Date of Completion

7-9-2013

Embargo Period

7-9-2015

Keywords

Stroke, sex chromosomal complement, aging, inflammation, cerebral blood flow, estrogen, testosterone

Major Advisor

Dr. Louise D. McCullough

Associate Advisor

Dr. Lauren H. Sansing

Associate Advisor

Dr. Betty Eipper

Associate Advisor

Dr. Stephen Crocker

Associate Advisor

Dr. Stormy Chamberlain

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Ischemic stroke is now well recognized to be a sexually dimorphic disease. Women enjoy a lower stroke incidence as compared to men, until an advanced age, when this epidemiology reverses and elderly women bear the major brunt of this injury. The etiology underlying this change in stroke risk with age and sex is not well understood at this time. Therefore, the primary objective of this thesis was to determine the etiological factors underlying the sexual dichotomy in ischemic stroke and its reversal with advanced age. Changes in functional and histological outcomes with aging and sex were characterized. It was found that the aged animals have worse functional outcomes, but smaller injury after MCAO. This was not attributable to baseline or intra-ischemic perfusion changes in the aged brain. Moreover, an exaggerated inflammatory response to ischemic stroke was seen in the aged. To determine if sex chromosome complement or sex hormones determine stroke outcomes, we used the four core genotype mouse model. In these mice, Sry, the testes determining gene has been moved from the Y chromosome to an autosome, leading to formation of XY- Sry male mice (abbreviated to XYM). The four groups of mice derived by a cross between this XYM and a wild type XXF, gives the four core genotypes, XXF,XYF, XXM and XYM (Figure 1-14). Stroke outcome studies in these mice demonstrated that there is no role of sex chromosomal complement in shaping the sexual dimorphism in ischemic stroke. It was seen that the sex differences seen in ischemic stroke are predominantly due to the organizational and activational effects of sex hormones. The reversal in stroke epidemiology in males and females at an advanced age appears to be due to gonadal senescence and loss of these sex hormones.

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