Purinergic signaling in the retina: From development to disease

Ventura, Ana Lúcia Marques; Santos-Rodrigues, Alexandre dos; Mitchell, Claire H.; Faillace, María Paula

doi:10.1016/j.brainresbull.2018.10.016

Cited by 28 publications

(15 citation statements)

References 236 publications

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“…Additionally, specific to the intermediate stage AMD cohort, we found increased levels of nucleotides and peptides related to purine metabolism (urate, N6-succinyladenosine) in association with RIT. The association between purine metabolism and AMD has been previously demonstrated [ 11 ], and while there is growing evidence for the role in the retina regarding ATP release [ 64 ], the potential mechanisms associated with DA remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

et al. 2021

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The purpose of this study was to analyze the association between plasma metabolite levels and dark adaptation (DA) in age-related macular degeneration (AMD). This was a cross-sectional study including patients with AMD (early, intermediate, and late) and control subjects older than 50 years without any vitreoretinal disease. Fasting blood samples were collected and used for metabolomic profiling with ultra-performance liquid chromatography–mass spectrometry (LC-MS). Patients were also tested with the AdaptDx (MacuLogix, Middletown, PA, USA) DA extended protocol (20 min). Two measures of dark adaptation were calculated and used: rod-intercept time (RIT) and area under the dark adaptation curve (AUDAC). Associations between dark adaption and metabolite levels were tested using multilevel mixed-effects linear modelling, adjusting for age, gender, body mass index (BMI), smoking, race, AMD stage, and Age-Related Eye Disease Study (AREDS) formulation supplementation. We included a total of 71 subjects: 53 with AMD (13 early AMD, 31 intermediate AMD, and 9 late AMD) and 18 controls. Our results revealed that fatty acid-related lipids and amino acids related to glutamate and leucine, isoleucine and valine metabolism were associated with RIT (p < 0.01). Similar results were found when AUDAC was used as the outcome. Fatty acid-related lipids and amino acids are associated with DA, thus suggesting that oxidative stress and mitochondrial dysfunction likely play a role in AMD and visual impairment in this condition.

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Section: Discussionmentioning

confidence: 99%

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

et al. 2021

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“…This effect is due to a reduction in the expression of L‐type Ca 2+ channels in the cell membrane (Lu et al, ; Lun Lee, Ostadalova, Kolar, & Dhalla, ) and of the intracellular ryanodine receptor (Pereira et al, ; Yaras et al, ), which generates an overall increase in basal Ca 2+ levels (Yaras et al, ). On the other hand, purinergic receptors are expressed throughout the entire retina, in retinal neurons and prominently in Müller glia cells (Ho et al, ; Ho, Vessey, & Fletcher, ; Puthussery & Fletcher, ; Ventura, Santos‐rodrigues, Mitchell, & Paula, ). We observed an increase of calcium responses to ATP stimulation under HG compared with MG conditions, which could be interpreted as a consequence of glial activation under prolonged HG conditions.…”

Section: Discussionmentioning

confidence: 99%

Physiological assessment of high glucose neurotoxicity in mouse and rat retinal explants

Calbiague

Vielma

Cadiz

et al. 2019

J of Comparative Neurology

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“…Likewise, the ability of P2Y 12 receptor antagonist ARC66096 to reduce autofluorescence in the absence of added agonist suggests that endogenous receptor stimulation by agonist ADP is occurring 14. As purinergic receptors have been implicated in multiple retinal diseases and basic visual functions,30–33 a more thorough understanding of the endogenous signaling pathways will be of benefit.…”

Section: Discussionmentioning

confidence: 99%

Oral Delivery of the P2Y₁₂Receptor Antagonist Ticagrelor Prevents Loss of Photoreceptors in an ABCA4^−/−Mouse Model of Retinal Degeneration

Campagno

Tso

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Purpose Accumulation of lysosomal waste is linked to neurodegeneration in multiple diseases, and pharmacologic enhancement of lysosomal activity is hypothesized to reduce pathology. An excessive accumulation of lysosomal-associated lipofuscin waste and an elevated lysosomal pH occur in retinal pigment epithelial cells of the ABCA4 −/− mouse model of Stargardt's retinal degeneration. As treatment with the P2Y 12 receptor antagonist ticagrelor was previously shown to lower lysosomal pH and lipofuscin-like autofluorescence in these cells, we asked whether oral delivery of ticagrelor also prevented photoreceptor loss. Methods Moderate light exposure was used to accelerate photoreceptor loss in albino ABCA4 −/− mice as compared to BALB/c controls. Ticagrelor (0.1%–0.15%) was added to mouse chow for between 1 and 10 months. Photoreceptor function was determined with electroretinograms, while cell survival was determined using optical coherence tomography and histology. Results Protection by ticagrelor was demonstrated functionally by using the electroretinogram, as ticagrelor-treated ABCA4 −/− mice had increased a- and b-waves compared to untreated mice. Mice receiving ticagrelor treatment had a thicker outer nuclear layer, as measured with both optical coherence tomography and histologic sections. Ticagrelor decreased expression of LAMP1, implicating enhanced lysosomal function. No signs of retinal bleeding were observed after prolonged treatment with ticagrelor. Conclusions Oral treatment with ticagrelor protected photoreceptors in the ABCA4 −/− mouse, which is consistent with enhanced lysosomal function. As mouse ticagrelor exposure levels were clinically relevant, the drug may be of benefit in preventing the loss of photoreceptors in Stargardt's disease and other neurodegenerations associated with lysosomal dysfunction.

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Purinergic signaling in the retina: From development to disease

Cited by 28 publications

References 236 publications

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

Physiological assessment of high glucose neurotoxicity in mouse and rat retinal explants

Oral Delivery of the P2Y₁₂Receptor Antagonist Ticagrelor Prevents Loss of Photoreceptors in an ABCA4^−/−Mouse Model of Retinal Degeneration

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Purinergic signaling in the retina: From development to disease

Cited by 28 publications

References 236 publications

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

Physiological assessment of high glucose neurotoxicity in mouse and rat retinal explants

Oral Delivery of the P2Y12Receptor Antagonist Ticagrelor Prevents Loss of Photoreceptors in an ABCA4−/−Mouse Model of Retinal Degeneration

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Oral Delivery of the P2Y₁₂Receptor Antagonist Ticagrelor Prevents Loss of Photoreceptors in an ABCA4^−/−Mouse Model of Retinal Degeneration