t the inflammatory changes of aging and estrogen loss cannot be decreased by replacement of lost EETs, they may nonetheless be counterbalanced by increasing EETs levels beyond those naturally produced, either with EETs supplementation or sEHi administration. Further 15996703 investigation of the in vivo effects of elevated EETs levels are needed. In addition to developmental functions, estrogens have been found to reduce incidence of coronary heart disease, maintain bone mineral density, and, in the CNS, promote neuronal survival and hippocampal neurogenesis. Neuro-imaging IMR-1 web studies reveal that estrogen therapy improves cerebral blood flow and performance in hippocampal-dependent memory tasks in women age 55 and older. Other observational studies have found that estrogen helps alleviate age-related cognitive decline by preserving executive function in young and postmenopausal women. Meta-analysis suggested that the risk of Alzheimer’s disease could be reduced by estrogen replacement therapy by as much as 34%. Although the Women’s Heath Initiative study attempted to investigate the impact of ERT on dementia, the study concluded prematurely due to reported risk of stroke and breast cancer. These findings have led several authors to the conclusion that estrogen therapy remains a treatment or prophylactic option for cognitive impairment and AD, if carcinogenic and thromboembolic effects can be ameliorated. Raloxifene is 
a second generation SERM used clinically for the treatment of osteoporosis in postmenopausal women, which acts as an antiestrogen in breast and endometrial tissues and has been shown to reduce the lifetime risk of vertebral 18347191 fractures and breast cancer. Additionally, clinical trials showed a trend towards decreased risk for cognitive impairment, with no effect on coronary events, although these effects must be balanced against raloxifene’s known increased lifetime risk of thromboembolic events. Raloxifene has also been found to enhance levels of the vasodilator NO through actions on endothelial nitric oxide synthase ; however, age-related attenuated eNOS activity has been speculated as a cause of increased thromboembolic events in postmenopausal women. Since NO is known to inhibit thrombus formation through inhibition of platelet recruitment, adhesion and aggregation, it appeared worthwhile to test the novel concept that an NO-donor SERM could abrogate or circumvent 1 NO-Donor SERM Circumvents NOS Dysfunction adverse events linked to eNOS dysfunction in postmenopausal women. The activation of NO signaling in combination with estrogen therapy may be of use in an aging population including AD patients, since eNOS activity may decrease with age. This loss of activity may be associated with the critical period hypothesis, wherein women who are $10 years post-menopause are less responsive or nonresponsive to the neuroprotective and procognitive effects of estrogens. It is likely that multiple pathways contribute to the attenuated estrogen response, and based upon mechanistic studies, these may include signaling via estrogen receptors, GPR30, and eNOS . The development of the next generation SERM, arzoxifene, was driven by the need to improve on the poor bioavailability of raloxifene. Arzoxifene, is a prodrug of desmethylarzoxifene that differs from raloxifene by only one atom, and retains efficacy in reducing the risk of vertebral fracture and invasive breast cancer in postmenopausal women, but failed to demonstrate a significant improveme
