Hybrid compound sa-2 is neuroprotective in animal models of retinal ganglion cell death

Dorota Luiza Stankowska, Adnan Dibas, Linya Li, Wei Zhang, Vignesh R. Krishnamoorthy, Sai Chavala, Tam Pho Nguyen, Thomas Yorio, Dorette Zoe Ellis, Suchismita Acharya

Research output: Contribution to journalArticleResearchpeer-review

Abstract

PURPOSE. Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress–induced retinal ganglion cell (RGC) death in neurodegenerative animal models. METHODS. Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5% O2) conditions. RESULTS. Compound SA-2 did not induce any appreciable change in retinal thickness, or in a-or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2% wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P ≤ 0.001) in comparison with the vehicle and control groups. CONCLUSIONS. Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.

Original languageEnglish
Pages (from-to)3064-3073
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume60
Issue number8
DOIs
StatePublished - 1 Jul 2019

Fingerprint

Retinal Ganglion Cells
Cell Death
Nerve Crush
Animal Models
Retina
Ischemic Optic Neuropathy
Choroid
Reperfusion
Rodentia
Cell Survival
Antioxidants
Intravitreal Injections
Cytoprotection
Nitric Oxide Donors
Optical Coherence Tomography
Wounds and Injuries
Neuroprotective Agents
Optic Nerve
Reperfusion Injury
Inbred C57BL Mouse

Keywords

  • Glaucoma
  • Hybrid small molecule
  • Neuroprotection
  • Nitric oxide
  • RGC
  • SOD

Cite this

@article{ca134c8cef334e3eb18ca9bb983afed6,
title = "Hybrid compound sa-2 is neuroprotective in animal models of retinal ganglion cell death",
abstract = "PURPOSE. Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress–induced retinal ganglion cell (RGC) death in neurodegenerative animal models. METHODS. Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5{\%} O2) conditions. RESULTS. Compound SA-2 did not induce any appreciable change in retinal thickness, or in a-or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2{\%} wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P ≤ 0.001) in comparison with the vehicle and control groups. CONCLUSIONS. Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.",
keywords = "Glaucoma, Hybrid small molecule, Neuroprotection, Nitric oxide, RGC, SOD",
author = "Stankowska, {Dorota Luiza} and Adnan Dibas and Linya Li and Wei Zhang and Krishnamoorthy, {Vignesh R.} and Sai Chavala and Nguyen, {Tam Pho} and Thomas Yorio and Ellis, {Dorette Zoe} and Suchismita Acharya",
year = "2019",
month = "7",
day = "1",
doi = "10.1167/iovs.18-25999",
language = "English",
volume = "60",
pages = "3064--3073",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "8",

}

Hybrid compound sa-2 is neuroprotective in animal models of retinal ganglion cell death. / Stankowska, Dorota Luiza; Dibas, Adnan; Li, Linya; Zhang, Wei; Krishnamoorthy, Vignesh R.; Chavala, Sai; Nguyen, Tam Pho; Yorio, Thomas; Ellis, Dorette Zoe; Acharya, Suchismita.

In: Investigative Ophthalmology and Visual Science, Vol. 60, No. 8, 01.07.2019, p. 3064-3073.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Hybrid compound sa-2 is neuroprotective in animal models of retinal ganglion cell death

AU - Stankowska, Dorota Luiza

AU - Dibas, Adnan

AU - Li, Linya

AU - Zhang, Wei

AU - Krishnamoorthy, Vignesh R.

AU - Chavala, Sai

AU - Nguyen, Tam Pho

AU - Yorio, Thomas

AU - Ellis, Dorette Zoe

AU - Acharya, Suchismita

PY - 2019/7/1

Y1 - 2019/7/1

N2 - PURPOSE. Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress–induced retinal ganglion cell (RGC) death in neurodegenerative animal models. METHODS. Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5% O2) conditions. RESULTS. Compound SA-2 did not induce any appreciable change in retinal thickness, or in a-or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2% wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P ≤ 0.001) in comparison with the vehicle and control groups. CONCLUSIONS. Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.

AB - PURPOSE. Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress–induced retinal ganglion cell (RGC) death in neurodegenerative animal models. METHODS. Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5% O2) conditions. RESULTS. Compound SA-2 did not induce any appreciable change in retinal thickness, or in a-or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2% wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P ≤ 0.001) in comparison with the vehicle and control groups. CONCLUSIONS. Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.

KW - Glaucoma

KW - Hybrid small molecule

KW - Neuroprotection

KW - Nitric oxide

KW - RGC

KW - SOD

UR - http://www.scopus.com/inward/record.url?scp=85069696726&partnerID=8YFLogxK

U2 - 10.1167/iovs.18-25999

DO - 10.1167/iovs.18-25999

M3 - Article

VL - 60

SP - 3064

EP - 3073

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 8

ER -