Characterization Of Novel Neuroprotectants For Rescuing Retinal Ganglion Cell Loss In An Ocular Hypertensive Model Of Glaucoma

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Characterization of Novel Neuroprotectants for Rescuing Retinal Ganglion Cell Loss in an Ocular Hypertensive Model of Glaucoma

Author : Qingling Fu
Publisher : Open Dissertation Press
ISBN 13 : 9781361420676
Total Pages : pages
Book Rating : 4.4/5 (26 download)

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Book Synopsis Characterization of Novel Neuroprotectants for Rescuing Retinal Ganglion Cell Loss in an Ocular Hypertensive Model of Glaucoma by : Qingling Fu

Download or read book Characterization of Novel Neuroprotectants for Rescuing Retinal Ganglion Cell Loss in an Ocular Hypertensive Model of Glaucoma written by Qingling Fu and published by Open Dissertation Press. This book was released on 2017-01-27 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Characterization of Novel Neuroprotectants for Rescuing Retinal Ganglion Cell Loss in an Ocular Hypertensive Model of Glaucoma" by Qingling, Fu, 付清玲, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Characterization of Novel Neuroprotectants for Rescuing Retinal Ganglion Cell Loss in an Ocular Hypertensive Model of Glaucoma Submitted by FU Qing-Ling for the degree of Doctor of Philosophy at The University of Hong Kong in September 2007 Glaucoma is a progressive neuropathy characterized by loss of vision as a result of retinal ganglion cell (RGC) death. There are no effective neuroprotective agents to treat this disorder. In this study, several novel neuroprotectants were identified to rescue damaged RGCs in a rat glaucoma model of ocular hypertension. The first part of my study was focused on the role of erythropoietin (EPO)/ EPO receptor (EPOR) on RGCs after glaucomatous injury. EPO is a neuroprotectant for central nerve system (CNS) neurons in addition to being a hematopoietic cytokine in the serum. Here we found that Muller cell is the main source of EPO in the retina. Expression of EPO and EPOR was increased significantly after ocular hypertension. Disturbing the activity of endogenous EPO and EPOR with soluble EPOR exacerbated RGC loss after injury, suggesting EPO as an endogenous neurotrophin in response to injury. Similarly, local or systemic treatment of recombinant human EPO rescued damaged RGCs. Hence EPO may be a self-protective factor after damage and exogenous administration of EPO may promote RGC survival. The second part of this study was to investigate the effect of LINGO-1 antagonists on RGC survival after ocular hypertension. Three myelin proteins bind to Nogo66 receptor (NgR1) that mediates the inhibition of axonal regeneration via two transmembrane co-receptors, LINGO-1 and p75/TROY in the CNS. This study demonstrated that exogenously added soluble human LINGO-1 (LINGO-1-Fc) and anti-LINGO-1 mAb 1A7 promoted RGC survival up to 4 weeks after the induction of elevated IOP. More importantly, it is found that LINGO-1 binds to and negatively regulates activation of TrkB receptor by BDNF. Administering LINGO-1-Fc or 1A7 activated TrkB after binding with the high level endogenous BDNF in the injured retina and anti-BDNF antibody significantly reversed the neuroprotective activity of LINGO-1-Fc or 1A7. These results indicate that LINGO-1-Fc and 1A7 have neuroprotective activity and may act by up-regulating the function of BDNF/TrkB. The third part of this study was to examine the effect of soluble NgR1-Fc protein (sNgR310-Fc) on the RGC survival after glaucomatous injury. Intra-vitreous administration of sNgR310-Fc efficiently rescues RGC loss in a rat ocular hypertension glaucoma model up to 4 weeks without altering the IOP. This neuroprotective mechanism is partially attributed to 1] the removal of accumulating neurotoxic β-amyloids in the glaucoma eye and/or, 2] an agonistic interaction between sNgR310-Fc and the neurotropin-X receptor in the retina. Hence, sNgR310-Fc confers neuroprotection in addition to neuro-repair therapeutic advantages, and is a promising candidate for treating axonopathies, retinopathies and CNS injuries. In conclusion, our data indicate that LINGO-1 and NgR1 antagonists also have neuroprotective effects on damaged RGCs in a well-established rat chronic glaucoma model in addition to axonal regeneration. Thus, the antagonists may provide an attractive dual therapeutic strategy of both preventing neurodegeneration a

