Total Retinal Nitric Oxide Production is Increased in Intraocular Pressure-elevated Rats

Siu, Andrew M. H.; Leung, Mason C.P.; To, Chi Ho; Siu, Flora K.W.; Ji, J.Z.; So, Kwok-Fai

doi:10.1006/exer.2002.2029

Cited by 27 publications

(26 citation statements)

References 31 publications

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“…If individual variability was ignored and a mean group RGC loss was calculated, it would result in a calculated RGC loss of ~7% for the Wistar group and ~24% for the B-N group. These rates of overall loss are lower than the rates reported by other investigators (Sawada 1999;Ahmed 2001;Ko 2001;Naskar 2002;Siu 2002) for the same model of glaucoma, despite obtaining comparable IOP elevations for sufficiently long periods of time. These variable findings are further evidence that IOP alone may not be the only determining factor for retinal pathology in this rat glaucoma model.…”

Section: Discussioncontrasting

confidence: 60%

“…However, other unknown factors (e.g. housing, food intake, lighting etc) that might affect RGC numbers are potentially significant when one compares our results with those reported by other investigators (Ko 2000;Ahmed 2001;Ko 2001;Naskar 2002;Siu 2002;Wang 2004). In addition to IOP and RGC count, we report electrophysiologic testing on the eyes of these animals to detect potential functional defects.…”

Section: Discussionmentioning

confidence: 65%

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Characterization of retinal damage in the episcleral vein cauterization rat glaucoma model

Danias

Shen

Kavalarakis

et al. 2006

Experimental Eye Research

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Episcleral vein cauterization (EVC) is used in rats to generate a glaucoma model with high intraocular pressure (IOP). The long-term retinal damage in this glaucoma model however, has not been accurately quantified. We report the location and amount of retinal ganglion cell (RGC) damage caused by (EVC) induced IOP elevation in two rat strains.IOP was raised in one eye of Wistar(N=5) and Brown-Norway(B-N)(N=7) rats by EVC and monitored monthly until IOP in contralateral eyes equalized at 5 months post-surgery. Animals were maintained for 3.5-4.5 additional months. B-N rats(N=7) that had no EVC served as controls for this strain. Scotopic flash ERGs were recorded at baseline and just prior to euthanasia. Automated counts of all retrogradely labeled RGCs in retinal flat-mounts were determined and compared between contralateral eyes. RGC density maps were constructed and RGC size distribution was determined.Oscillatory potentials in the group of eyes which had elevated IOP were decreased at the time of euthanasia, when IOP had returned to normal. A group of normal B-N rats had similar RGC counts between contralateral eyes. In the experimental group the mean number of RGCs was not significantly different between control and experimental eyes, but 1 of 5 Wistar and 2 of 7 B-N experimental eyes had at least 30% fewer RGCs from contralateral control eyes. Total retinal area in B-N experimental eyes was higher compared with contralateral eyes. Cumulative IOP exposure of the experimental eyes was modestly correlated with RGC loss while oscillatory potentials appeared to be inversely related to RGC loss. In retinas with extensive (>30% RGC loss) but not complete damage, smaller cells were preserved better than larger ones.The above results indicate that RGC loss in both Wistar and B-N strains is variable after a prolonged elevation of IOP via EVC. Such variability despite equivalent IOP levels and ERG abnormalities, suggests unknown factors that can protect IOP-stressed RGCs. Identification and enhancement of such factors could prove useful for glaucoma therapy.

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Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 65%

Characterization of retinal damage in the episcleral vein cauterization rat glaucoma model

Danias

Shen

Kavalarakis

et al. 2006

Experimental Eye Research

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“…Proposed mechanisms of RGC apoptosis in glaucoma include: mechanical compression of the optic nerve head preventing axonal transport of neurotrophins required for RGC survival (also known as "physiologic axotomy") (4), excitotoxic damage by hyperactive NMDA receptors, elevated glutamate, Ca 2ϩ fluxes, and nitric oxide (5,6); ischemic and other retinal injury leading to activation of microglia (7), ␤-amyloid toxicity (8), and inflammatory damage through tumor necrosis factor-␣ (TNF␣) (9,10). However, none of these mechanisms explain two key issues.…”

