Age and intraocular pressure in murine experimental glaucoma

Pierdomenico, Johnny Di; Henderson, Delaney Cm; Giammaria, Sara; Smith, Victoria; Jamet, Aliénor J.; Smith, Corey A.; Hooper, Michele L.; Chauhan, Balwantray C.

doi:10.1016/j.preteyeres.2021.101021

Cited by 18 publications

(10 citation statements)

References 239 publications

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“…A main hurdle in developing new therapies and understanding the molecular mechanism of glaucoma is the lack of an animal model that recapitulates all aspects of the disease. While some laboratories focus on developing animal models of chronic IOP elevation, others use mice with natural mutations that slowly develop age‐related hypertension and RGC loss (Di Pierdomenico et al, 2022 ). We have been particularly interested in studying an animal model that allow us to capture the time course of molecular changes upon glaucomatous stress, such as mild ocular hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, our molecular analysis detects senescence as one of the pathways involved in the response to stress mechanism of the retina upon IOP elevation, what we previously documented in human glaucomatous tissue(Skowronska-Krawczyk et al, 2015).A main hurdle in developing new therapies and understanding the molecular mechanism of glaucoma is the lack of an animal model that recapitulates all aspects of the disease. While some laboratories focus on developing animal models of chronic IOP elevation, others use mice with natural mutations that slowly develop agerelated hypertension and RGC loss(Di Pierdomenico et al, 2022).We have been particularly interested in studying an animal model that allow us to capture the time course of molecular changes upon glaucomatous stress, such as mild ocular hypertension. Since age is the strongest risk factor for developing glaucoma, we developed and characterized the aged animal model for our future molecular studies.The molecular analysis of transcriptional changes between IOP-treated and non-treated retinas has detected a high numberF I G U R E 4 ATAC-seq analysis of stress-related epigenetic change.…”

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confidence: 99%

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Stress induced aging in mouse eye

Rydz

Huu

et al. 2022

Aging Cell

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Aging, a universal process that affects all cells in an organism, is a major risk factor for a group of neuropathies called glaucoma, where elevated intraocular pressure is one of the known stresses affecting the tissue. Our understanding of molecular impact of aging on response to stress in retina is very limited; therefore, we developed a new mouse model to approach this question experimentally. Here we show that susceptibility to response to stress increases with age and is primed on chromatin level.We demonstrate that ocular hypertension activates a stress response that is similar to natural aging and involves activation of inflammation and senescence. We show that multiple instances of pressure elevation cause aging of young retina as measured on transcriptional and DNA methylation level and are accompanied by local histone modification changes. Our data show that repeated stress accelerates appearance of aging features in tissues and suggest chromatin modifications as the key molecular components of aging. Lastly, our work further emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related diseases, including glaucoma.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Stress induced aging in mouse eye

Rydz

Huu

et al. 2022

Aging Cell

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“…Age and elevated intraocular pressure (IOP) are the two primary risk factors for glaucoma [1][2][3][4][5][6], the leading cause of irreversible blindness [7]. For example, glaucoma prevalence increases from 0.2% to 2.7% between the ages of 50 and 59 can reach 12.8% in those over 80 [6,[8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Aging and intraocular pressure homeostasis in mice

Li,

van Batenburg-Sherwood,

Safa

et al. 2023

Preprint

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Age and elevated intraocular pressure (IOP) are the two primary risk factors for glaucoma, an optic neuropathy that is the most common cause of irreversible blindness. In most people, IOP is tightly regulated over a lifetime by the conventional outflow tissues. However, the mechanistic contributions of age to conventional outflow dysregulation, elevated IOP and glaucoma are unknown. To address this gap in knowledge, we studied how age affects the morphology, biomechanical properties and function of conventional outflow tissues in C57BL/6 mice, which have an outflow system similar to humans. As reported in humans, we observed that IOP in mice was maintained within a tight range over their lifespan. Remarkably, despite a constellation of age-related changes to the conventional outflow tissues that would be expected to hinder aqueous drainage and impair homeostatic function (decreased cellularity, increased pigment accumulation, increased cellular senescence and increased stiffness), outflow facility, a measure of conventional outflow tissue fluid conductivity, was stable with age. We concluded that the murine conventional outflow system has significant functional reserve in healthy eyes. However, these age-related changes, when combined with other underlying factors, such as genetic susceptibility, are expected to increase risk for ocular hypertension and glaucoma.

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“…There are several markers that allow the identification of large populations of rodent RGCs (pan-markers) such as Brn3a or RBPMS ( Nadal-Nicolas et al, 2023 ) or specific related RGCs groups, also named subclasses, such as the intrinsically photosensitive RGCs ( Vidal-Villegas et al, 2021a , b ) or the alfa RGCs (αRGCs; Gallego-Ortega et al, 2022 ), among others ( Tran et al, 2019 ). Immunohistochemical studies using a combination of markers allow the study, in parallel but independently, of how different RGCs respond to different retinal injuries ( Vidal-Sanz et al, 2015a ; Agudo-Barriuso et al, 2016 ; Di Pierdomenico et al, 2022b ) and protection ( Valiente-Soriano et al, 2015 ; Rovere et al, 2016 ; Sanchez-Migallon et al, 2018 ). For instance, the expression of Brn3a by rodent RGCs has allowed to identification of the main population of RGCs, which accounts for approximately 96% of the RGC population ( Nadal-Nicolas et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

Di Pierdomenico,

Gallego-Ortega,

Norte-Muñoz

et al. 2024

Front. Neuroanat.

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PurposeThe aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA.MethodsAdult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose–response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs.ResultsAdministration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity.ConclusionSubcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity.

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Age and intraocular pressure in murine experimental glaucoma

Cited by 18 publications

References 239 publications

Stress induced aging in mouse eye

Stress induced aging in mouse eye

Aging and intraocular pressure homeostasis in mice

Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

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