Role of the ETB receptor in retinal ganglion cell death in glaucomaThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

Recent observations suggest that the vasoactive peptide endothelin-1 (ET-1) may be an important contributor to the etiology of glaucoma. ET-1 administration has been shown to produce optic nerve axonal loss and apoptosis of retinal ganglion cells. Ocular ET-1 levels are elevated in aqueous humor in response to elevated intraocular pressure both in glaucoma patients and in animal models of glaucoma; however, the precise mechanisms by which ET-1 mediates glaucomatous optic neuropathy are not clear. Presently we report that ET-1-mediated apoptosis was markedly attenuated in ETB receptor-deficient rats, suggesting a key role for ETB receptors in apoptosis of retinal ganglion cells by ET-1 treatment. Using virally transformed rat retinal ganglion cells (RGC-5 cells), we found that ET-1 (100 nmol/L) treatment produced apoptotic changes in these cells that was determined by flow cytometric analyses, release of mitochondrial cytochrome c to the cytosol, and increased phosphorylation of c-Jun N-terminal kinase. Pretreatment with the ETB-receptor antagonist BQ788 (1 μmol/L) was able to significantly attenuate ET-1-mediated apoptosis in RGC-5 cells. ET-1-mediated apoptotic changes in RGC-5 cells were associated with ETB-receptor activation and were accompanied by a significant upregulation of ETB-receptor expression. These studies suggest that ocular ET-1 acts through ETB receptors to mediate apoptosis of retinal ganglion cells, a key event in glaucoma and related optic neuropathies.

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Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

Cell Death and Disease ◽

10.1038/s41419-020-02990-0 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Olivia J. Marola ◽

Stephanie B. Syc-Mazurek ◽

Gareth R. Howell ◽

Richard T. Libby

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Ganglion Cells ◽

Retinal Vessel ◽

Vessel Diameter ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Ganglion Cell Death

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

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The Role of N-Methyl-D-Aspartate Receptor Activation in Homocysteine-Induced Death of Retinal Ganglion Cells

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.10-6870 ◽

2011 ◽

Vol 52 (8) ◽

pp. 5515 ◽

Cited By ~ 52

Author(s):

Preethi S. Ganapathy ◽

Richard E. White ◽

Yonju Ha ◽

B. Renee Bozard ◽

Paul L. McNeil ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Receptor Activation ◽

Retinal Ganglion ◽

Aspartate Receptor

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The development of the pattern of retinal ganglion cells in the chick retina: mechanisms that control differentiation

Development ◽

10.1242/dev.126.24.5713 ◽

1999 ◽

Vol 126 (24) ◽

pp. 5713-5724 ◽

Cited By ~ 13

Author(s):

K.L. McCabe ◽

E.C. Gunther ◽

T.A. Reh

Keyword(s):

Cell Differentiation ◽

Ganglion Cell ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Receptor Activation ◽

Peripheral Retina ◽

Retinal Ganglion ◽

Fgf Receptor ◽

Chick Retina ◽

Regular Arrays

Neurons in both vertebrate and invertebrate eyes are organized in regular arrays. Although much is known about the mechanisms involved in the formation of the regular arrays of neurons found in invertebrate eyes, much less is known about the mechanisms of formation of neuronal mosaics in the vertebrate eye. The purpose of these studies was to determine the cellular mechanisms that pattern the first neurons in vertebrate retina, the retinal ganglion cells. We have found that the ganglion cells in the chick retina develop as a patterned array that spreads from the central to peripheral retina as a wave front of differentiation. The onset of ganglion cell differentiation keeps pace with overall retinal growth; however, there is no clear cell cycle synchronization at the front of differentiation of the first ganglion cells. The differentiation of ganglion cells is not dependent on signals from previously formed ganglion cells, since isolation of the peripheral retina by as much as 400 μm from the front of ganglion cell differentiation does not prevent new ganglion cells from developing. Consistent with previous studies, blocking FGF receptor activation with a specific inhibitor to the FGFRs retards the movement of the front of ganglion cell differentiation, while application of exogenous FGF1 causes the precocious development of ganglion cells in peripheral retina. Our observations, taken together with those of previous studies, support a role for FGFs and FGF receptor activation in the initial development of retinal ganglion cells from the undifferentiated neuroepithelium peripheral to the expanding wave front of differentiation.

