Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer's disease model mice

Sun, Yue; Fan, Jianling; Zhu, Zhiyuan; Guo, Xiaodan; Zhou, Tingting; Duan, Wenhu; Shen, Xu

doi:10.1016/j.ejphar.2015.05.050

Cited by 14 publications

(7 citation statements)

References 56 publications

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“…Combination treatment with RARα, β -agonist Am80 (tamibarotene), and pan-RXR agonist HX630 significantly improved the memory deficits and suppressed insoluble Aβ peptide concentrations in the AβPP23 mouse model of AD [ 152 ]. More recently, thiophene derivative methyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (TBTC) which was suggested to function as a preferential agonist of RXRα and is able to induce heterodimerisation of RXRα/LXRα and PPARγ/RXRα was demonstrated to reduce Aβ levels in cell culture as well as in AD animal model [ 153 ]. Genistein was similarly shown to enhance clearance of Aβ through PPARγ/ApoE activation in 8-month-old APP/PS1 mice [ 154 ].…”

Section: Rxr and Its Partners In Neurological Disordersmentioning

confidence: 99%

Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

et al. 2022

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Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.

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Section: Rxr and Its Partners In Neurological Disordersmentioning

confidence: 99%

Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

et al. 2022

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“…They further improve cognitive deficits in AD mouse models by inducing transcription and lipidation of APOE and by suppression of microglial proinflammatory genes [ 173 ]. These beneficial effects were also confirmed on the behavioral level in an AD mouse model [ 174 ].…”

Section: Ppis and Dementia - Relevance Of Pharmacodynamics Pharmacokinetics And Pharmacogenomicsmentioning

confidence: 77%

The Janus-like Association between Proton Pump Inhibitors and Dementia

Papazoglou

Arshaad

Henseler

et al. 2021

CAR

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: Early pharmacoepidemiological studies suggested that Proton Pump Inhibitors (PPIs) might increase the risk of Alzheimer’s Disease (AD) and non-AD related dementias. These findings were supported by preclinical studies, specifically stressing the proamyloidogenic and indirect anticholinergic effects of PPIs. However, further large-scale pharmacoepidemiological studies showed inconsistent results on the association between PPIs and dementia. Pharmacodynamically, these findings might be related to the LXR/RXR-mediated amyloid clearance effect and anti-inflammatory action of PPIs. Further aspects that influence PPI effects on AD are related to patient-specific pharmacokinetic and pharmacogenomic characteristics. In conclusion, a personalized (individualized) medicinal approach is necessary to model and predict the potential harmful or beneficial effects of PPIs in AD and non-AD-related dementias in the future.

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“…Similar mechanisms were observed with two other RXR agonists, tributyltin chloride and LG268, which activated PPARg/RXR and LXRa/RXR signaling. This treatment modulated cellular lipid homeostasis and cholesterol efflux in RAW264 and THP-1 macrophages via increased expression of ABCA1 and ABCG1 (Repa et al, 2000;Chawla et al, 2001;Cui et al, 2011;Sun et al, 2015). Additionally, LG101305 enhanced ABCA1 mRNA expression and cholesterol efflux in macrophages (Claudel et al, 2001).…”

Section: Enhancement Of Atp-binding Cassette A1 and Atp-binding Cassette G1 Expression By Retinoid X Receptor Agonistsmentioning

confidence: 98%

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

et al. 2019

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Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT). RCT facilitates removal of cholesterol from peripheral tissues, including atherosclerotic plaques, and its subsequent hepatic clearance into bile. Therefore, RCT is expected to limit plaque formation and progression. Cellular cholesterol efflux is initiated and propagated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Their expression and function are expected to be rate-limiting for cholesterol efflux, which makes them interesting targets to stimulate RCT and lower atherosclerotic risk. This systematic review discusses the molecular mechanisms relevant for RCT and ABCA1 and ABCG1 function, followed by a critical overview of potential pharmacological strategies with small molecules to enhance cellular cholesterol efflux and RCT. These strategies include regulation of ABCA1 and ABCG1 expression, degradation, and mRNA stability. Various small molecules have been demonstrated to increase RCT, but the underlying mechanisms are often not completely understood and are rather unspecific, potentially causing adverse effects. Better understanding of these mechanisms could enable the development of safer drugs to increase RCT and provide more insight into its relation with atherosclerotic risk.Significance Statement--Hypercholesterolemia is an important risk factor of atherosclerosis, which is a leading pathological mechanism underlying cardiovascular disease. Cholesterol is removed from atherosclerotic plaques and subsequently cleared by the liver into bile. This transport is mediated by high-density lipoprotein particles, to which cholesterol is transferred via ATP-binding cassette transporters ABCA1 and ABCG1. Small-molecule pharmacological strategies stimulating these transporters may provide promising options for cardiovascular disease treatment.

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Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer's disease model mice

Cited by 14 publications

References 56 publications

Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

The Janus-like Association between Proton Pump Inhibitors and Dementia

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

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