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Sigma 1 agonist

Qi-Jun Gao, Bo Yang, Jing Chen, Shao-Bo Shi, Hong-Jie Yang, Xin Liu
Background: The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma-1 receptor agonist PRE-084 exhibits a cardioprotective effect in some studies, the benefits in cases of myocardial ischemia/reperfusion (I/R) are not clear. The aim of this study was to explore the mechanism of action and assess the effect of PRE-084 on myocardial I/R injury in rats. Methods: In this study, rats were assigned randomly to three groups with computer (n = 14 for each group): a sham group, an I/R group, and a PRE-084 group...
March 5, 2018: Chinese Medical Journal
Jiahong Qin, Peng Wang, Yi Li, Lan Yao, Yuanshan Liu, Tao Yu, Jiali Lin, Xiangshao Fang, Zitong Huang
BACKGROUND: Global cerebral ischemic/reperfusion (I/R) injury after cardiac arrest (CA) is a major cause of mortality and morbidity in survivors of resuscitation. We utilized a rat model of asphyxia CA to explore the functional effects and mechanisms of Sigma-1 receptor (Sig-1R) activation in cerebral protection using the Sig-1R agonist cutamesine (SA-4503). METHODS: After resuscitation, the surviving rats were randomly divided into three groups (n = 18 each): (1) the CPR group (0...
February 8, 2018: Shock
Xiaolei Wang, Chang Feng, Yong Qiao, Xin Zhao
No study has been conducted to examine the interactions of sigma-1 receptor (Sigma-1R) and high mobility group box 1 protein (HMGB1) in the development of diabetic peripheral neuropathy. Thus, we examined the effects of streptozotocin (STZ) treatment on expression of HMGB1 in subcellular levels in the dorsal root ganglion (DRG) in both wild-type and Sigma-1R-/- mice and evaluated the effects of repeated intrathecal administrations of selective Sigma-1R antagonists BD1047, agonist PRE-084, or HMGB1 inhibitor glycyrrhizin on peripheral neuropathy in wild-type mice...
February 5, 2018: Neuroscience Letters
Jingying Zhu, Songsong Zang, Xufeng Chen, Lei Jiang, Aihua Gu, Jie Cheng, Li Zhang, Jun Wang, Hang Xiao
Methamphetamine (Meth) is an illicit psychostimulant with high abuse potential and severe neurotoxicity. Recent studies have shown that dysfunctions in learning and memory induced by Meth may partially reveal the mechanisms of neuronal channelopathies. Kv2.1, the primary delayed rectifying potassium channel in neurons, is responsible for mediating apoptotic current surge. However, whether Kv2.1 is involved in Meth-mediated neural injury remains unknown. In the present study, the treatment of primary cultured hippocampal neurons with Meth indicated that Meth induced a time- and dose-dependent augmentation of Kv2...
January 3, 2018: Journal of Applied Toxicology: JAT
Hélène Hall, M Florencia Iulita, Palma Gubert, Lisi Flores Aguilar, Adriana Ducatenzeiler, Abraham Fisher, A Claudio Cuello
INTRODUCTION: AF710B (aka ANAVEX 3-71) is a novel selective allosteric M1 muscarinic and sigma-1 receptor agonist. In 3×Tg-AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer-like hallmarks. We now report on the long-lasting disease-modifying properties of AF710B in McGill-R-Thy1-APP transgenic (Tg) rats. METHODS: Chronic treatment with AF710B (10 μg/kg) was initiated in postplaque 13-month-old Tg rats. Drug or vehicle was administered orally daily for 4...
December 29, 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Emanuele Amata, Antonio Rescifina, Orazio Prezzavento, Emanuela Arena, Maria Dichiara, Valeria Pittalà, Ángeles Montilla-García, Francesco Punzo, Pedro Merino, Enrique J Cobos, Agostino Marrazzo
Methoxycarbonyl-1-phenyl-2-cyclopropylmethyl based derivatives cis-(+)-1a [cis-(+)-MR200], cis-(-)-1a [cis-(-)-MR201], and trans-(±)-1a [trans-(±)-MR204], have been identified as new potent sigma (σ) receptor ligands. In the present paper, novel enantiomerically pure analogues were synthesized and optimized for their σ receptor affinity and selectivity. Docking studies rationalized the results obtained in the radioligand binding assay. Absolute stereochemistry was unequivocally established by X-ray analysis of precursor trans-(+)-5a as camphorsulfonyl derivative 9...
