The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease

Quinn, Joseph F.; Harris, Christopher; Hack, Wyatt R.; Gray, Nora E.; Kulik, Veronika; Bostick, Zoe; Brumbach, Barbara H.; Copenhaver, Philip F.

doi:10.1016/j.nbd.2022.105888

Cited by 7 publications

(10 citation statements)

References 64 publications

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“…Although the majority of estrogen-induced neuroprotection has been attributed to classical nuclear ERs, there is growing evidence for the neuroprotective potential of nonnuclear ERs. Initially, researchers focused on GPER1, which became a main focus in studying the neuroprotective capacity of phytoestrogens (e.g., ginsenoside Rg1), flavonoids (geinstein, daidzein), and synthetic SERMs (e.g., STX) [ 1 , 2 , 11 , 72 ]. Selective activation of GPER1 appeared to cause neuroprotection in animal models of mood disorders, Alzheimer’s disease, and Parkinson’s disease, but there is no consensus on the role played by GPER1 in ischemic stroke [ 73 ].…”

Section: Neuroprotection Mediated By Membrane Ersmentioning

confidence: 99%

“…Since lipid rafts are important elements for mERα/mERβ-mediated signaling, activating the receptors may cause even stronger therapeutic effects than diet supplementation alone. Additionally, the localization of mERβ and/or mERα within the mitochondrial membrane provides unique regulatory mechanisms that are essential for cellular homeostasis; thus, strategies directed at membrane-associated ERs may play causative roles in preventing the neural degeneration that is triggered by energy loss, e.g., in Parkinson’s disease [ 9 , 10 , 11 ].…”

Section: Perspectivesmentioning

confidence: 99%

“…Nuclear- and membrane-initiated estrogen signaling cooperate to orchestrate the pleiotropic effects of estrogens. It is generally accepted that ER-mediated signaling plays key roles in neurogenesis [ 5 , 6 , 7 ], neurodevelopment [ 8 ], and neuroprotection [ 9 , 10 , 11 ], and its impairment may lead to a predisposition to neurodegenerative diseases [ 12 , 13 ] and mood disorders [ 14 ]. However, the application of estrogens as neuroprotectants in humans presents numerous limitations, mainly due to detrimental side effects triggered by the activation of classical ERs in peripheral tissues.…”

Section: Introductionmentioning

confidence: 99%

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Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

Wnuk

Przepiórska

Pietrzak

et al. 2023

IJMS

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Nuclear- and membrane-initiated estrogen signaling cooperate to orchestrate the pleiotropic effects of estrogens. Classical estrogen receptors (ERs) act transcriptionally and govern the vast majority of hormonal effects, whereas membrane ERs (mERs) enable acute modulation of estrogenic signaling and have recently been shown to exert strong neuroprotective capacity without the negative side effects associated with nuclear ER activity. In recent years, GPER1 was the most extensively characterized mER. Despite triggering neuroprotective effects, cognitive improvements, and vascular protective effects and maintaining metabolic homeostasis, GPER1 has become the subject of controversy, particularly due to its participation in tumorigenesis. This is why interest has recently turned toward non-GPER-dependent mERs, namely, mERα and mERβ. According to available data, non-GPER-dependent mERs elicit protective effects against brain damage, synaptic plasticity impairment, memory and cognitive dysfunctions, metabolic imbalance, and vascular insufficiency. We postulate that these properties are emerging platforms for designing new therapeutics that may be used in the treatment of stroke and neurodegenerative diseases. Since mERs have the ability to interfere with noncoding RNAs and to regulate the translational status of brain tissue by affecting histones, non-GPER-dependent mERs appear to be attractive targets for modern pharmacotherapy for nervous system diseases.

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Section: Neuroprotection Mediated By Membrane Ersmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

Wnuk

Przepiórska

Pietrzak

et al. 2023

IJMS

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“…Oestrogen receptor modulator, reduces Aβ levels, associated mitochondrial toxicity, and synaptic deficits and improves spatial memory [274,275].…”

Section: Stx Rodent Models and Cultured Cellsmentioning

confidence: 99%

“…Oestrogen administration has also been linked with the improved transmission of serotonin [ 271 ] and acetylcholine [ 272 ], as well as enhanced LTP magnitude correlating with improved cognitive performance of AD rats [ 269 ]. Application of the hormone or oestrogen receptor modulators has been proposed to reduce pathological Aβ accumulation [ 268 , 274 , 275 , 318 ] and promote tau clearance [ 273 ]. The therapeutic potential of oestrogen therapy in targeting multiple pathological elements of AD is unsurprising considering the reported neuroprotective role of the hormone.…”

Section: Targeting Neuromodulator Function For Ad Treatmentmentioning

confidence: 99%

Alternative Pharmacological Strategies for the Treatment of Alzheimer’s Disease: Focus on Neuromodulator Function

et al. 2022

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Alzheimer’s disease (AD) is a neurodegenerative disorder, comprising 70% of dementia diagnoses worldwide and affecting 1 in 9 people over the age of 65. However, the majority of its treatments, which predominantly target the cholinergic system, remain insufficient at reversing pathology and act simply to slow the inevitable progression of the disease. The most recent neurotransmitter-targeting drug for AD was approved in 2003, strongly suggesting that targeting neurotransmitter systems alone is unlikely to be sufficient, and that research into alternate treatment avenues is urgently required. Neuromodulators are substances released by neurons which influence neurotransmitter release and signal transmission across synapses. Neuromodulators including neuropeptides, hormones, neurotrophins, ATP and metal ions display altered function in AD, which underlies aberrant neuronal activity and pathology. However, research into how the manipulation of neuromodulators may be useful in the treatment of AD is relatively understudied. Combining neuromodulator targeting with more novel methods of drug delivery, such as the use of multi-targeted directed ligands, combinatorial drugs and encapsulated nanoparticle delivery systems, may help to overcome limitations of conventional treatments. These include difficulty crossing the blood-brain-barrier and the exertion of effects on a single target only. This review aims to highlight the ways in which neuromodulator functions are altered in AD and investigate how future therapies targeting such substances, which act upstream to classical neurotransmitter systems, may be of potential therapeutic benefit in the sustained search for more effective treatments.

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Gardenin A treatment attenuates inflammatory markers, synuclein pathology and deficits in tyrosine hydroxylase expression and improves cognitive and motor function in A53T-α-syn mice

Hack,

Gladen-Kolarsky,

Chatterjee

et al. 2024

Biomedicine & Pharmacotherapy

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The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease

Cited by 7 publications

References 64 publications

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

Alternative Pharmacological Strategies for the Treatment of Alzheimer’s Disease: Focus on Neuromodulator Function

Gardenin A treatment attenuates inflammatory markers, synuclein pathology and deficits in tyrosine hydroxylase expression and improves cognitive and motor function in A53T-α-syn mice

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