scholarly journals Oral administration of a dual ETA/ETB receptor antagonist promotes neuroprotection in a rodent model of glaucoma

2020 ◽  
Author(s):  
Nolan R. McGrady ◽  
Dorota L. Stankowska ◽  
Hayden B. Jefferies ◽  
Raghu R. Krishnamoorthy
Keyword(s):  
Intraocular Pressure ◽  
Oral Administration ◽  
Receptor Antagonist ◽  
Ocular Hypertension ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Brown Norway ◽  
Retinal Ganglion ◽  
Elevated Intraocular Pressure ◽  
Iop Elevation

AbstractPurposeGlaucoma is a neurodegenerative disease associated with elevated intraocular pressure and characterized by optic nerve axonal degeneration, cupping of the optic disc and loss of retinal ganglion cells (RGCs). The endothelin (ET) system of vasoactive peptides (ET-1, ET-2, ET-3) and their G-protein coupled receptors (ETA and ETB receptors) have been shown to be contributors to the pathophysiology of glaucoma. The purpose of this study was to determine if administration of the endothelin receptor antagonist, macitentan, after the onset of IOP elevation, was neuroprotective to retinal ganglion cells in ocular hypertensive rats.MethodsBrown Norway rats were subjected to the Morrison model of ocular hypertension by injection of hypertonic saline through episcleral veins. Macitentan (5 and 10 mg/kg body wt/day) was administered orally following the elevation of IOP and rats with IOP elevation were maintained for 4 weeks. RGC function was determined by pattern electroretinography at 2 and 4 weeks post IOP elevation. Rats were euthanized by approved humane methods and retinal flat-mounts generated were immunostained with RGC-selective markers RBPMS and Brn3a. RGC counts were conducted in a masked manner.ResultsA significant protection of retinal ganglion cells against cell loss was found following oral administration of macitentan (5 and 10 mg/kg body wt/day) in rats with elevated intraocular pressure. In addition, treatment with macitentan was able to preserve RGC function as measured by pattern ERG analysis.ConclusionsMacitentan was able to promote neuroprotection independent of IOP-lowering suggesting that this could complement existing treatments to prevent neurodegeneration during ocular hypertension. The findings presented have implications for the use of macitentan as an oral formulation to promote neuroprotection in glaucoma patients.

scholarly journals The Endothelin Receptor Antagonist Macitentan Ameliorates Endothelin-Mediated Vasoconstriction and Promotes Neuroprotection of Retinal Ganglion Cells in Rats

2020 ◽  
Author(s):  
Dorota L. Stankowska ◽  
Wei Zhang ◽  
Shaoqing He ◽  
Vignesh R. Krishnamoorthy ◽  
Payton Harris ◽  
...  
Keyword(s):  
Body Weight ◽  
Receptor Antagonist ◽  
Intravitreal Injection ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Endothelin Receptor Antagonist ◽  
Brown Norway ◽  
Retinal Ganglion ◽  
Endothelin Receptor ◽  
Norway Rats

AbstractPurposeTo determine if dietary administration of the dual ETA/ ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 (ET-1) mediated vasoconstriction in Brown Norway rats.MethodsAdult male and female Brown Norway rats were either untreated or treated with macitentan (5 mg/kg body weight) once a day for 3 days followed by intravitreal injection of either 4 μl of 500 μM ET-1 (2 nmole/eye) or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out at various time points, including, 5, 10, 15, 25 and 30 minutes. Following the imaging of the vasculature, rats were either treated with macitentan (5 mg/kg/body weight in dietary gels) or untreated (control gels without medication). Following treatments, rats were euthanized, retinal flat mounts were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner.ResultsVasoconstrictive effects following intravitreal ET-1 injection were greatly reduced in rats administered with macitentan in the diet prior to the ET-1 administration. ET-1 intravitreal injection produced a 31% loss of RGCs which was significantly reduced in macitentan-treated rats. Following ET-1 administration, GFAP immunostaining was increased in the ganglion cell layer as well as in the retrolaminar region, suggestive of astrocytic activation by ET-1 administration. RGC numbers in macitentan treated and ET-1 injected rats were similar to that observed in control retinas.ConclusionsET-1-mediated neurodegeneration could occur through both vascular and cellular mechanisms. The endothelin receptor antagonist, macitentan, has neuroprotective effects in retinas of Brown Norway rats that occurs through different mechanisms, including, enhancement of RGC survival and reduction ET-1 mediated vasoconstriction.

