Late-Onset Inner Retinal Dysfunction in Mice Lacking Sigma Receptor 1 (σR1)

Ha, Yonju; Saul, Alan; Tawfik, Amany; Williams, Cory; Bollinger, Kathryn E.; Smith, Robert G.; Tachikawa, Masanori; Zorrilla, Eric P.; Ganapathy, Vadivel; Smith, Sylvia B.

doi:10.1167/iovs.11-8169

Cited by 68 publications

(113 citation statements)

References 51 publications

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“…We do not know which retinal cell type-the degenerating neuron or supportive cells such as Müller cells-is targeted using (+)-PTZ. Earlier in vitro studies demonstrated attenuation of oxidative stress-induced death of isolated RGCs when pretreated with (+)-PTZ, suggesting that the ligand has a direct protective effect on neurons (29). However, (+)-PTZ treatment also can attenuate cytokine release (16) and oxidative stress (31) in isolated Müller cells.…”

Section: Discussionmentioning

confidence: 97%

“…Sig1R is bound to ceramide-enriched microdomains in complex with the binding protein/glucose regulated protein 78 (GRP78/BiP) protein and functions as an ER chaperone involved in Ca 2+ mobilization (12). It regulates neuronal nitric oxide synthase, prevents apoptotic neuronal cell death (13,14), and modulates the activity of pleiotropic transcription factors including NFκB (15,16) (27) that is worsened by stress such as optic nerve crush or diabetes (28)(29)(30). Retinal Müller glial cells isolated from Sig1R…”

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confidence: 99%

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Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Wang

Saul

Roon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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119

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Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β rd10 (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Wang

Saul

Roon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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119

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“…ROS has been reported to be involved in signaling RGC death by acting as a second messenger and/or modulating protein function in conditions such as glaucoma [121][122][123] and ischemic injuries of the retina [107,124]. Hypoxia and oxidative stress are also involved in the development of diabetic retinopathy [125] resulting in RGC death [126]. Increased lipid peroxidation (LPO) and depletion of antioxidants such as GSH in response to hypoxia/reoxygenation have been reported by us to cause damage to RGCs [43].…”

Section: Hypoxia and Oxidative Stressmentioning

confidence: 99%

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

Kaur¹,

Rathnasamy²,

Foulds³

et al. 2015

J Neurol Exp Neurosci

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Loss of retinal ganglion cells (RGCs) occurs in retinal degenerative diseases, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion and ischemic central retinal vein thrombosis in adults and in retinopathy of prematurity in infants. A critical role of hypoxia, which underlies most of the above disorders, has been reported in causing RGC death. Disruption of blood-retinal barrier (BRB) occurs due to increased production of vascular endothelial growth factor and nitric oxide in response to hypoxia resulting in extravasation of serum derived substances and retinal edema and this may be one of important factors mediating RGC death. Activation of microglial cells in response to hypoxia and subsequent increased release of proinflammatory cytokines by them such as tumor-necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) target the TNF-receptor 1 and IL-receptor 1 on RGCs. Excess release of glutamate in retinal tissue under hypoxia activates the ionotropic glutamate receptors causing excitotoxicity through increased influx of calcium into the RGCs. Increased production of TNF-α, IL-1β and enhanced intracellular calcium results in RGC death through activating several pathways such as caspase signaling, mitochondrial dysfunction and oxidative stress. In our investigations, melatonin, an antioxidant, was shown to reduce RGC death in the adult and neonatal hypoxic retina, through suppression of TNF-α, IL-1β and glutamate levels as well as oxidative stress. Moreover, the function and structure of BRB was well preserved in these animals along with reduction in retinal edema. In view of our observations, we suggest that melatonin could be considered as a therapeutic agent to reduce RGC death in various retinal pathologies, in addition to other potential drugs/molecules of therapeutic interest that could render protection to RGCs. However, future in-depth research on the effects of melatonin on the retina under hypoxic conditions needs to be undertaken to explore its full potential in preventing/ameliorating RGC death. Factors Mediating RGC DeathSeveral factors induced or upregulated by hypoxia may be involved in causing RGC death. These factors include, among others, disruption of the blood-retinal barrier, activation of microglial cells and the accompanying enhanced release of inflammatory cytokines and excess release and accumulation of glutamate in the retinal tissues. Hypoxia and the blood-retinal barrierThe BRB regulates the passage of molecules from blood into the retina [11,12]. It consists of an inner BRB formed by the tight junctions (TJ) between capillary endothelial cells and an outer barrier formed by TJ between retinal pigment epithelial cells [12][13][14][15][16]. The TJ are made up of transmembrane proteins such as occludin, claudin-5 and cytoplasmic proteins such as zona occludens (ZO)-1 that are structurally and functionally important for maintaining the integrity of the BRB. The proper functioning of the inner BRB also requires the collective co...

