Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

Abstract

Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.

The Effects of Terminal Tagging on Homomeric Interactions of the Sigma 1 Receptor

“…Sigma 1 receptor has been extensively studied at molecular level using biochemical and pharmacological approaches (Hayashi and Su, 2007;Narayanan et al, 2011;Gromek et al, 2014;Katz et al, 2016;Romero et al, 2016;Nguyen et al, 2017;Mavylutov et al, 2018). In this study, we investigated the effects of terminal tagging on σ1R oligomerization and pharmacology, and revealed the ability of N-terminal modification to interfere with the oligomerization of σ1R.…”

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J

“…This channel is the principal pathway for calcium influx from the ER stores to the mitochondrion, with adenosine triphosphate production rate depending significantly on calcium concentration (9). s1R is involved in synaptic plasticity and neuroprotection, with human postmortem evidence of altered expression in Alzheimer disease (10)(11)(12). Early PET imaging studies have used the radioligand 11 C-SA-4503 ( 11 C-labeled 1-[2-(3,4dimethoxyphenthyl)]-4-(3-phenylpropyl)-piperazine dihydrochloride) to evaluate s1R status in healthy, Parkinson disease, and Alzheimer disease cohorts, though an evaluation of the optimal imaging methodology for 11 C-SA-4503 has yet to be established (13)(14)(15).…”

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

“…Neurodegeneration can be caused by chronic disease progression or by acute injury (cerebral ischemia-stroke or trauma) [67]. Ischemic stroke represents a vascular ailment with neurological consequences produced by the obstruction of the arteries in a part of the brain, therefore by blood supply privation [68].…”

“…Ischemic stroke represents a vascular ailment with neurological consequences produced by the obstruction of the arteries in a part of the brain, therefore by blood supply privation [68]. Stroke can determine long-term neurological and psychiatric impairments, its therapy being focused on confining secondary injury processes [67].…”