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Neuroprotective and Anti-Inflammatory Effects of a Hydrophilic Saffron Extract in a Model of Glaucoma

International Journal of Molecular Sciences ◽

10.3390/ijms20174110 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4110 ◽

Cited By ~ 11

Author(s):

Jose A. Fernández-Albarral ◽

Ana I. Ramírez ◽

Rosa de Hoz ◽

Nerea López-Villarín ◽

Elena Salobrar-García ◽

...

Keyword(s):

Cell Death ◽

Intraocular Pressure ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Saffron Extract ◽

Anti Inflammatory ◽

Ganglion Cell Death

Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs). An increase in the intraocular pressure is the principal risk factor for such loss, but controlling this pressure does not always prevent glaucomatous damage. Activation of immune cells resident in the retina (microglia) may contribute to RGC death. Thus, a substance with anti-inflammatory activity may protect against RGC degeneration. This study investigated the neuroprotective and anti-inflammatory effects of a hydrophilic saffron extract standardized to 3% crocin content in a mouse model of unilateral, laser-induced ocular hypertension (OHT). Treatment with saffron extract decreased microglion numbers and morphological signs of their activation, including soma size and process retraction, both in OHT and in contralateral eyes. Saffron extract treatment also partially reversed OHT-induced down-regulation of P2RY12. In addition, the extract prevented retinal ganglion cell death in OHT eyes. Oral administration of saffron extract was able to decrease the neuroinflammation associated with increased intraocular pressure, preventing retinal ganglion cell death. Our findings indicate that saffron extract may exert a protective effect in glaucomatous pathology.

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μ-Opioid Receptor Activation Directly Modulates Intrinsically Photosensitive Retinal Ganglion Cells

Neuroscience ◽

10.1016/j.neuroscience.2019.04.005 ◽

2019 ◽

Vol 408 ◽

pp. 400-417 ◽

Cited By ~ 2

Author(s):

Allison M. Cleymaet ◽

Shannon K. Gallagher ◽

Ryan E. Tooker ◽

Mikhail Y. Lipin ◽

Jordan M. Renna ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Opioid Receptor ◽

Ganglion Cells ◽

Receptor Activation ◽

Retinal Ganglion ◽

Μ Opioid Receptor

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Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies

Frontiers in Pharmacology ◽

10.3389/fphar.2021.729249 ◽

2021 ◽

Vol 12 ◽

Author(s):

Najam A. Sharif

Keyword(s):

Optic Nerve ◽

Anterior Chamber ◽

Ocular Hypertension ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Surgical Techniques ◽

Nitric Oxide Donor ◽

Glaucomatous Optic Neuropathy ◽

Retinal Ganglion ◽

Outflow Pathway

Damage to the optic nerve and the death of associated retinal ganglion cells (RGCs) by elevated intraocular pressure (IOP), also known as glaucoma, is responsible for visual impairment and blindness in millions of people worldwide. The ocular hypertension (OHT) and the deleterious mechanical forces it exerts at the back of the eye, at the level of the optic nerve head/optic disc and lamina cribosa, is the only modifiable risk factor associated with glaucoma that can be treated. The elevated IOP occurs due to the inability of accumulated aqueous humor (AQH) to egress from the anterior chamber of the eye due to occlusion of the major outflow pathway, the trabecular meshwork (TM) and Schlemm’s canal (SC). Several different classes of pharmaceutical agents, surgical techniques and implantable devices have been developed to lower and control IOP. First-line drugs to promote AQH outflow via the uveoscleral outflow pathway include FP-receptor prostaglandin (PG) agonists (e.g., latanoprost, travoprost and tafluprost) and a novel non-PG EP2-receptor agonist (omidenepag isopropyl, Eybelis®). TM/SC outflow enhancing drugs are also effective ocular hypotensive agents (e.g., rho kinase inhibitors like ripasudil and netarsudil; and latanoprostene bunod, a conjugate of a nitric oxide donor and latanoprost). One of the most effective anterior chamber AQH microshunt devices is the Preserflo® microshunt which can lower IOP down to 10–13 mmHg. Other IOP-lowering drugs and devices on the horizon will be also discussed. Additionally, since elevated IOP is only one of many risk factors for development of glaucomatous optic neuropathy, a treatise of the role of inflammatory neurodegeneration of the optic nerve and retinal ganglion cells and appropriate neuroprotective strategies to mitigate this disease will also be reviewed and discussed.

