Sigma-1 receptor as a potential pharmacological target for the treatment of neuropathology

Bolshakova, Anastasia; Kukanova, E. O.; Gainullina, Anastasia N.; Zhemkov, Vladimir; Korban, Svetlana A.; Bezprozvanny, Ilya

doi:10.1016/j.spjpm.2016.03.003

Cited by 14 publications

(12 citation statements)

References 60 publications

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“…The benefits of ibogaine may be associated with its effects on serotonin and dopamine transporters, sigma, N-methyl-d-aspartate, nicotinic acetylcholine, and opioid receptors, 29,33,34 and the production of glial-derived neurotrophic factors 35 and brain-derived neurotropic factor 36 which are identified sites of interest in the treatment of cognitive impairment in neuropsychiatric disorders. [37][38][39][40][41][42] The primary adverse effects of ibogaine include cardiovascular effects (e.g., Q-wave/Twave interval prolongation, bradycardia, arrythmias, and in rare cases, sudden cardiac death), 43 ataxia, nausea, and vomiting, 44 and psychological effects (e.g., auditory and visual hallucinations, re-experiencing traumatic memories, acute fear, distress, or guilt). 31,45 5-Methoxy-N,N-Dimethyltryptamine 5-MeO-DMT is a psychedelic tryptamine found in plant species 46 and notably in the venomous secretions of the Sonoran Desert/Colorado River toad.…”

Section: Ibogainementioning

confidence: 99%

Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

et al. 2020

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Background U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans. Method We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%). Results Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives. Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary. Conclusion U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.

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Section: Ibogainementioning

confidence: 99%

Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

et al. 2020

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“…Thus, dimer and monomer forms may be functional chaperone states, whereas higher oligomeric complexes of S1R may act as a repository for the active forms. In addition, the S1R monomer is known to bind to protein partners on the plasma membrane, forming a functional unit potentially indicative of a secondary function of S1R and independent of its chaperone activity ( Figure 2 ; Gromek et al, 2014 ; Mavlyutov et al, 2015 ; Bolshakova et al, 2016 ). In conclusion, the equilibrium of S1R in different states of oligomerization, i.e., monomers, dimers, or higher oligomeric forms, may explain its multiple interactions with such a wide number of heterogeneous classes of proteins.…”

Section: Introductionmentioning

confidence: 99%

Sigma Receptors as Endoplasmic Reticulum Stress “Gatekeepers” and their Modulators as Emerging New Weapons in the Fight Against Cancer

et al. 2018

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Despite the interest aroused by sigma receptors (SRs) in the area of oncology, their role in tumor biology remains enigmatic. The predominant subcellular localization and main site of activity of SRs are the endoplasmic reticulum (ER). Current literature data, including recent findings on the sigma 2 receptor subtype (S2R) identity, suggest that SRs may play a role as ER stress gatekeepers. Although SR endogenous ligands are still unknown, a wide series of structurally unrelated compounds able to bind SRs have been identified. Currently, the identification of novel antiproliferative molecules acting via SR interaction is a challenging task for both academia and industry, as shown by the fact that novel anticancer drugs targeting SRs are in the preclinical-stage pipeline of pharmaceutical companies (i.e., Anavex Corp. and Accuronix). So far, no clinically available anticancer drugs targeting SRs are still available. The present review focuses literature advancements and provides a state-of-the-art overview of SRs, with emphasis on their involvement in cancer biology and on the role of SR modulators as anticancer agents. Findings from preclinical studies on novel anticancer drugs targeting SRs are presented in brief.

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“…S1R has been extensively studied in the past decades, and its modulators have been proposed as viable tools for different therapeutic applications, reaching advanced stages of drug development (e.g. MR309, a Sigma-1 antagonist is currently in Phase II clinical trial for the treatment of neuropathic pain) [31,49,50]. On the other hand, aquaporins are still largely unexplored from a medicinal chemistry standpoint and have been recognized as druggable molecular targets only recently [17,[51][52][53][54][55].…”

Section: Discussionmentioning

confidence: 99%

Dual Aquaporin and Sigma1 Receptor (DAS) Modulators: New Tools for Counteracting Oxidative Stress

Pellavio¹,

Rossino²,

Gastaldi³

et al. 2020

Preprint

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Specific aquaporins (AQP), called peroxyporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasting during oxidative stress. Another target involved in oxidative stress is the Sigma1 Receptor (S1R), since its activation is triggered by oxidative or endoplasmic reticulum stress. Herein we evaluated the effect of S1R modulators on AQP-dependent water permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in Hela cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. All compounds except one were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together, our results support the hypothesis that the investigated compounds act as dual aquaporin and Sigma1 receptor (DAS) modulators. The finding that small molecules can modulate both AQP and S1R opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, like cancer and degenerative diseases.

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Sigma-1 receptor as a potential pharmacological target for the treatment of neuropathology

Cited by 14 publications

References 60 publications

Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

Sigma Receptors as Endoplasmic Reticulum Stress “Gatekeepers” and their Modulators as Emerging New Weapons in the Fight Against Cancer

Dual Aquaporin and Sigma1 Receptor (DAS) Modulators: New Tools for Counteracting Oxidative Stress

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