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

Dorota L. Stankowska; Adnan Dibas; Linya Li; Wei Zhang; Vignesh R. Krishnamoorthy; Sai H. Chavala; Tam Pho Nguyen; Thomas Yorio; Dorette Z. Ellis; Suchismita Acharya

doi:10.1167/iovs.18-25999

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

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

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

P_URPOSE. 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. M_ETHODS. 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. R_ESULTS. 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. C_ONCLUSIONS. 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 language	English
Pages (from-to)	3064-3073
Number of pages	10
Journal	Investigative Ophthalmology and Visual Science
Volume	60
Issue number	8
DOIs	https://doi.org/10.1167/iovs.18-25999
State	Published - Jul 2019

Keywords

Glaucoma
Hybrid small molecule
Neuroprotection
Nitric oxide
RGC
SOD

Access to Document

10.1167/iovs.18-25999

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 L.} and Adnan Dibas and Linya Li and Wei Zhang and Krishnamoorthy, {Vignesh R.} and Chavala, {Sai H.} and Nguyen, {Tam Pho} and Thomas Yorio and Ellis, {Dorette Z.} and Suchismita Acharya",

note = "Funding Information: Supported by Bright Focus Foundation grant (G2018056) to Suchismita Acharya (PI) and partial support from Fight for Sight Grant-In-Aid to Dorota L. Stankowska (PI). Disclosure: D.L. Stankowska, None; A. Dibas, None; L. Li, None; W. Zhang, None; V.R. Krishnamoorthy, None, S.H. Chavala, None; T.P. Nguyen, None; T. Yorio, None; D.Z. Ellis, None; S. Acharya, None Publisher Copyright: {\textcopyright} 2019, Association for Research in Vision and Ophthalmology Inc.. All rights reserved.",

year = "2019",

month = jul,

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",

}

TY - JOUR

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

AU - Stankowska, Dorota L.

AU - Dibas, Adnan

AU - Li, Linya

AU - Zhang, Wei

AU - Krishnamoorthy, Vignesh R.

AU - Chavala, Sai H.

AU - Nguyen, Tam Pho

AU - Yorio, Thomas

AU - Ellis, Dorette Z.

AU - Acharya, Suchismita

N1 - Funding Information: Supported by Bright Focus Foundation grant (G2018056) to Suchismita Acharya (PI) and partial support from Fight for Sight Grant-In-Aid to Dorota L. Stankowska (PI). Disclosure: D.L. Stankowska, None; A. Dibas, None; L. Li, None; W. Zhang, None; V.R. Krishnamoorthy, None, S.H. Chavala, None; T.P. Nguyen, None; T. Yorio, None; D.Z. Ellis, None; S. Acharya, None Publisher Copyright: © 2019, Association for Research in Vision and Ophthalmology Inc.. All rights reserved.

PY - 2019/7

Y1 - 2019/7

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

C2 - 31348824

AN - SCOPUS:85069696726

SN - 0146-0404

VL - 60

SP - 3064

EP - 3073

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

IS - 8

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this