Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries.

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Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity

Neuroreport ◽

10.1097/00001756-200508010-00018 ◽

2005 ◽

Vol 16 (11) ◽

pp. 1223-1226 ◽

Cited By ~ 76

Author(s):

Agostino Marrazzo ◽

Filippo Caraci ◽

Elisa Trovato Salinaro ◽

Tsung-Ping Su ◽

Agata Copani ◽

...

Keyword(s):

Beta Amyloid ◽

Neuroprotective Effects ◽

Sigma 1 Receptor ◽

Receptor Agonists ◽

Sigma 1

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Neuroprotective effects of cutamesine, a ligand of the sigma-1 receptor chaperone, against noise-induced hearing loss

Journal of Neuroscience Research ◽

10.1002/jnr.23543 ◽

2015 ◽

Vol 93 (5) ◽

pp. 788-795 ◽

Cited By ~ 5

Author(s):

Daisuke Yamashita ◽

Guang-wei Sun ◽

Yong Cui ◽

Shiro Mita ◽

Naoki Otsuki ◽

...

Keyword(s):

Hearing Loss ◽

Noise Induced Hearing Loss ◽

Neuroprotective Effects ◽

Sigma 1 Receptor ◽

Sigma 1

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Neuroprotective effects of high affinity sigma 1 receptor selective compounds

Brain Research ◽

10.1016/j.brainres.2011.12.047 ◽

2012 ◽

Vol 1441 ◽

pp. 17-26 ◽

Cited By ~ 14

Author(s):

Robert R. Luedtke ◽

Evelyn Perez ◽

Shao-Hua Yang ◽

Ran Liu ◽

Suwanna Vangveravong ◽

...

Keyword(s):

Neuroprotective Effects ◽

Sigma 1 Receptor ◽

High Affinity ◽

Sigma 1

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BCL-2 and BAX Protect Adult Mice from Lethal Sindbis Virus Infection but Do Not Protect Spinal Cord Motor Neurons or Prevent Paralysis

Journal of Virology ◽

10.1128/jvi.76.20.10393-10400.2002 ◽

2002 ◽

Vol 76 (20) ◽

pp. 10393-10400 ◽

Cited By ~ 34

Author(s):

Douglas A. Kerr ◽

Thomas Larsen ◽

Susan H. Cook ◽

Yih-Ru Fannjiang ◽

Eunkyung Choi ◽

...

Keyword(s):

Spinal Cord ◽

Cell Death ◽

Motor Neurons ◽

Hind Limb ◽

Sindbis Virus ◽

Apoptotic Cell ◽

Lumbar Spinal Cord ◽

Newborn Mice ◽

Adult Mice ◽

Hind Limb Paralysis

ABSTRACT Cellular proteins that regulate apoptotic cell death can modulate the outcome of Sindbis virus (SV) encephalitis in mice. Both endogenous and overexpressed BCL-2 and BAX proteins protect newborn mice from fatal SV infection by blocking apoptosis in infected neurons. To determine the effects of these cellular factors on the course of infection in older animals, a more neurovirulent SV vector (dsNSV) was constructed from a viral strain that causes both prominent spinal cord infection with hind-limb paralysis and death in weanling mice. This vector has allowed assessment of the effects of BCL-2 and BAX on both mortality and paralysis in these hosts. Similar to newborn hosts, weanling mice infected with dsNSV encoding BCL-2 or BAX survived better than animals infected with control viruses. This finding indicates that BCL-2 and BAX both protect neurons that mediate host survival. Neither cellular factor, however, could suppress the development of hind-limb paralysis or prevent the degeneration of motor neurons in the lumbar spinal cord. Infection of BAX knockout mice with dsNSV demonstrated that endogenous BAX also enhances the survival of animals but has no effect on paralysis. These findings for the spinal cord are consistent with earlier data showing that dying lumbar motor neurons do not exhibit an apoptotic morphology. Thus, divergent cell death pathways are activated in different target populations of neurons during neurovirulent SV infection of weanling mice.

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Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice

Experimental Neurology ◽

10.1016/j.expneurol.2012.06.030 ◽

2012 ◽

Vol 237 (2) ◽

pp. 388-395 ◽

Cited By ~ 31

Author(s):

E. Griesmaier ◽

A. Posod ◽

M. Gross ◽

V. Neubauer ◽

K. Wegleiter ◽

...

