ABSTRACTExtensive research has focused on cellular cholesterol and its regulation, primarily due to its crucial physiological roles and its association with numerous diseases resulting from dysregulated homeostasis. Consequently, investigating cholesterol metabolism and the network of regulating proteins remains an ongoing challenge for biomedical research seeking new molecular targets to manage aberrant cholesterol levels in pathologic conditions. There is evidence that Sigma‐2/TMEM97 receptor regulates cholesterol metabolism. However, the mechanisms remain incompletely understood to date. Therefore, this study aimed to employ a pharmacological approach based on selective Sigma‐2/TMEM97 agonists, rimcazole and siramesine, to uncover the contribution of this receptor to cholesterol homeostasis. Our results indicate that Sigma‐2/TMEM97 activation modulates cholesterol uptake by altering key proteins involved in, leading to free cholesterol and neutral lipids accumulation. This sheds light on potential mechanisms implied, contributing a new piece to the intricate puzzle of cholesterol metabolism homeostasis.

2024-06-05·ACS Chemical Neuroscience

Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding

Article

作者: Fraser, Douglas G ; Beeler, Aaron B ; Houser, Mei C Q ; Le, Nhat T T ; Harris, David A ; Mercer, Robert C C

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel antiprion compounds based on their known ability to bind to the sigma receptors, σ₁R and σ₂R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ₁R and σ₂R (Sigmar1 and Tmem97) in prion-infected N2a cells did not alter the antiprion activity of these compounds, demonstrating that these receptors are not the direct targets responsible for the antiprion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remain to be determined, the present work forms the basis for further investigation of these compounds in preclinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease.

2024-05-01·European Journal of Neuroscience

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats

Article

作者: Bartole, Mattingly K ; Newman, Amy Hauck ; Hiranita, Takato ; Chun, Lauren E ; Jones, Claire S ; Mereu, Maddalena ; Lopez, Jessica P ; Cao, Jianjing ; Tanda, Gianluigi ; Chen, Andy Y ; Katz, Jonathan L ; Hersey, Melinda

AbstractPsychostimulant use disorders (PSUD) are prevalent; however, no FDA‐approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3‐24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine‐induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8‐091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine‐induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.

项与 Rimcazole hydrochloride 相关的新闻（医药）

2024-05-15

·Science Daily

Drug compounds to combat neurodegenerative diseases

Prions are the abnormal, pathogenic agents that are transmissible and are able to induce abnormal folding of specific normal cellular proteins. Prion disease is an umbrella term for a group of fatal and currently untreatable neurodegenerative diseases that not only affect humans, but also wild and captive animals. These diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or 'mad cow disease'), and chronic wasting disease (CWD) affecting deer, elk and moose. Prions are the abnormal, pathogenic agents that are transmissible and are able to induce abnormal folding of specific normal cellular proteins.Prion disease is an umbrella term for a group of fatal and currently untreatable neurodegenerative diseases that not only affect humans, but also wild and captive animals. These diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or "mad cow disease"), and chronic wasting disease (CWD) affecting deer, elk and moose. The central event in these diseases is the conversion of the prion protein (PrPC) from its normal shape into a pathological structure (PrPSc) that is toxic to neurons and can replicate itself through binding to unconverted PrPC molecules. This ability to self-replicate makes these misfolded proteins infectious, which has enormous implications for public health. In a new study, researchers from Boston University Chobanian & Avedisian School of Medicine have identified 10 compounds that are able to reduce PrPSc levels in infected cells and have shown that the most potent molecules can also prevent the toxicity that was observed when applying PrPSc to cultured neurons. "Excitingly, five of these molecules have a history of use in humans: rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and SA 4503 and ANAVEX2-73, which are in clinical trials for ischemic stroke and Alzheimer's disease, respectively," explained lead author Robert C.C. Mercer, PhD, an instructor of biochemistry and cell biology at the school. The researchers had initially explored the anti-prion properties of these molecules because they were known to bind to the sigma receptors (σ1R and σ2R), which they had reason to believe were involved in prion proliferation. Using gene knockout technology (CRISPR), they determined that the sigma receptors were not the relevant targets of these drugs, from the perspective of their anti-prion properties. Using Neuro2a cells (N2a) from an experimental model that had been infected with prions, these cells were then exposed to increasing concentrations of each drug, and the levels of PrPSc were determined. They then used CRISPR technology to "edit" the σ1R and σ2R genes, such that they no longer coded for a protein, and found this had no effect upon the decrease in PrPSc levels they observed when applying the drugs. This led them to conclude that σ1R and σ2R were not responsible for the anti-prion effects of these drugs. They then went on to test the ability of these drugs to inhibit the PrPC to PrPSc conversion and found they had no effect on these cell-free reactions, indicating that another protein mediates the effects of these drugs. According to the researchers, prion diseases have enormous public health implications from the safety of the blood supply to the proper decontamination of surgical tools used in neurosurgery. "From a clinical standpoint, we believe this research has uncovered anti-prion properties of drugs that have already been shown to be safe to use in humans. Because of this, especially considering the absence of any effective treatment for these diseases, these compounds could be re-purposed for treatment of prion diseases," said corresponding author David A. Harris, MD, PhD, the Edgar Minas Housepian professor and chair of biochemistry & cell biology at the school. These findings appear online in the journal ACS Chemical Neuroscience. Funding for this study was provided by the National Institutes of Health grant number 5R01NS065244, awarded to David A. Harris. Robert C.C. Mercer is supported by grants from the Department of Defense (W81XWH-21-1-0141) and the Creutzfeldt-Jakob Disease Foundation.

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