PRE-084 as a tool to uncover potential therapeutic applications for selective sigma-1 receptor activation

Motawe, Zeinab Y.; Abdelmaboud, Salma S.; Cuevas, Javier; Breslin, Jerome W.

doi:10.1016/j.biocel.2020.105803

Cited by 27 publications

(18 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, we used PRE-084 to provide a proof of concept that S1R activation is a relevant therapeutic strategy to treat WS. The drug is a prototypic S1R agonist, shown to be effective in numerous neurodegenerative disorders ( 38 , 45 , 47 , 84 ), but it is only a pharmacological tool used in investigational research that will not be developed at the clinical stage. A selective, effective, bioavailable, and innocuous S1R agonist has yet to be proposed and developed at the clinical stage.…”

Section: Discussionmentioning

confidence: 99%

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

et al. 2022

View full text Add to dashboard Cite

The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the WSF1 gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein’s stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

et al. 2022

View full text Add to dashboard Cite

show abstract

“…15 This ligand is able to regulate cytokine production in stroke, 16 reduce microglial activation in traumatic brain injury, induce protective effects in neurogenic inflammation 17 and endothelial barrier damage. 18 NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2phenylethoxy)-phenyl]-ethylamine monohydrochloride) is an antagonist of the S1R, 19 which was shown to block sigma-1 agonist (SA4503) induced thoracic aortic vasodilation. 13 The third ligand we investigated was a recently identified new compound, 20 (S)-L1 (S-N-benzyl-6,7-dimethoxy-in vivo treatment of diabetic rats by sigma-1 1,2,3,3,4-tetrahydro-1-isoquinolinetanamine), the pharmacological nature of which is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Effects of sub-chronic,in vivoadministration of sigma-1 receptor ligands on platelet and aortic arachidonate cascade in streptozotocin-induced diabetic rats

Váczi

Barna

Laczi

et al. 2022

Preprint

View full text Add to dashboard Cite

Diabetes mellitus is a chronic metabolic disorder which induces endothelial dysfunction and platelet activation. Eicosanoids produced from arachidonic acid regulate cellular and vascular functions. Sigma-1 receptor expressed in platelets and endothelial cells can regulate intracellular signalization. Our aim was to examine the influence of sub-chronic, in vivo administered sigma-1 receptor ligands (2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate, PRE-084; S-N-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineethanamine, a new compound (S)-L1; and N,N-dipropyl-2-[4-methoxy-3- (2-phenylethoxy)-phenyl]-ethylamine monohydrochloride, NE-100) on the ex vivo arachidonic acid metabolism of platelets and aorta in streptozotocin-induced diabetic rats. The serum level of sigma-1 receptor ligands was detected by liquid chromatography-mass spectrometry before the ex vivo analysis. Sigma-1 receptor and cyclooxygenase gene expression in platelets were determined by reverse transcription coupled quantitative polymerase chain reaction. The eicosanoid synthesis was examined by using of radiolabeled arachidonic acid substrate and enzyme-linked immunosorbent assay. In diabetic rats, the sub-chronic, in vivo administration of the sigma-1 receptor ligands modified the transcript levels of sigma-1 receptor and cyclooxygenase-1, the concentration of cyclooxygenase in platelets and the eicosanoid synthesis in both platelets and aorta. Sigma-1 receptor ligands, by changing platelet and blood vessel eicosanoid synthesis, may play a role in modulating diabetic complications.

show abstract

Section: Introductionmentioning

confidence: 99%

“…PRE-084 (2-(4-morpholinoethyl)-1-phenylcyclohexane-1-carboxylate hydrochloride) is a highly selective σ1R agonist displaying minimal cross reactivity with other receptors [for extensive review see ( Motawe et al, 2020 )]. It had been shown in vivo that PRE-084 binds with σ1R and is rapidly distributed in the CNS ( Motawe et al, 2020 ). Using excitotoxic injury in organotypic spinal cord slices, Guzmán-Lenis et al demonstrated that PRE-084 not only induces a neuroprotective effect and decreases neuronal damage but also enhances axonal re-growth ( Guzman-Lenis et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

“…In vivo , the beneficial effects of PRE-084 has been reported in animal models of neurological diseases such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, spinal muscular atrophy, Huntington disease, vascular dementia, amnesia, embolic stroke and multiple sclerosis. Though, PRE-084 did not improve outcomes following seizures [for review see ( Motawe et al, 2020 )].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Negative Impact of Sigma-1 Receptor Agonist Treatment on Tissue Integrity and Motor Function Following Spinal Cord Injury

et al. 2021

View full text Add to dashboard Cite

In traumatic spinal cord injury, the initial trauma is followed by a cascade of impairments, including excitotoxicity and calcium overload, which ultimately induces secondary damages. The sigma-1 receptor is widely expressed in the central nervous system and is acknowledged to play a key role in calcium homeostasis. Treatments with agonists of the sigma-1 receptor induce beneficial effects in several animal models of neurological diseases. In traumatic injury the use of an antagonist of the sigma-1 receptor reversed several symptoms of central neuropathic pain. Here, we investigated whether sigma-1 receptor activation with PRE-084 is beneficial or detrimental following SCI in mice. First, we report that PRE-084 treatment after injury does not improve motor function recovery. Second, using ex vivo diffusion weighted magnetic resonance imaging completed by histological analysis, we highlight that σ1R agonist treatment after SCI does not limit lesion size. Finally, PRE-084 treatment following SCI decreases NeuN expression and increases astrocytic reactivity. Our findings suggest that activation of sigma-1 receptor after traumatic spinal cord injury is detrimental on tissue preservation and motor function recovery in mice.

show abstract

PRE-084 as a tool to uncover potential therapeutic applications for selective sigma-1 receptor activation

Cited by 27 publications

References 99 publications

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

Effects of sub-chronic,in vivoadministration of sigma-1 receptor ligands on platelet and aortic arachidonate cascade in streptozotocin-induced diabetic rats

Negative Impact of Sigma-1 Receptor Agonist Treatment on Tissue Integrity and Motor Function Following Spinal Cord Injury

Contact Info

Product

Resources

About