Effect of elevated intraocular pressure on endothelin-1 in a rat model of glaucoma

Prasanna, Ganesh; Hulet, C.; Desai, Devashish H.; Krishnamoorthy, Raghu R; Narayan, Santosh; Brun, Anne-Marie; Suburo, Ángela M.; Yorio, Thomas

doi:10.1016/j.phrs.2004.04.006

Cited by 84 publications

(72 citation statements)

References 31 publications

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“…[1][2][3] It has been suggested that mechanical and vascular factors, through the induction of oxidative damage, lead to the same final pathologic consequence by working synergistically. 4 The increase in oxidative DNA damage in the cellular component of the trabecular meshwork affects the architecture of the extracellular matrix and the related IOP regulation, leading to the clinical onset of glaucoma. 5,6 On the basis of these premises, the anterior chamber of the eye can be regarded as a highly specialized vascular compartment whose inner walls are composed of the endothelia of iris, cornea, and trabecular meshwork.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Izzotti

Saccà²,

Marco

et al. 2007

Eye

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Purpose A growing evidence in the scientific literature suggests that oxidative damage plays a pathogenic role in primary open-angle glaucoma. Therefore, it is of interest to test whether drugs effective against glaucoma display antioxidant activity. We test the hypothesis that the classic b-blocker therapy for glaucoma with timolol involves the activation of antioxidant protective mechanisms towards endothelial cells. Methods Oxidative stress was induced in cultured human endothelial cells by iron/ ascorbate with or without timolol pretreatment. Analysed parameters included cell viability (neutral red uptake and tetrazolium salt tests), lipid peroxidation (thiobarbituric reactive substances), and occurrence of molecular oxidative damage to DNA (8-hydroxy-2 0 -deoxyguanosine).Results Oxidative stress decreased 1.8-fold cell viability, increased 3.0-fold lipid peroxidation and 64-fold oxidative damage to DNA. In the presence of timolol, oxidative stress did not modify cell viability, whereas lipid peroxidation was increased 1.3-fold, and DNA oxidative damage 3.6-fold only.Conclusions The obtained results indicate that timolol exerts a direct antioxidant activity protecting human endothelial cells from oxidative stress. These cells employ mechanisms similar to those observed in the vascular endothelium. It is hypothesized that this antioxidant activity is involved in the therapeutic effect of this drug against glaucoma.

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Section: Introductionmentioning

confidence: 99%

Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Izzotti

Saccà²,

Marco

et al. 2007

Eye

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“…Prevention of ET B upregulation indeed inhibits hepatic stellate cell activation and collagen synthesis (Chi et al, 2003). An upregulation of ET B receptors has also been observed in human glaucomatous optic nerve head as well as elevated IOP models of glaucoma (Prasanna et al, 2005 andWang et al, 2006;). In our previous study, we have shown that ET-1 treatment in LC cells resulted in an upregulation of ET B receptors that was significant at 100 nM concentrations of ET-1 (Rao et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

“…POAG subjects have significantly higher levels of ET-1 in plasma and aqueous humor compared to their age matched controls (Sugiyama et al, 1995 andNoske et al, 1997). Animal models of glaucoma with elevated IOP also demonstrate significant increase in ET-1 levels (Kallberg et al, 2002;Prasanna et al, 2005). Intravitreal administration of ET-1 in various animal models results in loss of retinal ganglion cells by apoptosis, blockade of axonal transport, activation of optic nerve head astrocytes contributing to optic neuropathy similar to that observed in glaucoma (Stokely et al, 2002;Chauhan et al, 2004;Lau et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa

Rao

Krishnamoorthy

Yorio

2008

Experimental Eye Research

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Endothelin-1(ET-1), a potent vaso-active peptide, mediates extracellular matrix regulation resulting in an increase in collagen deposition in various cell types and tissues and has been proposed to play a key role in glaucoma pathology. The role of ET-1 in the regulation of extracellular matrix collagens at the level of optic nerve head is not known. In this study we have examined the role of ET-1 in extracellular matrix collagen regulation in primary cultures of human lamina cribrosa cells. Our hypothesis is that ET-1 increases remodeling of the ECM of cells of the lamina cribrosa. Such actions could contribute to the development of optic neuropathy. QPCR analysis revealed that ET-1 mediated an increase in mRNA levels of collagen type I alpha 1 and collagen type VI alpha 1 chains at all doses of ET-1 with a significant increase at 1nM and 10nM concentration in LC cells. A dose dependent increase in collagen type I and type VI protein deposition and secretion was also observed by Western blot in response to ET-1 and was significant at 10nM and 100nM concentrations of ET-1. ET-1 increased the [ 3 H] proline uptake in LC cells suggesting that ET-1 contributed to an increase in total collagen synthesis in LC cells. ET-1 -mediated increase in collagen type I, type VI and total collagen synthesis was significantly blocked by the ET A receptor antagonist, BQ610, as well as with the ET B receptor antagonist, BQ788, suggesting the involvement of both receptor subtypes in ET-1 mediated collagen synthesis in LC cells. These results suggest that ET-1 regulates extra cellular matrix-collagen synthesis in LC cells and may contribute to ECM remodeling at the level of LC of POAG subjects who have elevated plasma and aqueous humor levels of endothelin-1.

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“…However the precise mechanisms underlying ET-1 mediated neurodegeneration are not completely understood. ET-1 levels are elevated in the aqueous humor of primary open angle glaucoma patients (Noske et al, 1997;Tezel et al, 1997) and in animal models of glaucoma (Kallberg et al, 2002;Thanos and Naskar 2004;and Prasanna et al, 2005). The clinical relevance of these findings is not completely clear but it appears plausible that ET-1 in aqueous humor could be secreted in response to an increase in IOP.…”

Section: Endothelinsmentioning

confidence: 99%

Neuroprotection in Glaucoma

Mueller¹,

Stankowska²,

Krishnamoorthy³

2011

Glaucoma - Basic and Clinical Concepts

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Effect of elevated intraocular pressure on endothelin-1 in a rat model of glaucoma

Cited by 84 publications

References 31 publications

Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa

Neuroprotection in Glaucoma

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