mentioning

confidence: 99%

α2-Macroglobulin Is a Mediator of Retinal Ganglion Cell Death in Glaucoma

Shi

Rudzinski²,

Meerovitch

et al. 2008

Journal of Biological Chemistry

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Glaucoma is defined as a chronic and progressive optic nerve neuropathy, characterized by apoptosis of retinal ganglion cells (RGC) that leads to irreversible blindness. Ocular hypertension is a major risk factor, but in glaucoma RGC death can persist after ocular hypertension is normalized. To understand the mechanism underlying chronic RGC death we identified and characterized a gene product, ␣2-macroglobulin (␣2M), whose expression is up-regulated early in ocular hypertension and remains up-regulated long after ocular hypertension is normalized. In ocular hypertension retinal glia up-regulate ␣2M, which binds to low-density lipoprotein receptor-related protein-1 receptors in RGCs, and is neurotoxic in a paracrine fashion. Neutralization of ␣2M delayed RGC loss during ocular hypertension; whereas delivery of ␣2M to normal eyes caused progressive apoptosis of RGC mimicking glaucoma without ocular hypertension. This work adds to our understanding of the pathology and molecular mechanisms of glaucoma, and illustrates emerging paradigms for studying chronic neurodegeneration in glaucoma and perhaps other disorders.Vision impairment due to glaucoma affects 50 million people worldwide. In open angle glaucoma, visual field loss is caused by retinal ganglion cell (RGC) 3 apoptosis, concomitant with elevated intraocular pressure (IOP). Current treatments are limited to reduction of high IOP. Unfortunately, whereas these treatments are often successful at normalizing IOP, progressive RGC death and visual field loss often continue (1-3). In addition ϳ20% of patients are affected by normal tension glaucoma, a distinct optic nerve neuropathy in the absence of high IOP.Proposed mechanisms of RGC apoptosis in glaucoma include: mechanical compression of the optic nerve head preventing axonal transport of neurotrophins required for RGC survival (also known as "physiologic axotomy") (4), excitotoxic damage by hyperactive NMDA receptors, elevated glutamate, Ca 2ϩ fluxes, and nitric oxide (5, 6); ischemic and other retinal injury leading to activation of microglia (7), ␤-amyloid toxicity (8), and inflammatory damage through tumor necrosis factor-␣ (TNF␣) (9, 10). However, none of these mechanisms explain two key issues. First, all the cells in the inner retina are exposed to these deleterious effects, thus it is puzzling that RGCs are preferentially susceptible to apoptosis. Second, normalization of pressure often does not result in the complete arrest of RGC death, which continues chronically.To address these questions, we hypothesized that a short span of ocular hypertension can trigger long-lived changes in retinal gene expression, changes that are deleterious to RGCs. Five unique criteria were set to identify intraocular pressure regulated early gene (IPREG) candidates. Altered gene expression should: (i) occur specifically in the retina and be caused specifically by ocular hypertension; (ii) occur relatively early following ocular hypertension and prior to RGC damage; (iii) be long-lived; (iv) independent of the continuous p...

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“…There is evidence that the trabecular meshwork has intrinsic contractile elements, which can be relaxed by nitric oxide, leading to increased aqueous humour outflow . Although glaucoma is usually the result of 5,7,10,12,13 ocular hypertension, glaucoma that does not result from high IOP may equally benefit from vasodilatory effects of NO. Neufeld posits that the increased presence of endothelial NO synthetase (eNOS) in the vascular endothelia could be neuroprotective in causing vasodilation and increased blood flow in the optic nerve head.…”

Section: Discussionmentioning

confidence: 99%

Effect of single dose oral isosorbide dinitrate tablets on the intraocular pressure

Megwas¹,

Emereole²

2011

Jrnl Nig Opto Assoc.

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Total Retinal Nitric Oxide Production is Increased in Intraocular Pressure-elevated Rats

Cited by 27 publications

References 31 publications

Characterization of retinal damage in the episcleral vein cauterization rat glaucoma model

Characterization of retinal damage in the episcleral vein cauterization rat glaucoma model

α2-Macroglobulin Is a Mediator of Retinal Ganglion Cell Death in Glaucoma

Effect of single dose oral isosorbide dinitrate tablets on the intraocular pressure

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