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“…The sources and concentrations of primary and secondary antibodies are provided in the Table. Retinal cryosections were prepared from cbs þ/þ , cbs þ/À , and cbs À/À mice per our previously described method. 21 Sections were fixed with 4% paraformaldehyde, washed with PBS-Triton X-100, incubated with Power Block (BioGenex), and then incubated with primary antibody for either 3 hours at 378C or overnight at 48C; the sections were washed thrice with PBSTriton X-100 followed by incubation with secondary antibody for 1 hour at 378C. Sections were washed with PBS-Triton X-100 and coverslipped with Fluoroshield with 4 0 6-diamidino-2-phenylindole (DAPI) (Sigma Chemical Corp., St. Louis, MO) to label nuclei.…”

Section: Immunofluorescence Of Vascular Markers In Retinal Cryosectionsmentioning

confidence: 99%

Alterations of Retinal Vasculature in Cystathionine-Beta-Synthase Mutant Mice, a Model of Hyperhomocysteinemia

Tawfik

Al‐Shabrawey

Roon³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Mice with moderate/severe hyperhomocysteinemia due to deficiency or absence of the cbs gene encoding cystathionine-beta-synthase (CBS) have marked retinal disruption, ganglion cell loss, optic nerve mitochondrial dysfunction, and ERG defects; those with mild hyperhomocysteinemia have delayed retinal morphological/functional phenotype. Excess homocysteine is a risk factor for cardiovascular diseases; however, it is not known whether excess homocysteine alters retinal vasculature. METHODS. Cbs, and cbs À/À mice (age~3 weeks) were subjected to angiography; retinas were harvested for cryosections, flat-mount preparations, or trypsin digestion and subjected to immunofluorescence microscopy to visualize vessels using isolectin-B4, to detect angiogenesis using anti-VEGF and anti-endoglin (anti-CD105) and activated glial cells (anti-glial fibrillary acidic protein [anti-GFAP]) and to investigate the blood-retinal barrier using the tight junction markers zonula occludens-1 (ZO-1) and occludin. Expression RESULTS. Angiography revealed vascular leakage in cbs À/À mice; immunohistochemical analysis demonstrated vascular patterns consistent with ischemia; isolectin-B4 labeling revealed a capillary-free zone centrally and new vessels with capillary tufts midperipherally. This was associated with increased vegf mRNA and protein, CD105, and GFAP in cbs À/À retinas concomitant with a marked decrease in ZO-1 and occludin. Homocysteine-treated HRECs showed increased permeability.CONCLUSIONS. Severe elevation of homocysteine in cbs À/À mutant mice is accompanied by alterations in retinal vasculature (ischemia, neovascularization, and incompetent bloodretinal barrier). The marked disruption of retinal structure and decreased visual function reported in cbs À/À mice may reflect vasculopathy as well as neuropathy. (Invest Ophthalmol Vis Sci. 2013;54:939-949)

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Late-Onset Inner Retinal Dysfunction in Mice Lacking Sigma Receptor 1 (σR1)

Abstract: These data suggest that lack of σR1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy.

Cited by 68 publications

References 51 publications

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

Alterations of Retinal Vasculature in Cystathionine-Beta-Synthase Mutant Mice, a Model of Hyperhomocysteinemia

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