January 11, 2018: Journal of Medicinal Chemistry
Xi-Ping Huang, Tao Che, Thomas J Mangano, Valerie Le Rouzic, Ying-Xian Pan, Susruta Majumdar, Michael D Cameron, Michael H Baumann, Gavril W Pasternak, Bryan L Roth
W-18 (4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide). Here, we describe the comprehensive pharmacological profiles of W-18 and W-15, as examination of their structural features predicted that they might lack opioid activity. We found W-18 and W-15 to be without detectible activity at μ, δ, κ, and nociception opioid receptors in a variety of assays...
November 16, 2017: JCI Insight
Stefanie D Krämer, Thomas Betzel, Linjing Mu, Ahmed Haider, Adrienne Herde Müller, Anna K Boninsegni, Claudia Keller, Marina Szermerski, Roger Schibli, Bernhard Wünsch, Simon M Ametamey
Clinical and preclinical research with modulators binding to the NMDA receptor GluN2B N-terminal domain (NTD) aim for the treatment of various neurological diseases. However, the interpretation of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of candidate drugs. We have developed [11 C]Me-NB1 as a PET tracer for imaging GluN1/GluN2B-containing NMDA receptors and used it to investigate in rats the dose-dependent receptor occupancy of eliprodil, a GluN2B NTD modulator...
November 30, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Tangui Maurice, Manon Strehaiano, Fanny Duhr, Nathalie Chevallier
The sigma-1 receptor (S1R) is a molecular chaperone which activity modulates several intracellular signals including calcium mobilization at mitochondria-associated endoplasmic reticulum membranes. S1R agonists are potent neuroprotectants against neurodegenerative insults and particularly in rodent models of Alzheimer's disease (AD). We here analyzed whether S1R inactivation modifies vulnerability to amyloid toxicity in AD models. Two strategies were used: (1) amyloid β[25-35] (Aβ25-35 ) peptide (1, 3, 9nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE-100 or in S1RKO mice, and (2) WT, APPSweInd , S1RKO, and APPSweInd /S1RKO mice were created and female littermates analyzed at 8 months of age...
February 26, 2018: Behavioural Brain Research
Nino Goguadze, Elene Zhuravliova, Didier Morin, Davit Mikeladze, Tangui Maurice
The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca(2+) exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IP3Rs). The σ1R is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer's disease (AD) models in vitro and in vivo. σ1R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood...
November 10, 2017: Neurotoxicity Research
Catherine F Moore, Gabrielle S Schlain, Samantha Mancino, Valentina Sabino, Pietro Cottone
Obesity and eating disorders are widespread in Western societies. Both the increased availability of highly palatable foods and dieting are major risk factors contributing to the epidemic of disorders of feeding. The purpose of this study was to characterize an animal model of maladaptive feeding induced by intermittent access to a palatable diet alternation in mice. In this study, mice were either continuously provided with standard chow food (Chow/Chow), or provided with standard chow for 2days and a high-sucrose, palatable food for 1day (Chow/Palatable)...
October 31, 2017: Pharmacology, Biochemistry, and Behavior
Simona Collina, Marta Rui, Silvia Stotani, Emanuele Bignardi, Daniela Rossi, Daniela Curti, Fabrizio Giordanetto, Alessio Malacrida, Arianna Scuteri, Guido Cavaletti
Effective therapies for multiple sclerosis (MS) are still missing. This neurological disease affects more than 2.5 million people worldwide. To date, biological immunomodulatory drugs are effective and safe during short-term treatment, but they are suitable only for parenteral administration and they are expensive. Accordingly, academic and industrial environments are still focusing their efforts toward the development of new MS drugs. Considering that neurodegeneration is a contributory factor in the onset of MS, herein we will focus on the crucial role played by sigma 1 receptors (S1Rs) in MS...
November 2017: Future Medicinal Chemistry
Anna M Klawonn, Anna Nilsson, Carl F Rådberg, Sarah H Lindström, Mia Ericson, Björn Granseth, David Engblom, Michael Fritz
Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction...
2017: Frontiers in Pharmacology
Barbara A Mysona, Jing Zhao, Sylvia Smith, Kathryn E Bollinger
Glaucoma is an incurable optic neuropathy characterized by dysfunction and death of retinal ganglion cells (RGCs). Brain derived neurotrophic factor (BDNF) is an essential neurotrophin that supports RGC function and survival. Despite BDNF's importance, our knowledge of molecular mechanisms that modulate BDNF processing and secretion is incomplete. Sigma-1 receptor (S1R) is associated with increased BDNF in hippocampus and with BDNF secretion by brain-derived astrocytes and neuronal cell lines. Much less is known about the relationship between S1R and BDNF in the visual system...
