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 journalArticle

2 Scopus citations

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 - Jul 2019

Keywords

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

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