scholarly journals Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 211 ◽  
Author(s):  
Maximilian Christ ◽  
Heike Huesmann ◽  
Heike Nagel ◽  
Andreas Kern ◽  
Christian Behl
Keyword(s):  
Clinical Investigation ◽  
Receptor Activation ◽  
Autophagic Flux ◽  
Neuroprotective Effects ◽  
Sigma 1 Receptor ◽  
C Elegans ◽  
Protein Clearance ◽  
Sigma 1

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.

scholarly journals Pharmacological and functional similarities of the human neuropeptide Y system in C. elegans challenges phylogenetic views on the FLP/NPR system

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Miron Mikhailowitsch Gershkovich ◽  
Victoria Elisabeth Groß ◽  
Anette Kaiser ◽  
Simone Prömel
Keyword(s):  
Neuropeptide Y ◽  
Pharmacological Study ◽  
Receptor Activation ◽  
Cross Reactivity ◽  
Model Organisms ◽  
Loss Of Function ◽  
C Elegans ◽  
Molecular Studies

Abstract Background The neuropeptide Y system affects various processes, among others food intake, and is frequently discussed in the context of targeting obesity. Studies in model organisms are indispensable to enable molecular studies in a physiological context. Although the NPY system is evolutionarily conserved in all bilaterians, in the widely used model Caenorhabditis elegans there is controversy on the existence of NPY orthologous molecules. While the FMRFamide-like peptide (FLP)/Neuropeptide receptor-Resemblance (NPR) system in the nematode was initially suggested to be orthologous to the mammalian NPY system, later global phylogenetic studies indicate that FLP/NPR is protostome-specific. Methods We performed a comprehensive pharmacological study of the FLP/NPR system in transfected cells in vitro, and tested for functional substitution in C. elegans knockout strains. Further, we phenotypically compared different flp loss-of-function strains. Differences between groups were compared by ANOVA and post-hoc testing (Dunnett, Bonferroni). Results Our pharmacological analysis of the FLP/NPR system including formerly functionally uncharacterized NPY-like peptides from C. elegans demonstrates that G protein-coupling and ligand requirements for receptor activation are similar to the human NPY system. In vitro and in vivo analyses show cross-reactivity of NPY with the FLP/NPR system manifesting in the ability of the human GPCRs to functionally substitute FLP/NPR signaling in vivo. The high pharmacological/functional similarities enabled us to identify C. elegans FLP-14 as a key molecule in avoidance behavior. Conclusions Our data demonstrate the pharmacological and functional similarities of human NPY and C. elegans NPR systems. This adds a novel perspective to current phylogenetic reconstructions of the neuropeptide Y system. NPY and NPR receptors are pharmacologically so similar that the human receptors can functionally compensate for the C. elegans ones, suggesting orthologous relationships. This is also underlined by the presence of NPY-like peptides and parallels in peptide requirements for receptor activation. Further, the results presented here highlight the potential of this knowledge for physiological as well as molecular studies on neuropeptide GPCRs such as the NPY system in the future.

scholarly journals N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jose A. Morales-Garcia ◽  
Javier Calleja-Conde ◽  
Jose A. Lopez-Moreno ◽  
Sandra Alonso-Gil ◽  
Marina Sanz-SanCristobal ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Spatial Learning And Memory ◽  
South American ◽  
New Production ◽  
Sigma 1 Receptor ◽  
Neurogenic Niche ◽  
Sigma 1 ◽  
Functional Relevance

Abstract N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

scholarly journals In vitro and in vivo sigma 1 receptor imaging studies in different disease states

2020 ◽  
Author(s):  
Hebaalla Agha ◽  
Christopher R. McCurdy
Keyword(s):  
Clinical Trials ◽  
Molecular Imaging ◽  
Receptor Imaging ◽  
Imaging Studies ◽  
Sigma 1 Receptor ◽  
The Road ◽  
Disease States ◽  
Sigma 1

Molecular imaging studies have paved the road for the development of successful σ1R ligands currently in clinical trials.

Sigma-1 Receptor Activation Prevents Intracellular Calcium Dysregulation in Cortical Neurons during in Vitro Ischemia

2006 ◽  
Vol 319 (3) ◽  
pp. 1355-1365 ◽  
Author(s):  
Christopher Katnik ◽  
Waldo R. Guerrero ◽  
Keith R. Pennypacker ◽  
Yelenis Herrera ◽  
Javier Cuevas
Keyword(s):  
Intracellular Calcium ◽  
Cortical Neurons ◽  
Receptor Activation ◽  
Calcium Dysregulation ◽  
Sigma 1 Receptor ◽  
In Vitro Ischemia ◽  
Sigma 1

scholarly journals Protective Effects and Mechanism of Radix Polygalae Against Neurological Diseases as Well as Effective Substance

2021 ◽  
Vol 12 ◽  
Author(s):  
Ning Jiang ◽  
Shanshan Wei ◽  
Yiwen Zhang ◽  
Wenlu He ◽  
Haiyue Pei ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Chinese Herb ◽  
Receptor Activation ◽  
Mechanisms Of Action ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Apoptotic Effects

