AGING, HYPERTENSION AND ESTROGEN NEUROPROTECTION

Luther College, Decorah IA

Investigators

Abstract

Following menopause many women experience progressive cognitive impairment and have a significantly higher risk of dementia. While the mechanisms which contribute to these progressive cognitive deficits are unknown, the loss of estrogen appears to be a major underlying factor. The loss of estrogen at menopause is also associated with an increased risk of hypertension which contributes to cognitive impairment. Previous work from our laboratory has shown that male spontaneously hypertensive rats (SHR) display age-related learning and memory impairments that are associated with neuronal remodeling in the retrosplenial cortex, an area that is important for spatial learning in rats and humans. While these deficits normally become apparent in aged (2 year-old) male Sprague-Dawley rats, they are first identifiable in male SHR at a significantly younger age (1 year-old). Chronic anti-hypertensive therapy (captopril) significantly delays both cognitive impairment and neuronal remodeling in SHR, suggesting that hypertension contributes to these changes. Few studies have examined the effects of hypertension and estrogen loss on cognitive function. We have established for the first time that elimination of both endogenous estrogen (ovariectomy) and exogenous estrogens (plant phytoestrogens in the diet) has a dramatic effect on arterial pressure control in female SHR, i.e., female SHR normally do not show an increase in arterial pressure when fed a high NaCl diet, but following elimination of both endogenous and exogenous estrogen, they respond to a high NaCl diet with a very large increase in arterial pressure (> 60 mm Hg). This provides a provocative model with which to test the hypothesis that both the loss of estrogen and hypertension can accelerate the age-related decline in cognitive ability and neuronal stability in female SHR. The proposed studies test the hypotheses that: Specific Aim 1. Estrogen depletion accelerates cognitive impairment and neuronal remodeling in the retrosplenial cortex, and that estrogen replacement protects against these changes. Specific Aim 2. Estrogen-depletion reduces cerebral blood flow in female SHR and estrogen replacement reverses these decreases. Specific Aim 3. Estrogen-depletion impairs vascular reactivity and causes arteriolar hypertrophy in female SHR, and that estrogen replacement reverses these effects.