Design of Experiments for Exposure of Astrocytes to Elevated Hydrostatic Pressure and Hypoxia

2008 ◽  
Author(s):  
Shadi Rajabi ◽  
Craig A. Simmons ◽  
C. Ross Ethier
Keyword(s):  
Intraocular Pressure ◽  
Visual Field ◽  
Retinal Ganglion Cells ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Visual Field Loss ◽  
Retinal Ganglion ◽  
Common Cause ◽  
Elevated Intraocular Pressure

Glaucoma, a chronic optic neuropathy, is the second most common cause of blindness, affecting 67 million people worldwide. The damage in glaucoma occurs at the optic nerve head (ONH), where the axons of the retinal ganglion cells leave the eye posteriorly. Glaucoma is frequently associated with elevated intraocular pressure (IOP), and visual field loss can be prevented by significant lowering of IOP. Hence, the role of pressure in glaucoma is important. Unfortunately, the mechanism by which pressure leads to vision loss in glaucoma is very poorly understood.

scholarly journals Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

2019 ◽  
Author(s):  
Lorena Raquel Rocha ◽  
Viet Anh Nguyen Huu ◽  
Claudia Palomino La Torre ◽  
Qianlan Xu ◽  
Mary Jabari ◽  
...  
Keyword(s):  
Ocular Hypertension ◽  
Retinal Ganglion Cells ◽  
Visual Evoked Potential ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Early Removal ◽  
Transcriptional Changes ◽  
Secretory Phenotype ◽  
Iop Elevation ◽  
Retinal Functions

AbstractExperimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimicks events occurring in human glaucoma. Senescence-related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence-associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix-degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies.

scholarly journals Natural Products: Evidence for Neuroprotection to Be Exploited in Glaucoma

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3158
Author(s):  
Annagrazia Adornetto ◽  
Laura Rombolà ◽  
Luigi Antonio Morrone ◽  
Carlo Nucci ◽  
Maria Tiziana Corasaniti ◽  
...  
Keyword(s):  
Natural Products ◽  
Risk Factor ◽  
Intraocular Pressure ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Main Risk Factor ◽  
Number Of Patients ◽  
Elevated Intraocular Pressure ◽  
Underlying Mechanisms

Glaucoma, a leading cause of irreversible blindness worldwide, is an optic neuropathy characterized by the progressive death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is recognized as the main risk factor. Despite effective IOP-lowering therapies, the disease progresses in a significant number of patients. Therefore, alternative IOP-independent strategies aiming at halting or delaying RGC degeneration is the current therapeutic challenge for glaucoma management. Here, we review the literature on the neuroprotective activities, and the underlying mechanisms, of natural compounds and dietary supplements in experimental and clinical glaucoma.

scholarly journals Neuroprotective effect of Erigeron Breviscapus (vant) Hand-mazz extract on retinal ganglion cells in rabbits with chronic elevated intraocular pressure

2011 ◽  
Vol 5 (2) ◽  
pp. 195-203 ◽  
Author(s):  
Yi-sheng Zhong ◽  
Min-hong Xiang ◽  
Wen Ye ◽  
Ping Huang ◽  
Yu Cheng ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Neuroprotective Effect ◽  
Treated Group ◽  
Ultrastructural Changes ◽  
Retinal Ganglion ◽  
Elevated Intraocular Pressure ◽  
Erigeron Breviscapus

Abstract Background: Retinal ganglion cells (RGCs) are protected in rats with acute elevated intraocular pressure (IOP) by Erigeron breviscapus (vant.) hand-mazz (EBHM). However, it is unclear whether EBHM has neuroprotective effect on RGCs in animal with chronic elevated IOP. Objective: Investigate the protective effect of EBHM extract on RGCs in rabbits with chronic elevated IOP. Methods: Unilateral chronic elevated IOP was produced in rabbits by repeated injection of 2% methylcellulose into the anterior chamber. Secondary degeneration was measured with and without EBHM extract treatment for 60 days. At 60 days, the cells density of the RGCs layer, the thickness of retinal nerve fiber layer (RNFL), and the optic nerve axons were observed and analyzed using an image analysis system. The ultrastructural changes of RGCs and optic nerve axons were observed using transmission electron microscopy. Results: Compared with their contralateral control eyes with normal IOP, in the retinas of 3-4 mm from the optic disc, the cells density of the RGCs layer in the eyes with chronic elevated IOP was 23.2±6.5 cells (n = 6) and 36.0±8.9 cells (n = 10) per three 400x fields at 60 days in untreated and EBHM-treated group, respectively. The RNFL thickness in eyes with chronic elevated IOP was 3.4±0.4 μm (n = 6) and 5.0±1.0 μm (n = 10) at 60 days in untreated and EBHM-treated group, respectively. The axons number per 15057.8 μm2 in eyes with chronic elevated IOP was 370.4±41.0 (n = 6) and 439.0±50.8 (n = 10) at 60 days in untreated and EBHM-treated group, respectively. The number of the organelles in RGCs plasm appeared decreased and mitochondrion vacuolated in the elevated IOP eyes of EBHM-treated group, while some dispersive mitochondrion and rough surfaced endoplasmic reticulum and ribosome still existed in the RGCs plasm. The myelin sheath plates condensed and degenerated, and the microfilaments and microtubules decreased or disappeared in the elevated IOP eyes, but the axons degeneration in the chronic elevated IOP with EBHM treatment was less than that in the chronic elevated IOP without treatment. Conclusion: EBHM extract provided a neuroprotective effect on retinal ganglion cells in rabbits with chronic elevated IOP.

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