Radix Polygalae (also known as Yuanzhi in China) is the dried rhizome of Polygala tenuifolia Willd. or Polygala sibirica L., which is a famous Chinese herb and has been widely used for centuries in traditional medicines including expectorants, tonics, tranquilizers, antipsychotic, and so on. This article reviews the neuroprotective effects of Radix Polygalae in preclinical models of central nervous system (CNS) disorders, especially anxiety, depression, declining cognition, Alzheimer's disease (AD), and Parkinson's disease (PD). The chemical composition of Radix Polygalae as well as the underlying mechanisms of action were also reviewed. We found that Radix Polygalae possesses a broad range of beneficial effects on the abovementioned conditions. The multifold mechanisms of action include several properties such as antioxidant and associated apoptotic effects; anti-inflammatory and associated apoptotic effects; neurogenesis, regeneration, differentiation, and neuronal plasticity improvement; hypothalamic–pituitary–adrenal axis (HPA) regulation; neurotransmitter release; and receptor activation (A2AR, NMDA-R, and GluR). Nevertheless, the detailed mechanisms underlying this array of pharmacological effects observed in vitro and in vivo still need further investigation to attain a coherent neuroprotective profile.

scholarly journals Neuroprotective Effects of Extracts from Tiger Milk Mushroom Lignosus rhinocerus Against Glutamate-Induced Toxicity in HT22 Hippocampal Neuronal Cells and Neurodegenerative Diseases in Caenorhabditis elegans

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 30
Author(s):  
Parinee Kittimongkolsuk ◽  
Nattaporn Pattarachotanant ◽  
Siriporn Chuchawankul ◽  
Michael Wink ◽  
Tewin Tencomnao
Keyword(s):  
Oxidative Stress ◽  
Neuroprotective Effect ◽  
Water Extract ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
Antioxidant Genes ◽  
C Elegans ◽  
Intracellular Ros

Despite the Tiger Milk Mushroom Lignosus rhinocerus (LR) having been used as a traditional medicine, little is known about the neuroprotective effects of LR extracts. This study aims to investigate the neuroprotective effect of three extracts of LR against glutamate-induced oxidative stress in mouse hippocampal (HT22) cells as well as to determine their effect in Caenorhabditis elegans. In vitro, we assessed the toxicity of three LR extracts (ethanol extract (LRE), cold-water extract (LRC) and hot-water extract (LRH)) and their protective activity by MTT assay, Annexin V-FITC/propidium iodide staining, Mitochondrial Membrane Potential (MMP) and intracellular ROS accumulation. Furthermore, we determined the expression of antioxidant genes (catalase (CAT), superoxide dismutase (SOD1 and SOD2) and glutathione peroxidase (GPx)) by qRT-PCR. In vivo, we investigated the neuroprotective effect of LRE, not only against an Aβ-induced deficit in chemotaxis behavior (Alzheimer model) but also against PolyQ40 formation (model for Morbus Huntington) in transgenic C. elegans. Only LRE significantly reduced both apoptosis and intracellular ROS levels and significantly increased the expression of antioxidant genes after glutamate-induced oxidative stress in HT22 cells. In addition, LRE significantly improved the Chemotaxis Index (CI) in C. elegans and significantly decreased PolyQ40 aggregation. Altogether, the LRE exhibited neuroprotective properties both in vitro and in vivo.

scholarly journals Synthesis and evaluation of sigma receptor ligands

2010 ◽  
Author(s):  
◽  
Kuo-Hsien Fan
Keyword(s):  
Sigma Receptor ◽  
Imaging Agents ◽  
Receptor Ligands ◽  
Receptor Ligand ◽  
Sigma 1 Receptor ◽  
Lead Compounds ◽  
In Vivo Distribution ◽  
Sigma 1

Sigma receptors are unique binding sites located in the central nervous system (CNS) and peripheral organs. Two sigma receptor subtypes ([signma]1 and [sigma]2) have been described so far. It is known that the [sigma]1 receptor is involved in a number of CNS disorders and the [sigma]2 receptor is involved in tumor proliferation among others. Because of the important biological functions of the [sigma] receptor, development of structure activity relationships (SAR) can aid in the identification of potential medications and imaging agents. Three series of analogs based on three lead compounds have been synthesized and evaluated for their in vitro affinity and selectivity for the [sigma]1 and [sigma]2 subtypes. Lead I is a selective [sigma]1 receptor ligand with anti-cocaine activity, but its in vivo distribution is unknown. Our in vitro binding results showed that all the Lead I analogs are potent [sigma]1 receptor ligands. Furthermore, one of the Lead I analogs was radioiodinated and evaluated for its in vivo distribution. In vivo evaluation of the radioiodinated Lead I analog has shown high brain uptake and specific binding to [sigma]1 receptor of the radioligand. Lead II is also a selective [sigma]1 receptor ligand and radioiodinated Lead II has been shown to be a potential imaging agent for the [sigma]1 receptor. Two of the Lead II analogs were shown to be potent [sigma]1 receptor ligands. The radioiodinated Lead II analogs were demonstrated to be potential imaging agents for [sigma]1 receptor in vivo. Lead III is one of the most selective [sigma]2 receptor ligands known to date. Only one of the newly synthesized Lead III analogs was found to be a selective [sigma]2 receptor ligand. The SAR study of Lead III analogs successfully indentified the important structural features in Lead III for [sigma]2 receptor binding. To summarize, the SAR studies based on the lead compounds have generated useful information and three potential [sigma]1 imaging agents were prepared in the studies.

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