O4‐07‐08: Design of selective estrogen receptor modulators as neuroprotective and procognitive agents
Year: 2010
Type: article
Abstract: Neuroprotective, procognitive, and antidepressant effects of estrogens in the brain have been demonstrated in many studies, however, the extensive Women's Health Initiative Study of estrogen replacement therapy (ERT/HRT) did not reveal protection against dementia and rather showed increased vascular dementia, highlighting the demonstrated thromboembolic risk associated with estrogenic activity in older women. Limited reports on selective estrogen receptor modulators (SERMs), notably the benzothiophene SERM, raloxifene, have indicated positive neurological and cognitive effects. A small library of novel benzothiophene SERMs was developed and compared with raloxifene, arzoxifene, and estrogens for classical estrogenic and antiestrogenic effects in vivo and in vitro, including estrogen receptor (ER) binding. These compounds were further studied in neuroblastoma cell lines and in primary rat neuronal cell cultures for neuroprotective activity. The neuroprotective SERMs and estrogens were probed for mechanism using pharmacological pathway inhibitors. For selected SERMs, reversal of scopolamine induced cognitive deficits was assayed in wild type and nitric oxide synthase 3 knockout (eNOS(-/-)) mice, and correlated with brain and plasma bioavailability. Cardiovascular actions were studied in rat aortic tissue vasodilation. The potential for prothomboembolic actions was assayed in rats by measuring drug anticoagulant effects. One SERM was studied for its ability to restore long term potentiation (LTP) in hippocampal slices from amyloid transgenic mice. SERMS and estrogens were neuroprotective in neuroblastoma cell lines, but only a structural subset of SERMs and estradiol were observed to deliver concentration dependent neuroprotection in primary neurons after transient oxygen/glucose deprivation (OGD). The protection against OGD cell death was mediated by extranuclear ER for estradiol, but not for the neuroprotective SERMs, although G-protein coupled receptor 30 (GPR-30) antagonism inhibited neuroprotection by both families of compounds. The procognitive activity of SERMs in mice treated with scopolamine appeared to correlate with brain bioavailability and was lost after treatment of wild type mice with NOS inhibitor and also lost in eNOS(-/-) mice. The collected data suggest that novel benzothiophene SERMs devoid of unwanted gynecological estrogenic activity, but with central procognitive and neuroprotective activity have potential for use in Alzheimer's therapy or possibly prevention.
Source: Alzheimer s & Dementia
Authors: Gregory R.J. Thatcher, Ramy Abdelhamid, Jia Luo, Zhihui Qin
Institution: University of Illinois Chicago
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2056235178