Age-dependent neuroprotection of retinal ganglion cells by tempol-C8 acyl ester in a rat NMDA toxicity model

Fiedorowicz, Michał; Ręjdak, Robert; Schuettauf, Frank; Woźniak, Michał; Grieb, Paweł; Thaler, Sebastian

doi:10.5114/fn.2014.45570

Cited by 3 publications

(3 citation statements)

References 24 publications

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“…A hydrophobic analog of TEMPOL, TEMPOL-C8 acyl ester was more potent (1 mg/kg) when delivered intraperitoneally in protecting RGC from NMDA-induced excitotoxic death than its hydrophilic equivalent 4-hydroxy TEMPOL. 44 Here we have performed an ivt dosing of SA-2 to the retinas to demonstrate the potency and efficacy of SA-2 in protecting against RGC death in ONC and I/R injuries. The biodistribution results showed that 2% (75 mM) of single ivt dose of compound SA-2 (vitreous concentration~15 mM) can provide 75-230 pM concentration of SA-2 to the retina and choroid in mouse eyes after 1 hour of dosing.…”

Section: Discussionmentioning

confidence: 99%

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death

Stankowska

Dibas

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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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% O 2) 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.

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Section: Discussionmentioning

confidence: 99%

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death

Stankowska

Dibas

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Intravitreal administration of NMDA results in a selective RGC death in a dose-dependent manner (Nakazawa et al, 2005). After application of a dose corresponding to our experimental setting, RGC number starts to decrease after 6 h. After 24 h RGC count decrease by over 80% and after 7 days by over 90% (Manabe and Lipton, 2003; Fiedorowicz et al, 2014). After NMDA injection TUNEL-positive cells are observed both in the ganglion cell layer and the inner nuclear layer that contains both neurons (amacrine, horizontal, and bipolar cells) and glial cells (Müller cells) (Manabe and Lipton, 2003).…”

Section: Discussionmentioning

confidence: 83%

“…Retinal ganglion cell (RGC) damage was induced by intravitreal NMDA injection as we previously described (Thaler et al, 2010a; Fiedorowicz et al, 2014). Intravitreal NMDA injection induces inner retina damage by overstimulation of NMDA receptors for glutamate (i.e., excitotoxicity), the main excitatory neurotransmitter of the retinal neurons.…”

Section: Methodsmentioning

confidence: 99%

Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes

et al. 2019

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Kynurenines, products of tryptophan (TRP) metabolism, display neurotoxic (e.g., 3-hydroxykynurenine; 3-HK), or neuroprotective (e.g., kynurenic acid; KYNA) properties. Imbalance between the enzymes constituting the kynurenine pathway (KP) plays a role in several disease, including neurodegeneration. In this study, we track changes in concentrations of tryptophan and its selected metabolites after damage to retinal ganglion cells and link this data with expression of KP enzymes. Brown-Norway rats were subjected to intravitreal N-methyl-D-aspartate (NMDA) injection or partial optic nerve crush (PONC). Retinas were collected 2 and 7 days after the completion of PONC or NMDA injection. Concentrations of TRP, kynurenine (KYN), and KYNA were determined by high performance liquid chromatography (HPLC). Data on gene expression in the rat retina were extracted from GEO, public microarray experiments database. Two days after NMDA injection concentration of TRP decreased, while KYN and KYNA increased. At day 7 compared to day 2 decrease of KYN, KYNA and further reduction of TRP concentration were observed, but on day 7 KYN concentration was still elevated when compared to controls. At day 2 and 7 after NMDA injection no statistically significant alterations of 3-HK were observed. TRP and 3-HK concentration was higher in PONC group than in controls. However, both KYN and KYNA were lower. At day seven concentration of TRP, 3-HK, and KYN was higher, whereas concentration of KYNA declined. In vivo experiments showed that retinal damage or optic nerve lesion affect TRP metabolism via KP. However, the pattern of changes in metabolite concentrations was different depending on the model. In particular, in PONC KYNA and KYN levels were decreased and 3-HK elevated. These observations correspond with data on expression of genes encoding KP enzymes assessed after optic nerve crush or transection. After intraorbital optic nerve crush downregulation of KyatI and KyatIII between 24 h and 3 days after procedure was observed. Kmo expression was transiently upregulated (12 h after the procedures). After intraorbital optic nerve transsection (IONT) Kmo expression was upregulated after 48 h and 7 days, KyatI and KyatIII were downregulated after 12, 48 h, 7 days and upregulated after 15 days. Collected data point to the conclusion that development of therapeutic strategies targeting the KP could be beneficial in diseases involving retinal neurodegeneration.

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Dose-dependent effects of NMDA on retinal and optic nerve morphology in rats

et al. 2019

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Age-dependent neuroprotection of retinal ganglion cells by tempol-C8 acyl ester in a rat NMDA toxicity model

Abstract: A b s t r a c t

Cited by 3 publications

References 24 publications

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death

Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes

Dose-dependent effects of NMDA on retinal and optic nerve morphology in rats

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