Role of sigma 1 receptor in retinal degeneration of the Ins2Akita/+ murine model of diabetic retinopathy

Jing Wang, Xuezhi Cui, Penny Roon, Sylvia B Smith

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: Sigma receptor 1 (Sigma1R), a nonopioid putative molecular chaperone, has neuroprotective properties in retina. This study sought to determine whether delaying administration of (+)-pentazocine, a high-affinity Sigma1R ligand after onset of diabetes in Ins2Akita/+ diabetic mice would afford retinal neuroprotection and to determine consequences on retinal phenotype in Ins2Akita/+ diabetic mice in the absence of Sigma1R. Methods: Ins2Akita/+ diabetic and WT mice received intraperitoneal injections of (+)-pentazocine beginning 4 or 8 weeks after onset of diabetes; eyes were harvested at 25 weeks. Retinal histologic sections were analyzed to determine thicknesses of retinal layers, number of ganglion cells, and evidence of gliosis (increased glial fibrillary acidic protein levels). Ins2Akita/+/Sig1R−/−mice were generated and subjected to in vivo assessment of retinal architecture (optical coherence tomography [OCT]) and retinal vasculature using fluorescein angiography (FA) at 12 and 16 weeks compared with age-matched Ins2Akita/+ mice. Eyes were then harvested for retinal morphometric assessment and gliosis assessment. Results: Wild-type mice had 13 ± 0.06 cells/100 μm retinal length; cell bodies in Ins2Akita/+ mice injected 4 and 8 weeks after onset of diabetes with (+)-pentazocine retained significantly more ganglion cells compared with Ins2Akita/+ mice (9 ± 0.04) and demonstrated significant attenuation of gliosis. Ins2Akita/+/Sig1R−/−mouse retinas, analyzed to determine whether the Ins2Akita/+ phenotype was accelerated when lacking Sigma1R, revealed increased nerve fiber layer thickness (OCT), evidence of vitreal opacities, and vessel beading (FA) compared with Ins2Akita/+ mice. Morphometric analysis revealed significantly fewer ganglion cells in Ins2Akita/+/Sig1R−/−mice compared with Ins2Akita/+ mice. Conclusions: Sigma1R may be a novel retinal stress modulator, and targeting it even after disease onset may afford retinal neuroprotection.

Original languageEnglish (US)
Pages (from-to)2770-2781
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number6
DOIs
StatePublished - May 1 2016

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Retinal Degeneration
Diabetic Retinopathy
Pentazocine
Gliosis
Ganglia
Fluorescein Angiography
Optical Coherence Tomography
Retina
sigma-1 receptor
Phenotype
Molecular Chaperones
Glial Fibrillary Acidic Protein
Intraperitoneal Injections
Nerve Fibers
Cell Count

Keywords

  • (+)-pentazocine
  • FA
  • Fluorescein angiography
  • GFAP
  • Ganglion cells
  • Mouse
  • OCT
  • Retina
  • Sigma 1 receptor (σ1R)

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Role of sigma 1 receptor in retinal degeneration of the Ins2Akita/+ murine model of diabetic retinopathy. / Wang, Jing; Cui, Xuezhi; Roon, Penny; Smith, Sylvia B.

In: Investigative Ophthalmology and Visual Science, Vol. 57, No. 6, 01.05.2016, p. 2770-2781.

Research output: Contribution to journalArticle

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abstract = "Purpose: Sigma receptor 1 (Sigma1R), a nonopioid putative molecular chaperone, has neuroprotective properties in retina. This study sought to determine whether delaying administration of (+)-pentazocine, a high-affinity Sigma1R ligand after onset of diabetes in Ins2Akita/+ diabetic mice would afford retinal neuroprotection and to determine consequences on retinal phenotype in Ins2Akita/+ diabetic mice in the absence of Sigma1R. Methods: Ins2Akita/+ diabetic and WT mice received intraperitoneal injections of (+)-pentazocine beginning 4 or 8 weeks after onset of diabetes; eyes were harvested at 25 weeks. Retinal histologic sections were analyzed to determine thicknesses of retinal layers, number of ganglion cells, and evidence of gliosis (increased glial fibrillary acidic protein levels). Ins2Akita/+/Sig1R−/−mice were generated and subjected to in vivo assessment of retinal architecture (optical coherence tomography [OCT]) and retinal vasculature using fluorescein angiography (FA) at 12 and 16 weeks compared with age-matched Ins2Akita/+ mice. Eyes were then harvested for retinal morphometric assessment and gliosis assessment. Results: Wild-type mice had 13 ± 0.06 cells/100 μm retinal length; cell bodies in Ins2Akita/+ mice injected 4 and 8 weeks after onset of diabetes with (+)-pentazocine retained significantly more ganglion cells compared with Ins2Akita/+ mice (9 ± 0.04) and demonstrated significant attenuation of gliosis. Ins2Akita/+/Sig1R−/−mouse retinas, analyzed to determine whether the Ins2Akita/+ phenotype was accelerated when lacking Sigma1R, revealed increased nerve fiber layer thickness (OCT), evidence of vitreal opacities, and vessel beading (FA) compared with Ins2Akita/+ mice. Morphometric analysis revealed significantly fewer ganglion cells in Ins2Akita/+/Sig1R−/−mice compared with Ins2Akita/+ mice. Conclusions: Sigma1R may be a novel retinal stress modulator, and targeting it even after disease onset may afford retinal neuroprotection.",
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AU - Cui, Xuezhi

