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

ABSTRACT: The discovery of a highly selective putative sigma-1 (σ1) receptor agonist, PRE-084, has revealed the numerous potential uses of this receptor subtype as a therapeutic target. While much work has been devoted to determining the role of σ1 receptors in normal and pathophysiological states in the nervous system, recent work suggests that σ1 receptors may be important for modulating functions of other tissues. These discoveries have provided novel insights into σ1 receptor structure, function, and importance in multiple intracellular signaling mechanisms. These discoveries were made possible by σ1 receptor-selective agonists such as PRE-084. The chemical properties and pharmacological actions of PRE-084 will be reviewed here, along with the expanding list of potential therapeutic applications for selective activation of σ1 receptors.

SUBMITTER: Motawe ZY

PROVIDER: S-EPMC7484451 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Motawe Zeinab Y ZY Abdelmaboud Salma S SS Cuevas Javier J Breslin Jerome W JW

The international journal of biochemistry & cell biology 20200712

The discovery of a highly selective putative sigma-1 (σ1) receptor agonist, PRE-084, has revealed the numerous potential uses of this receptor subtype as a therapeutic target. While much work has been devoted to determining the role of σ1 receptors in normal and pathophysiological states in the nervous system, recent work suggests that σ1 receptors may be important for modulating functions of other tissues. These discoveries have provided novel insights into σ1 receptor structure, function, and ...[more]

PMID: 32668330

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Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by the loss of motoneurons (MNs) in the spinal cord, brainstem and motor cortex, causing progressive paralysis and death. Nowadays, there is no effective therapy and most patients die 2-5 years after diagnosis. Sigma-1R is a transmembrane protein highly expressed in the CNS and specially enriched in MNs. Mutations on the Sigma-1R leading to frontotemporal lobar degeneration-ALS were recently described in human patients. We previously reported the therapeutic role of the selective sigma-1R agonist 2-(4-morpholi-nethyl)1-phenylcyclohexanecarboxylate (PRE-084) in SOD1G93A ALS mice, that promoted spinal MN preservation and extended animal survival by controlling NMDA receptor calcium influx. Resveratrol (RSV, trans-3,4',5-trihydroxystilbene) is a natural polyphenol with promising neuroprotective effects. We recently found that RSV administration to SOD1G93A mice preserves spinal MN function and increases mice survival. These beneficial effects were associated to activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) pathways, leading to the modulation of autophagy and an increase of mitochondrial biogenesis. The main goal of this work was to assess the effect of combined RSV and PRE-084 administration in SOD1G93A ALS mice.MethodsWe determined the locomotor performance of the animals by rotarod test and evaluated spinal motoneuron function using electrophysiological tests.ResultsRSV plus PRE-084 treatment from 8 weeks of age significantly improved locomotor performance and spinal MN function, accompanied by a significant reduction of MN degeneration and an extension of mice lifespan. In agreement with our previous findings, there was an induction of PKC-specific phosphorylation of the NMDA-NR1 subunit and an increased expression and activation of Sirt1 and AMPK in the ventral spinal cord of treated SOD1G93A animals.ConclusionsAlthough combined PRE and RSV treatment significantly ameliorated SOD1G93A mice, it did not show a synergistic effect compared to RSV-only and PRE-084-only treated groups.

Dataset Information

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

Publications

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

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