The Sigma Receptors in Alzheimer’s Disease: New Potential Targets for Diagnosis and Therapy

Wang, Tao; Jia, Hongmei

doi:10.3390/ijms241512025

Cited by 9 publications

(5 citation statements)

References 255 publications

(344 reference statements)

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“…However, aryl fluorides are usually rather stable in vivo, while alkyl fluorides carry the risk of defluorination, which would result in bone labeling via the formation of [ 18 F]CaF 2 . Several PET tracers bearing aromatic and aliphatic fluorine-18 have been reported in the literature [ 16 , 22 , 23 ].…”

Section: Fluorinated Pet Tracers Derived From the Promising σ ...mentioning

confidence: 99%

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[18F]Fluspidine—A PET Tracer for Imaging of σ1 Receptors in the Central Nervous System

Ludwig,

Laurini,

Schmidt

et al. 2024

Pharmaceuticals

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σ1 receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ1 receptor ligands. The relationship between structural modifications and σ1 receptor affinity and selectivity over σ2 receptors led to the 2-fluoroethyl derivative fluspidine (2, Ki = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH4 and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO- moiety of glutamate 172. The 18F-labeled radiotracers (S)-[18F]2 and (R)-[18F]2 were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (R)-[18F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[18F]2 was used to visualize σ1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[18F]2, the selective binding of pridopidine at σ1 receptors in the brain of healthy volunteers and HD patients was shown.

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Section: Fluorinated Pet Tracers Derived From the Promising σ ...mentioning

confidence: 99%

“…It was hypothesized that the activation of σ 1 receptors by donepezil contributes to its neuroprotective and anti-amnesic effects [ 15 ]. In PET studies, a low σ 1 receptor density was found for patients at an early stage of Alzheimer’s disease [ 16 ].…”

Section: Introduction: the Role Of σ 1 Receptors I...mentioning

confidence: 99%

[18F]Fluspidine—A PET Tracer for Imaging of σ1 Receptors in the Central Nervous System

Ludwig,

Laurini,

Schmidt

et al. 2024

Pharmaceuticals

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“…This occurs at three levels: cholesterol synthesis, cholesterol uptake in the form of LDL, and cholesterol release from lysosomes following autophagy or LDLR-mediated endocytosis of LDL (reviewed in Refs. [10,11,13,20,21]). The biosynthesis of cholesterol is controlled by SREBP-2, which induces the expression of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and the expression of LDLR.…”

Section: Function Of S2r In Cholesterol Homeostasis and Its Potential...mentioning

confidence: 99%

“…This functional connection and the substantial sharing of the ligands form the basis to group all four proteins under the umbrella term "sigma receptors". There are several outstanding in-depth reviews on the historical, pharmacological, biological, and structural aspects of these four proteins, authored by experts in this field [9,11,[16][17][18][19][20][21]. The goal of this present review is to provide a synopsis of the structural features of these proteins based on the most recent discoveries in the field and then to focus on the interesting roles of these proteins in iron/heme metabolism and homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Nguyen,

Jaramillo-Martinez,

Mathew

et al. 2023

IJMS

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Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein–protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.

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“…Several studies suggest that sigma receptor ligands can elevate Ach extracellular levels in prefrontal cortex rat brain [ 6 , 7 ]. Given the high sigma-1 receptor affinity of fluoxetine, this selective serotonin reuptake inhibitor (SSRI), which is commonly used to treat depression, attracts attention for managing cognitive deficits in AD [ 8 , 9 , 10 ]. Indeed, there is a growing evidence showing the neuroprotective effect of fluoxetine against amyloid beta Aβ plaques and hyperphosphorylated tau tangles, as the hallmark pathological features of AD and tau pathology [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Therapeutic Potential of Fluoxetine on Cognitive Decline in Alzheimer’s Disease: Systematic Review

Bougea,

Angelopoulou,

Vasilopoulos

et al. 2024

IJMS

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Fluoxetine, a commonly prescribed medication for depression, has been studied in Alzheimer’s disease (AD) patients for its effectiveness on cognitive symptoms. The aim of this systematic review is to investigate the therapeutic potential of fluoxetine in cognitive decline in AD, focusing on its anti-degenerative mechanisms of action and clinical implications. According to PRISMA, we searched MEDLINE, up to 1 April 2024, for animal and human studies examining the efficacy of fluoxetine with regard to the recovery of cognitive function in AD. Methodological quality was evaluated using the ARRIVE tool for animal AD studies and the Cochrane tool for clinical trials. In total, 22 studies were analyzed (19 animal AD studies and 3 clinical studies). Fluoxetine promoted neurogenesis and enhanced synaptic plasticity in preclinical models of AD, through a decrease in Aβ pathology and increase in BDNF, by activating diverse pathways (such as the DAF-16-mediated, TGF-beta1, ILK-AKT-GSK3beta, and CREB/p-CREB/BDNF). In addition, fluoxetine has anti-inflammatory properties/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome. Only three clinical studies showed that fluoxetine ameliorated the cognitive performance of people with AD; however, several methodological issues limited the generalizability of these results. Overall, the high-quality preclinical evidence suggests that fluoxetine may have neuroprotective, antioxidant, and anti-inflammatory effects in AD animal models. While more high-quality clinical research is needed to fully understand the mechanisms underlying these effects, fluoxetine is a promising potential treatment for AD patients. If future clinical trials confirm its anti-degenerative and neuroprotective effects, fluoxetine could offer a new therapeutic approach for slowing down the progression of AD.

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The Sigma Receptors in Alzheimer’s Disease: New Potential Targets for Diagnosis and Therapy

Cited by 9 publications

References 255 publications

[18F]Fluspidine—A PET Tracer for Imaging of σ1 Receptors in the Central Nervous System

[18F]Fluspidine—A PET Tracer for Imaging of σ1 Receptors in the Central Nervous System

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Emerging Therapeutic Potential of Fluoxetine on Cognitive Decline in Alzheimer’s Disease: Systematic Review

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