February 2018: Experimental Eye Research
Dong Li, Shu-Zhuo Zhang, Yu-Hong Yao, Yun Xiang, Xiao-Yun Ma, Xiao-Li Wei, Hai-Tao Yan, Xiao-Yan Liu
INTRODUCTION: Sigma-1 receptors (Sig-1Rs) are unique endoplasmic reticulum proteins that have been implicated in both neurodegenerative and ischemic diseases, such as Alzheimer's disease and stroke. Accumulating evidence has suggested that Sig-1R plays a role in neuroprotection and axon outgrowth. The underlying mechanisms of Sig-1R-mediated neuroprotection have been well elucidated. However, the mechanisms underlying the effects of Sig-1R on axon outgrowth are not fully understood. METHODS: To clarify this issue, we utilized immunofluorescence to compare the axon lengths of cultured naïve hippocampal neurons before and after the application of the Sig-1R agonist, SA4503...
October 8, 2017: CNS Neuroscience & Therapeutics
Inés Reynoso-Moreno, Israel Najar-Guerrero, Noé Escareño, Mario Eduardo Flores-Soto, Jürg Gertsch, Juan Manuel Viveros-Paredes
Guineensine is a dietary N-isobutylamide widely present in black and long pepper (Piper nigrum and Piper longum) previously shown to inhibit cellular endocannabinoid uptake. Given the role of endocannabinoids in inflammation and pain reduction, here we evaluated guineensine in mouse models of acute and inflammatory pain and endotoxemia. Significant dose-dependent anti-inflammatory effects (95.6 ± 3.1% inhibition of inflammatory pain at 2.5 mg/kg ip and 50.0 ± 15.9% inhibition of edema formation at 5 mg/kg ip) and acute analgesia (66...
October 25, 2017: Journal of Agricultural and Food Chemistry
Xinying Liu, Yingmei Fu, Huan Yang, Timur Mavlyutov, Jun Li, Christopher R McCurdy, Lian-Wang Guo, Bikash R Pattnaik
The sigma-1 receptor (σ1-R) and sigma-2 receptor (σ2-R) are potential drug targets for treatment of cancer, pain, depression, retinal degeneration and other neuronal diseases. Previous reports show that sigma-1 receptor modulates the activities of multiple channels. We are interested in possible sigma receptor modulation of Kv2.1, a K(+) channel abundant in retinal photoreceptors. We tested the effect of established sigma receptor ligands on Kv2.1 channels which were stably expressed in HEK293 cells. Surprisingly, σ1-R antagonists inhibited Kv2...
August 29, 2017: Oncotarget
Jing Zhao, Barbara A Mysona, Jing Wang, Graydon B Gonsalvez, Sylvia B Smith, Kathryn E Bollinger
The sigma 1 receptor (S1R) is a unique transmembrane protein that has been shown to regulate neuronal differentiation and cellular survival. It is expressed within several cell types throughout the nervous system and visceral organs, including neurons and glia within the eye. S1R ligands are therapeutic targets for diseases ranging from neurodegenerative conditions to neoplastic disorders. However, effects of S1R activation and inhibition within glia cells are not well characterized. Within the eye, the astrocytes at the optic nerve head are crucial to the health and survival of the neurons that send visual information to the brain...
2017: PloS One
Shivangi Patel, Dilip Sharma, Kiran Kalia, Vinod Tiwari
Disruption of oxidant/anti-oxidant ratio as well as endoplasmic reticulum (ER) stress are thought to be involved in the pathophysiology of schizophrenia. These stresses can lead to impairments in brain functions progressively leading to neuronal inflammation followed by neuronal cell death. Moreover, the cellular stresses are interlinked leading us to the conclusion that protein misfolding, oxidative stress and apoptosis are intricately intertwined events requiring further research into their mechanistic and physiological pathways...
September 7, 2017: Neuroscience and Biobehavioral Reviews
Rebecca L Brindley, Mary Beth Bauer, Nolan D Hartley, Kyle J Horning, Kevin P M Currie
Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca(2+) channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT1A receptors to control secretion...
October 2017: Journal of Neurochemistry
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