Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

Ye, Na; Qin, Wangzhi; Tian, Sheng; Xu, Qingfeng; Wold, Eric A.; Zhou, Jia; Zhen, Xuechu

doi:10.1021/acs.jmedchem.0c01192

Cited by 56 publications

(58 citation statements)

References 205 publications

(480 reference statements)

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“…In mouse models, Sigma1R agonists are neuroprotective and have improved motor neuron function in neurodegenerative conditions [50]. The Sigma1R agonist ANAVEX 2-73 (blarcamesine) has demonstrated disease-modifying improvements in preclinical models of the neurodegenerative disorder Rett syndrome, and is currently in phase 2b/3 clinical trials for Alzheimer's disease (NCT03790709) and Parkinson's disease dementia (NCT03774459) (Table 3) [41,[54][55][56][57]. Together, these data show that Sigma1R activity is required for normal motor neuron function.…”

Section: Neurodegenerationmentioning

confidence: 99%

“…The many functions of Sigma1R that are related to the pathology of DEEs and to central nervous system (CNS) physiology suggest a potential role for Sigma1R in the DEE pathophysiology of seizures and in aspects of higher cognitive function. For example, ANAVEX 2-73 (blarcamesine), which has agonist activity both at the Sigma1R and at muscarinic receptors, is currently in clinical trials for neurodegenerative diseases (NCT03774459, NCT03790709; Alzheimer's disease, Parkinson's disease dementia, and Rett syndrome (which manifests with seizures in most patients)) and was granted FDA's Orphan Drug Designation for infantile spasms in 2016 [41,42,[54][55][56][57].…”

Section: Introductionmentioning

confidence: 99%

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An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Martin

Reeder

Sourbron

et al. 2021

IJMS

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Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.

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Section: Neurodegenerationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Martin

Reeder

Sourbron

et al. 2021

IJMS

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“…In this sense, agonists and antagonists regulate the association between Sig-1R and BiP, controlling the interactome of Sig-1R [ 105 , 109 , 110 ]. The regulation of these mechanisms has a pivotal role in the context of MAMs and neurodegenerative diseases [ 111 ]. Transcriptional upregulation of Sig-1R induces its neuroprotective properties.…”

Section: Therapeutic Approaches Targeting Mamsmentioning

confidence: 99%

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

et al. 2022

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Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

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“…Blarcamesine is currently being evaluated for AD, Rett syndrome, and PD dementia patients (NCT04314934, NCT04304482, NCT04575259). Results of completed clinical trials of S1R agonists in variety of disorders have been comprehensively summarized in recent reviews [4,130].…”

Section: The S1r As a Therapeutic Target For The Treatment Of Neurodegenerative Diseasesmentioning

confidence: 99%

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Zhemkov

Geva²,

Hayden

et al. 2021

IJMS

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The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.

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Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

Cited by 56 publications

References 205 publications

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

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