New GABA modulators protect photoreceptor cells from light‐induced degeneration in mouse models

Schur, Rebecca; Gao, Songqi; Yu, Guan‐Ping; Chen, Yu; Maeda, Akiko; Palczewski, Krzysztof; Lü, Zheng Rong

doi:10.1096/fj.201701250r

Cited by 12 publications

(12 citation statements)

References 70 publications

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“…Previous studies have shown that acute exposure to light can promote apoptosis of retinal pigmented epithelium cells and photoreceptors, intensifying the progression of neurodegenerative diseases of the eye [8], and several studies have demonstrated that blue, or blue-rich white LEDs, are more toxic because they can initiate damage and death of photoreceptors more easily [9,10,11,12].…”

Section: Introductionmentioning

confidence: 99%

Intravitreal injection of peptides PnPa11 and PnPa13, derivatives of Phoneutria nigriventer spider venom, prevents retinal damage

Dourado

Silva

Toledo

et al. 2020

J. Venom. Anim. Toxins incl. Trop. Dis

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Background: PnPa11 and PnPa13 are synthetic peptides derived from Phoneutria nigriventer spider venom, which display antinociceptive and neuroprotective properties. In this work, we evaluated the safety of intravitreal use and the neuroprotective effect of these peptides. Methods: The cytotoxicity and the antiangiogenic activity of these peptides were evaluated by the sulforhodamine-B method and chicken chorioallantoic membrane (CAM) assay, respectively. The in vivo safety was analyzed in Wistar rats that were intravitreally injected with different doses (0.50; 1.25; 2.50; 3.75 and 5.00 µg/mL) of these peptides (right eye, n = 6). The retinal function was assessed by electroretinography exams (ERG), intraocular pressure (IOP), and histological analyzes. In order to investigate the neuroprotective effect, Wistar rats received intravitreal injections (right eye, n = 6) of peptides at 1.25 µg/mL and then were exposed to blue LED light. In addition, the visual function and the retinal microstructure were verified. Results: Cytotoxicity analyses demonstrated that the peptides did not present any toxicity over ARPE-19 (adult retinal pigmented epithelial) cell line and the antiangiogenic study highlighted that the peptides promoted the reduction of blood vessels. The intravitreal injection did not cause major changes, neither induced any irreversible damage. In the retinal degeneration assay, the ERG records demonstrated that the prior treatment with PnPa11 and PnPa13 protected the retina from damage. Morphological analyses confirmed the ERG findings. Immunoblotting analyses revealed that PnPa11 increased Erk1/2, NR2A, and NR2B retinal expression after the light stress model, but did not cause Akt1 activation, while PnPa13 prevented Erk1/2 and Akt1 dephosphorylation. Conclusions: The intraocular administration of these peptides was well tolerated and presented protective activity against retinal degeneration, suggesting the potential use of these peptides as neuroprotectors in the ophthalmological field.

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Section: Introductionmentioning

confidence: 99%

Intravitreal injection of peptides PnPa11 and PnPa13, derivatives of Phoneutria nigriventer spider venom, prevents retinal damage

Dourado

Silva

Toledo

et al. 2020

J. Venom. Anim. Toxins incl. Trop. Dis

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“…Previously, several studies showed that the inhibitory signaling progresses laterally through the retina. It was mediated mainly by GABA via amacrine cells and horizontal cells (Schur et al, 2018;Moore-Dotson and Eggers, 2019). The mCherry signal in amacrine cells was weakened, implicating that the inhibition signal may be interrupted.…”

Section: Discussionmentioning

confidence: 98%

Slc7a14 Is Indispensable in Zebrafish Retinas

Zhuang

Xiang

Wen

et al. 2019

Front. Cell Dev. Biol.

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Previous study has identified SLC7A14 as a new causative gene of retinitis pigmentosa (RP). However, the role of SLC7A14 has not been fully characterized. The goal of this study was to investigate the biological features of slc7a14 in zebrafish.To determine the expression of slc7a14 in developing zebrafish, we performed in situ hybridization (ISH) and quantitative real-time PCR. Morpholino knockdown and overexpression experiments were performed to study the role of slc7a14 in zebrafish retinas. Immunostaining was carried out to observe structural changes. Visual motor responses (VMR) and optokinetic responses (OKR) were analyzed to assess visual behaviors. Terminal deoxynucleotidyl transferase (dUTP) nick-end labeling (TUNEL) staining was performed to survey apoptotic retinal cells. We found that slc7a14 was highly expressed in neuronal tissues, including the brain, spinal cord and retina, and that the expression levels increased during early embryogenesis. Consistently, ISH showed a similar expression pattern. Knockdown of slc7a14 led to dose-dependent microphthalmia that was reversed by overexpression. The immunostaining results revealed that the rod-specific protein zpr-3 and the retinal pigment epithelium-specific protein zpr-2 (decreased to 44.48%) were significantly suppressed in the slc7a14silenced morphants. Notably, visual behaviors (the VMR and the OKR) were severely impaired in the slc7a14-deficient morphant, especially the VMR OFF response. In addition, apoptotic cells were observed in the retina at 3 days post fertilization (dpf) and 5 dpf by TUNEL assay. Our results demonstrated that slc7a14 is essential for visually mediated behaviors in zebrafish. Temporary silencing of slc7a14 in larvae led to severe visual impairments, consistent with the manifestations observed in RP patients. Our findings provide further insights into the genetic mechanisms of RP predisposition caused by SLC7A14 mutations.

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“…Then, glutamine was released in culture medium, and acted as the driving force for glutamate uptake and GS activity to avoid any glutamate toxicity [ 32 , 33 , 34 ]. Interestingly, in high glutamate concentration [ 19 ] as used in this study to mimic glutamate toxicity involved in retinal degeneration [ 20 , 21 ], the main striking effect of dietary supplementation on Müller cells is the modulation of the glutamate/glutamine cycle in favor of glutamine release. The increase in GS, responsible for conversion of glutamate into glutamine [ 35 ], leads to an increase in intracellular glutamine as well as in glutamine release from Müller cells.…”

Section: Discussionmentioning

confidence: 99%

“…Glutamate experimental conditions: High glutamate concentration (1 mM) in culture medium with nor glutamine, nor red phenol, or FBS was used for metabolic test. This concentration was chosen [ 18 , 19 ] in order to mimic glutamate toxicity involved in retinal degeneration conditions [ 20 , 21 ].…”

Section: Methodsmentioning

confidence: 99%

Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

et al. 2021

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To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.

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New GABA modulators protect photoreceptor cells from light‐induced degeneration in mouse models

Cited by 12 publications

References 70 publications

Intravitreal injection of peptides PnPa11 and PnPa13, derivatives of Phoneutria nigriventer spider venom, prevents retinal damage

Intravitreal injection of peptides PnPa11 and PnPa13, derivatives of Phoneutria nigriventer spider venom, prevents retinal damage

Slc7a14 Is Indispensable in Zebrafish Retinas

Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

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