Cognitive impairment following a stroke, known as vascular dementia (VaD), is a common outcome often overlooked in lieu of the motor and verbal impairments. Nonetheless, the executive and memory deficits in VaD can be drastically impairing. A successful treatment or intervention could improve the quality of life for millions of patients. Two aims were pursued in service of this goal. The first aim was to compare the gene expression profiles of frontal cortex tissue from diagnosed cases of VaD, intermediate Alzheimer's disease (AD), and no cognitive impairment. Gene expression products that were differentially expressed in VaD cases versus AD and controls were to be investigated for biological significance and therapeutic potential. Further validation studies were also used to identify targets worth pursuing further. The oxytocin receptor (OXTR) was identified as differentially upregulated in the frontal cortex in cases of VaD, and localization to astrocytes surrounding areas of infarction was noted. The second aim was designed to test the therapeutic potential of the OXTR in an animal model of VaD. Administration of the potent vasoconstrictor endothelin-1 (ET-1) into the prefrontal cortex of spontaneous hypertensive stroke prone rats (SHRSP) was used to create a model of focal stroke with a pre-morbidity leading to cognitive deficits without obstructing motor deficits. A pre-injury intervention of an adeno-associated virus expressing either the OXTR or green fluorescent protein (GFP) linked with the astrocytic promoter glial fibrillary acidic protein (GFAP) was applied. The animals were then subjected to a battery of cognitive tests to confirm deficits induced by the ischemic lesion and assess potential rescue by the pre-upregulation of the OXTR in astrocytes. OXTR upregulation improved performance in the novel object task compared to control, suggesting a rescue of working memory function that is mediated by the prefrontal cortex. Tissue processing assessed infarct size, white matter density, and viral expression, which showed no difference in white matter density but a reduction in the size of the infarct by the pre-upregulation of the receptor in the perimeter of the targeted prefrontal cortex site. An additional sub-aim of aim two was devised to compare the effects on known molecular participants in the pathway of ischemic injury within animals expressing ectopic OXTR or GFP in separate hemispheres to ET-1 or saline treated animals. At the 24 hour time point chosen, no difference was observed in either reactive oxygen species generation or the profiles of cytokines implicated in the course of ischemic injury. The results from the human tissue studies in aim one suggest that a specific peri-infarct specific upregulation of the OXTR on astrocytes is a hallmark of ischemic VaD. Rescue studies in a rat model in aim two suggest that this upregulation may be a compensatory response acting to salvage penumbra tissue and reduce the ensuing behavioral deficits. However, the specific mechanism remains undefined at this time. Further preclinical mechanistic studies are needed, particularly at different time points, to more rigorously evaluate the relative efficacy of targeting the OXTR as an intervention for VaD.
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