The role of aging and length of hypogonadism on the neuroprotective effects of dietary genistein following focal cerebral ischemia

The risk of ischemic stroke increases with increasing age. Women beyond menopause have an exponential increase in stroke risk with worse post-stroke prognosis and mortalities compared to men of similar ages. One of the key reasons for this discrepancy is the sudden and drastic drop in the levels of the circulating principal female sex hormones estrogen and progesterone after menopause. Both sex hormones have been shown in several studies to provide neuroprotection against ischemic insults in stroke models and other disease models including Alzheimer's Disease and Parkinson's Disease. However, from clinical studies, neither estrogen nor progesterone alone or in combination has met clinical needs for the prevention of chronic cardiovascular diseases. These clinical failures were mainly evidenced by the absence of benefits in the human population or an increased predisposition to adverse side effects. Reports from studies including the Women's Health Initiative and Nurse's Health Study showed that the timing of initiation and age of recipients significantly influence the outcome of estrogen therapy. In this dissertation project, we investigated the plant-based estrogenic compound genistein as a possible alternative to estrogen therapy. It was hypothesized that the neuroprotective benefits of genistein will be less sensitive to the length of hypogonadism and age under experimental ischemic conditions. We used a rodent model of transient middle cerebral artery occlusion under varied lengths of estrogen deprivation and age to test the neuroprotection of dietary genistein. Findings from this dissertation show that early initiation of dietary genistein after hypogonadism improves aspects of cognition, an effect that is diminished following the long absence of circulating estrogen. Furthermore, pre-treatment with dietary genistein improves age-associated locomotor deficits after long-term hypogonadism after stroke. This dissertation, therefore, provides new considerations on the time-dependent sensitivity of the brain to genistein's effect as a potential therapeutic option to improve aspects of cognition and reduce the severity of stroke in the target population with low circulating estrogens.