Comparison of Sigma 1 Receptor Ligands SA4503 and PRE084 to (+)-Pentazocine in the <i>rd10</i> Mouse Model of RP

Wang, Jing; Xiao, Haiyan; Barwick, Shannon R.; Smith, Sylvia B.

doi:10.1167/iovs.61.13.3

Cited by 13 publications

(18 citation statements)

References 63 publications

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“…All the compounds were dissolved in 0.9% saline solution and administered in a volume of 10 mL/kg. The dosage of Sig-1R ligands was chosen based on previous studies showing benefit in MN degeneration, ATR-X syndrome, retinopathy and pain models [24,25,54,55], and preliminary assays in our laboratory. Control animals were administered with saline.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

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

Gaja-Capdevila

Hernández

Zamanillo³

et al. 2021

IJMS

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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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Section: Animals and Experimental Designmentioning

confidence: 99%

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

Gaja-Capdevila

Hernández

Zamanillo³

et al. 2021

IJMS

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“…However, not all S1R agonists show similar beneficial effects in all experimental models. Neither S1R agonists SA4503 nor PRE084 provide neuroprotection in the rd10 model 48 . Importantly, many of the S1R agonists are non-selective drugs, with high affinity for other receptors.…”

Section: Discussionmentioning

confidence: 91%

“…For decades it has been difficult to develop drugs that are neuroprotective both in in vitro and in animal models, and which can also translate into efficacy in human studies of disease 59 . Furthermore, an in vitro effect does not necessarily translate into an in vivo effect 48 . The data garnered from the two glaucoma models used in this study, coupled with the mechanistic and pharmacological studies, together provide a rationale for continuing the investigation of pridopidine in early-phase clinical trials in glaucoma, and potentially other optic neuropathies.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that not all S1R agonists are equal. While (+) pentazocine (PTZ) has beneficial effects both in vitro and in vivo, other S1R activators SA4503 and PRE084 had only beneficial in vitro effects that did not translate to in vivo rescue of RGCs in the rd10 mouse model of retinopathy 48 . These data in two different in vivo models further highlight the translational potential of pridopidine for therapeutic purposes.…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma

Geva¹,

Gershoni-Emek²,

Naia

et al. 2021

Sci Rep

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Optic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

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“…Despite the three Sig-1R compounds assessed, PRE-084, SA4503 and BD1063, have demonstrated potential to bind the Sig-1R, the neuroprotective effects observed in the SOD1 G93A mouse model significantly differed between the three ligands. In the same line, Wang and others compared the Sig-1R ligands SA4503, PRE-084 and pentazocine (PTZ) in a model of severe retinopathy (Wang et al, 2020). In vitro results yielded similar outcomes, whereas neither PRE-084 or SA4503 afforded in vivo protection comparable to PTZ.…”

Section: Discussionmentioning

confidence: 99%

Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1G93A ALS Mice

et al. 2021

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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND). In this study we compared the potential therapeutic effect of three Sig-1R ligands, the agonists PRE-084 and SA4503 and the antagonist BD1063, in the SOD1G93A mouse model of ALS. Pharmacological administration was from 8 to 16 weeks of age, and the neuromuscular function and disease progression were evaluated using nerve conduction and rotarod tests. At the end of follow up (16 weeks), samples were harvested for histological and molecular analyses. The results showed that PRE-084, as well as BD1063 treatment was able to preserve neuromuscular function of the hindlimbs and increased the number of surviving MNs in the treated female SOD1G93A mice. SA4503 tended to improve motor function and preserved neuromuscular junctions (NMJ), but did not improve MN survival. Western blot analyses revealed that the autophagic flux and the endoplasmic reticulum stress, two pathways implicated in the physiopathology of ALS, were not modified with Sig-1R treatments in SOD1G93A mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action.

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Comparison of Sigma 1 Receptor Ligands SA4503 and PRE084 to (+)-Pentazocine in the rd10 Mouse Model of RP

Cited by 13 publications

References 63 publications

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

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

Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma

Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1G93A ALS Mice

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