AU - Roon, Penny

AU - Smith, Sylvia B

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N2 - Purpose: Sigma receptor 1 (Sigma1R), a nonopioid putative molecular chaperone, has neuroprotective properties in retina. This study sought to determine whether delaying administration of (+)-pentazocine, a high-affinity Sigma1R ligand after onset of diabetes in Ins2Akita/+ diabetic mice would afford retinal neuroprotection and to determine consequences on retinal phenotype in Ins2Akita/+ diabetic mice in the absence of Sigma1R. Methods: Ins2Akita/+ diabetic and WT mice received intraperitoneal injections of (+)-pentazocine beginning 4 or 8 weeks after onset of diabetes; eyes were harvested at 25 weeks. Retinal histologic sections were analyzed to determine thicknesses of retinal layers, number of ganglion cells, and evidence of gliosis (increased glial fibrillary acidic protein levels). Ins2Akita/+/Sig1R−/−mice were generated and subjected to in vivo assessment of retinal architecture (optical coherence tomography [OCT]) and retinal vasculature using fluorescein angiography (FA) at 12 and 16 weeks compared with age-matched Ins2Akita/+ mice. Eyes were then harvested for retinal morphometric assessment and gliosis assessment. Results: Wild-type mice had 13 ± 0.06 cells/100 μm retinal length; cell bodies in Ins2Akita/+ mice injected 4 and 8 weeks after onset of diabetes with (+)-pentazocine retained significantly more ganglion cells compared with Ins2Akita/+ mice (9 ± 0.04) and demonstrated significant attenuation of gliosis. Ins2Akita/+/Sig1R−/−mouse retinas, analyzed to determine whether the Ins2Akita/+ phenotype was accelerated when lacking Sigma1R, revealed increased nerve fiber layer thickness (OCT), evidence of vitreal opacities, and vessel beading (FA) compared with Ins2Akita/+ mice. Morphometric analysis revealed significantly fewer ganglion cells in Ins2Akita/+/Sig1R−/−mice compared with Ins2Akita/+ mice. Conclusions: Sigma1R may be a novel retinal stress modulator, and targeting it even after disease onset may afford retinal neuroprotection.

AB - Purpose: Sigma receptor 1 (Sigma1R), a nonopioid putative molecular chaperone, has neuroprotective properties in retina. This study sought to determine whether delaying administration of (+)-pentazocine, a high-affinity Sigma1R ligand after onset of diabetes in Ins2Akita/+ diabetic mice would afford retinal neuroprotection and to determine consequences on retinal phenotype in Ins2Akita/+ diabetic mice in the absence of Sigma1R. Methods: Ins2Akita/+ diabetic and WT mice received intraperitoneal injections of (+)-pentazocine beginning 4 or 8 weeks after onset of diabetes; eyes were harvested at 25 weeks. Retinal histologic sections were analyzed to determine thicknesses of retinal layers, number of ganglion cells, and evidence of gliosis (increased glial fibrillary acidic protein levels). Ins2Akita/+/Sig1R−/−mice were generated and subjected to in vivo assessment of retinal architecture (optical coherence tomography [OCT]) and retinal vasculature using fluorescein angiography (FA) at 12 and 16 weeks compared with age-matched Ins2Akita/+ mice. Eyes were then harvested for retinal morphometric assessment and gliosis assessment. Results: Wild-type mice had 13 ± 0.06 cells/100 μm retinal length; cell bodies in Ins2Akita/+ mice injected 4 and 8 weeks after onset of diabetes with (+)-pentazocine retained significantly more ganglion cells compared with Ins2Akita/+ mice (9 ± 0.04) and demonstrated significant attenuation of gliosis. Ins2Akita/+/Sig1R−/−mouse retinas, analyzed to determine whether the Ins2Akita/+ phenotype was accelerated when lacking Sigma1R, revealed increased nerve fiber layer thickness (OCT), evidence of vitreal opacities, and vessel beading (FA) compared with Ins2Akita/+ mice. Morphometric analysis revealed significantly fewer ganglion cells in Ins2Akita/+/Sig1R−/−mice compared with Ins2Akita/+ mice. Conclusions: Sigma1R may be a novel retinal stress modulator, and targeting it even after disease onset may afford retinal neuroprotection.

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KW - FA

KW - Fluorescein angiography

KW - GFAP

KW - Ganglion cells

KW - Mouse

KW - OCT

KW - Retina

KW - Sigma 1 receptor (σ1R)

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