brain Res 1623:63-73
He, Weiliang; Liu, Ran; Yang, Shao-Hua et al. (2015) Chemotherapeutic effect of tamoxifen on temozolomide-resistant gliomas. Anticancer Drugs 26:293-300
Ryou, M-G; Choudhury, G R; Li, W et al. (2015) Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress. Neuroscience 301:193-203
Reitman, Zachary J; Duncan, Christopher G; Poteet, Ethan et al. (2014) Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. J Biol Chem 289:23318-28
Li, W; Huang, R; Chen, Z et al. (2014) PTEN degradation after ischemic stroke: a double-edged sword. Neuroscience 274:153-61
Xie, Luokun; Sun, Fen; Wang, Jixian et al. (2014) mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol 192:6009-19

Showing the most recent 10 out of 34 publications