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Upregulation of Nogo receptor expression induces apoptosis of retinal ganglion cells in diabetic rats

Neural Regeneration Research ◽

10.4103/1673-5374.131597 ◽

2014 ◽

Vol 9 (8) ◽

pp. 815 ◽

Cited By ~ 9

Author(s):

Xuezheng Liu ◽

Zhongfu Zuo ◽

Wanpeng Liu ◽

Zhiyun Wang ◽

Yang Hou ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Diabetic Rats ◽

Receptor Expression ◽

Retinal Ganglion ◽

Nogo Receptor

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A Novel High-Content Flow Cytometric Method for Assessing the Viability and Damage of Rat Retinal Ganglion Cells

PLoS ONE ◽

10.1371/journal.pone.0033983 ◽

2012 ◽

Vol 7 (3) ◽

pp. e33983 ◽

Cited By ~ 6

Author(s):

Zhi-Yang Chang ◽

Da-Wen Lu ◽

Ming-Kung Yeh ◽

Chiao-Hsi Chiang

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Flow Cytometric Method ◽

Flow Cytometric

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NMDA-evoked [Ca2+]i increase in salamander retinal ganglion cells: Modulation by PKA and adrenergic receptors

Visual Neuroscience ◽

10.1017/s0952523802192029 ◽

2002 ◽

Vol 19 (3) ◽

pp. 249-256 ◽

Cited By ~ 7

Author(s):

YI HAN ◽

SAMUEL M. WU

Keyword(s):

Retinal Ganglion Cells ◽

Adrenergic Receptors ◽

Calcium Concentration ◽

Ganglion Cells ◽

Tiger Salamander ◽

Retinal Ganglion ◽

Pharmacological Mechanism ◽

Uk 14,304 ◽

Ganglion Cell Death ◽

Related Pathway

Application of NMDA induces a depolarization and increase of intracellular calcium concentration ([Ca2+]i) in retinal ganglion cells, which cause ganglion cell death in models of glaucoma. In the present study, we investigated the pharmacological mechanism of how NMDA-evoked increase in calcium could be modulated in dissociated retinal ganglion cells from tiger salamander. In these neurons, protein kinase A (PKA) up-regulated the NMDA-evoked [Ca2+]i increase. In the presence of 8-bromo-cAMP or forskolin to stimulate PKA, the elevation level of [Ca2+]i induced by NMDA became even higher; In the presence of H-89, a PKA inhibitor, the NMDA-evoked [Ca2+]i increase was attenuated. In addition, applications of adrenergic compounds were also found to influence the NMDA-evoked [Ca2+]i increase. UK-14,304, a selective α2 agonist, reduced the elevation level of [Ca2+]i caused by NMDA. In contrast, isoproterenol, a β agonist, augmented the NMDA-evoked [Ca2+]i increase. These adrenergic regulations were due to direct activation of adrenoceptors, since modulations of both UK-14,304 and isoproterenol on the NMDA-evoked [Ca2+]i increase were abolished by their respective antagonists. Furthermore, adrenergic regulations were mediated through a PKA-related pathway since PKA inhibitor blocked adrenergic regulations. The possible modulatory site(s) by PKA was also discussed.

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