Sigma-2 receptor as a potential therapeutic target for treating central nervous system disorders

Terada, Kazuki; Migita, Keisuke; Matsushima, Yukari; Kamei, Chiaki

doi:10.4103/1673-5374.259609

Cited by 13 publications

(13 citation statements)

References 9 publications

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“…Interestingly, co-treatment of the only potent σ 2 R-selective ligand and moderate GluN2B modulator ( K i = 202 nM) 19 with Aβ42 demonstrated 37.1 and 15.1% higher synaptic density levels compared to Aβ42 and vehicle levels, respectively. Our results support the previous findings on σ 2 R-linked neuroregeneration . Apolipoprotein-E (Apo-E), as the main source of cholesterol in the brain is required for axonal growth and synaptogenesis.…”

Section: Resultssupporting

confidence: 92%

“…Our results support the previous findings on σ 2 Rlinked neuroregeneration. 113 Apolipoprotein-E (Apo-E), as the main source of cholesterol in the brain is required for axonal growth and synaptogenesis. Apo-E is synthesized in astrocytes and microglia, and released into the extracellular unit.…”

Section: Determination Of In Vivo Synaptoprotective Activity Of Hit C...mentioning

confidence: 99%

“…Similarly, the σ 2 R agonist, PB28, was reported to enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, and this enhancement was completely blocked by the σ 2 R antagonist SM-21. 113,117 Therefore, the beneficial effects of simultaneously targeting hAChE and hBuChE with GluN2B or σRs could alter a significant pathophysiological mechanism of AD involving Apo-E/Aβ and provide disease-modifying treatment. This is a reasonable hypothesis given that some of the compounds (e.g., 19 and 49) enhance the synaptic connectivity to statistically higher levels compared to controls, and this could mean stronger synaptic integrity of the brain.…”

Section: Determination Of In Vivo Synaptoprotective Activity Of Hit C...mentioning

confidence: 99%

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Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

et al. 2022

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Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer’s disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σ1R, σ2R, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities. Nine fulfilled in silico drug-likeness criteria and did not display toxicity in three cell lines. Seven displayed cytoprotective activity in two stress-induced cellular models. Compared to donepezil, six showed equal/better synaptic protection in a zebrafish model of acute amyloidosis-induced synaptic degeneration. Two P2X7R antagonists alleviated the activation state of microglia in vivo. Permeability studies were performed, and four did not inhibit CYP450 3A4, 2D6, and 2C9. Therefore, four ChEI-based lead MTDLs are promising drug candidates for synaptic integrity protection and could serve as disease-modifying AD treatment. Our study also proposes zebrafish as a useful preclinical tool for drug discovery and development.

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Section: Resultssupporting

confidence: 92%

Section: Determination Of In Vivo Synaptoprotective Activity Of Hit C...mentioning

confidence: 99%

Section: Determination Of In Vivo Synaptoprotective Activity Of Hit C...mentioning

confidence: 99%

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Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

et al. 2022

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“…PC12 cells, a cell line from the rat pheochromocytoma of the adrenal medulla, have been extensively used as a mature neural cell model of neurite outgrowth [27][28][29]. In order to further validate the effect of the RhoA signaling pathway on neurite outgrowth, neuronally differentiated PC12 cells were treated with CT04 or Y27632 for 24 h. The results indicated that both CT04 and Y27632 treatments increased neurite outgrowth in neuronally differentiated PC12 cells ( Figure 2A-C,G,H).…”

Section: The Rhoa Pathway Negatively Regulates Neurite Outgrowth In Nmentioning

confidence: 98%

RhoA-GTPase Modulates Neurite Outgrowth by Regulating the Expression of Spastin and p60-Katanin

Tan

Zhang

Deng

et al. 2020

Cells

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RhoA-GTPase (RhoA) is widely regarded as a key molecular switch to inhibit neurite outgrowth by rigidifying the actin cytoskeleton. However, during neurite outgrowth, whether and how microtubule dynamics are regulated by RhoA remains to be elucidated. Herein, CT04 and Y27632 were used to inactivate RhoA and its downstream effector Rho-associated coiled coil-forming kinase (ROCK), while the RhoAQ63L lentiviral vector was utilized to overexpress the constitutively activated RhoA in dorsal root ganglion (DRG) neurons or neuronal differentiated PC12 cells. The current data illustrate that the RhoA signaling pathway negatively modulates neurite outgrowth and elevates the expression of Glu-tubulin (a marker for a stabilized microtubule). Meanwhile, the microtubule-severing proteins spastin and p60-katanin were downregulated by the RhoA signaling pathway. When spastin and p60-katanin were knocked down, the effects of RhoA inhibition on neurite outgrowth were significantly reversed. Taken together, this study demonstrates that the RhoA pathway-mediated inhibition of neurite outgrowth is not only related to the modulation of microfilament dynamics but is also attributable to the regulation of the expression of spastin and p60-katanin and thus influences microtubule dynamics.

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“…This receptor interacts with various other proteins—including caspase-3/7, cyclin D1, PARP-1, and EGFR—and is involved in the mobilization of ions (K + and Ca 2+ ) [ 13 , 16 , 17 ]. It has also been suggested that S2R may play important roles in neuroprotection and cognitive disorders, and could represent a potential target for the treatment of brain diseases [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Sigma receptors and neurological disorders

2021

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AbstarctSigma receptors were identified relatively recently, and their presence has been confirmed in the central nervous system and peripheral organs. Changes in sigma receptor function or expression may be involved in neurological diseases, and thus sigma receptors represent a potential target for treating central nervous system disorders. Many substances that are ligands for sigma receptors are widely used in therapies for neurological disorders. In the present review, we discuss the roles of sigma receptors, especially in the central nervous system disorders, and related therapies. Graphic abstract

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Sigma-2 receptor as a potential therapeutic target for treating central nervous system disorders

Cited by 13 publications

References 9 publications

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

RhoA-GTPase Modulates Neurite Outgrowth by Regulating the Expression of Spastin and p60-Katanin

Sigma receptors and neurological disorders

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