Keyword(s):

Brain Injury ◽

Perinatal Brain Injury ◽

Neuroprotective Effects ◽

Receptor Ligand ◽

Newborn Mice ◽

Sigma 1 Receptor ◽

Sigma 1

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Activation of Divergent Neuronal Cell Death Pathways in Different Target Cell Populations during Neuroadapted Sindbis Virus Infection of Mice

Journal of Virology ◽

10.1128/jvi.74.11.5352-5356.2000 ◽

2000 ◽

Vol 74 (11) ◽

pp. 5352-5356 ◽

Cited By ~ 46

Author(s):

Michael B. Havert ◽

Brian Schofield ◽

Diane E. Griffin ◽

David N. Irani

Keyword(s):

Cell Death ◽

Motor Neuron ◽

Motor Neurons ◽

Sindbis Virus ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Lumbar Spinal Cord ◽

Cell Death Pathways ◽

Adult Mice ◽

Lumbar Spinal

ABSTRACT Infection of adult mice with neuroadapted Sindbis virus (NSV) results in a severe encephalomyelitis accompanied by prominent hindlimb paralysis. We find that the onset of paralysis parallels morphologic changes in motor neuron cell bodies in the lumbar spinal cord and in motor neuron axons in ventral nerve roots, many of which are eventually lost over time. However, unlike NSV-induced neuronal cell death found in the brain of infected animals, the loss of motor neurons does not appear to be apoptotic, as judged by morphologic and biochemical criteria. This may be explained in part by the lack of detectable caspase-3 expression in these cells.

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Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

Cells ◽

10.3390/cells8030211 ◽

2019 ◽

Vol 8 (3) ◽

pp. 211 ◽

Cited By ~ 15

Author(s):

Maximilian Christ ◽

Heike Huesmann ◽

Heike Nagel ◽

Andreas Kern ◽

Christian Behl

Keyword(s):

Clinical Investigation ◽

Receptor Activation ◽

Autophagic Flux ◽

Neuroprotective Effects ◽

Sigma 1 Receptor ◽

C Elegans ◽

Protein Clearance ◽

Sigma 1

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.

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Comparison of Neuroprotective Effects of Monomethylfumarate to the Sigma 1 Receptor Ligand (+)-Pentazocine in a Murine Model of Retinitis Pigmentosa

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.61.3.5 ◽

2020 ◽

Vol 61 (3) ◽

pp. 5 ◽

Cited By ~ 4

Author(s):

Haiyan Xiao ◽

Jing Wang ◽

Alan Saul ◽

Sylvia B. Smith

Keyword(s):

Retinitis Pigmentosa ◽

Murine Model ◽

Neuroprotective Effects ◽

Receptor Ligand ◽

Sigma 1 Receptor ◽

Sigma 1

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Evaluating disease-modifying effects of a sigma-1 receptor agonist in an animal model of ALS

10.14293/s2199-1006.1.sor-.pp0dbwj.v1 ◽

2020 ◽

Author(s):

Hector Estevez-Silva ◽

Tomás Mediavilla ◽

Bruno Lima-Giacobbo ◽

Fahad Sultan ◽

Daniel Marcellino

Keyword(s):

Mouse Model ◽

Gait Analysis ◽

Motor Neurons ◽

Protein Misfolding ◽

Motor Coordination ◽

Screen Test ◽

Motor Deficits ◽

Sigma 1 Receptor ◽

Delayed Onset ◽

Sigma 1

Around 12-20% of familial amyotrophic lateral sclerosis (fALS) are related to mutations in Cu/Zn superoxide dismutase (SOD1) that produce degeneration of motor neurons by a toxic gain-of-function. The insertion of the human SOD1 G93A mutation in transgenic mice produces cachexia, hindlimb paralysis and subsequent death due to SOD1 protein misfolding and aggregation. The sigma-1 receptor (S1R) prevents aberrant protein conformations by acting as a molecular chaperone. In addition, some mutations in S1R are linked to juvenile ALS indicating an important role for S1R. Here, we used a delayed onset G93A mouse model that allowed for a prolonged monitoring of preclinical symptoms before onset of the severe phenotype with subsequent death at 28-32 weeks. At 18 weeks of age, and prior to the appearance of any symptoms, S1R agonist or vehicle was continuously administered during 4 weeks by subcutaneous osmotic pumps. Mice were monitored weekly and three behavioral tests were used to monitor muscle strength, motor coordination and balance: Inverted Screen Test (IST), the Pole Test (PT) and Gait Analysis. We found that mice treated with S1R agonist were resistant to weight loss observed in vehicle treated mice and this negatively affected performance in IST and PT, where significant differences between groups were not observed. However, 5 weeks after S1R agonist treatment had ended, improved parameters in Gait Analysis were observed in treated mice compared to untreated mice. Our results indicate that a S1R agonist can modify the progression of ALS-associated motor deficits in a delayed onset SOD-1 G93A mouse model.

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