title: An NO donor approach to neuroprotective and procognitive estrogen therapy overcomes loss of NO synthase function and potentially thrombotic risk.
abstract: Selective estrogen receptor modulators (SERMs) are effective therapeutics that preserve favorable actions of estrogens on bone and act as antiestrogens in breast tissue, decreasing the risk of vertebral fractures and breast cancer, but their potential in neuroprotective and procognitive therapy is limited by: 1) an increased lifetime risk of thrombotic events; and 2) an attenuated response to estrogens with age, sometimes linked to endothelial nitric oxide synthase (eNOS) dysfunction. Herein, three 3(rd) generation SERMs with similar high affinity for estrogen receptors (ERα, ERβ) were studied: desmethylarzoxifene (DMA), FDMA, and a novel NO-donating SERM (NO-DMA). Neuroprotection was studied in primary rat neurons exposed to oxygen glucose deprivation; reversal of cholinergic cognitive deficit was studied in mice in a behavioral model of memory; long term potentiation (LTP), underlying cognition, was measured in hippocampal slices from older 3×Tg Alzheimer's transgenic mice; vasodilation was measured in rat aortic strips; and anticoagulant activity was compared. Pharmacologic blockade of GPR30 and NOS; denudation of endothelium; measurement of NO; and genetic knockout of eNOS were used to probe mechanism. Comparison of the three chemical probes indicates key roles for GPR30 and eNOS in mediating therapeutic activity. Procognitive, vasodilator and anticoagulant activities of DMA were found to be eNOS dependent, while neuroprotection and restoration of LTP were both shown to be dependent upon GPR30, a G-protein coupled receptor mediating estrogenic function. Finally, the observation that an NO-SERM shows enhanced vasodilation and anticoagulant activity, while retaining the positive attributes of SERMs even in the presence of NOS dysfunction, indicates a potential therapeutic approach without the increased risk of thrombotic events.
authors: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Lawren
authors: L
authors: VandeVrede
authors: Ramy
authors: R
authors: Abdelhamid
authors: Zhihui
authors: Z
authors: Qin
authors: Jaewoo
authors: J
authors: Choi
authors: Sujeewa
authors: S
authors: Piyankarage
authors: Jia
authors: J
authors: Luo
authors: John
authors: J
authors: Larson
authors: Brian M
authors: BM
authors: Bennett
authors: Gregory R J
authors: GR
authors: Thatcher
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D015687:Cell Hypoxia; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000925:Anticoagulants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C532507:GPER1 protein, mouse; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D018697:Nootropic Agents; D010880:Piperidines; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; C571169:desmethylarzoxifene; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D005947:Glucose
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