Characterization of Novel Neuroprotectants for Rescuing Retinal Ganglion Cell Loss in an Ocular Hypertensive Model of Glaucoma

Author : Qingling Fu
Publisher :
ISBN 13 :
Total Pages : 404 pages
Book Rating : 4.:/5 (228 download)

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Book Synopsis Characterization of Novel Neuroprotectants for Rescuing Retinal Ganglion Cell Loss in an Ocular Hypertensive Model of Glaucoma by : Qingling Fu

Ocular Neuroprotection

Author : Leonard A. Levin
Publisher : CRC Press
ISBN 13 : 0203911946
Total Pages : 343 pages
Book Rating : 4.2/5 (39 download)

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Book Synopsis Ocular Neuroprotection by : Leonard A. Levin

Download or read book Ocular Neuroprotection written by Leonard A. Levin and published by CRC Press. This book was released on 2003-07-15 with total page 343 pages. Available in PDF, EPUB and Kindle. Book excerpt: Many retinal and optic nerve disorders have no effective therapy, or are treated incompletely and with considerable side effects. Recent advances have suggested the significant benefits associated with neuroprotection - that is, when treatment strategies are directed to photoreceptors, retinal ganglion cells, or other neural targets. Enter Ocular N

NEUROPROTECTIVE EFFECT OF GINK

Author : Ching Lai
Publisher : Open Dissertation Press
ISBN 13 : 9781374711532
Total Pages : 134 pages
Book Rating : 4.7/5 (115 download)

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Book Synopsis NEUROPROTECTIVE EFFECT OF GINK by : Ching Lai

Download or read book NEUROPROTECTIVE EFFECT OF GINK written by Ching Lai and published by Open Dissertation Press. This book was released on 2017-01-27 with total page 134 pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Neuroprotective Effect of Ginkgo Biloba Extract on Retinal Ganglion Cells in a Rat Glaucoma Model" by Ching, Lai, 賴晴, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Neuroprotective effect of Ginkgo biloba extract on retinal ganglion cells in a rat glaucoma model submitted by Ching Lai for the degree of Master of Philosophy at the University of Hong Kong in August 2003 Glaucoma is a progressive optic neuropathy that ultimately causes retinal ganglion cell (RGC) death and loss of vision. Current therapies on this disease only aim at controlling intraocular pressure (IOP). However, patients undergoing such therapies may still develop RGCs degeneration. Therefore a new "therapy" has been suggested and is named neuroprotection. Neuroprotection aims at protecting and rescuing RGCs from damage. One suggested neuroprotectant is the Ginkgo biloba extract (GBE). GBE is a traditional Chinese medicine, which has been shown to increase ocular blood flow velocity and thus may improve vision. However, the direct effect of GBE on RGCs survival has not been investigated. Therefore, the objective of this study is to investigate the neuroprotective effect of GBE on RGCs in an ocular hypertension model. By using a laser-induced ocular hypertension model, we have demonstrated the neuroprotective effect of GBE on RGC survival. After administered Sprague- Dawley rats with 12 mg/ml, 120 mg/ml and 200 mg/ml GBE, RGC death observed in experimental glaucoma was virtually abolished. The possible neuroprotective mechanisms of GBE on experimental glaucoma were also examined in this study. It has been proposed that GBE protects neurons by modulating glial responses. We found that the number of OX42 immunopositive microglia was increased after GBE treatment in glaucomatous retinas. Based on the morphological analysis, the numbers of both the resting and activated forms of microglia were increased with GBE administration. The protective effect of GBE on RGCs was partially removed by inhibiting the response of microglia with the microglia inhibitory factor. We have also studied the role of other glial cells in protecting RGCs. Macroglia such as astrocytes and Muller cells were studied by quantifying the GFAP immunolabeled glial cells in the glaucomatous retina. Immunoreactivity of GFAP was enhanced after 1.2 mg/ml, 12 mg/ml and 120 mg/ml GBE treatments. In experiments on different survival periods after GBE administration, GBE was shown to induce an earlier onset and a sustained expression of GFAP in the glaucomatous retina when compared with the controls. Application of GBE may therefore be a potentially useful treatment in preventing the loss of vision in glaucoma patients. DOI: 10.5353/th_b2949405 Subjects: Retinal ganglion cells Ginkgo - Therapeutic use Glaucoma Rats as laboratory animals

Neuroprotection and Neuroregeneration for Retinal Diseases

Author : Toru Nakazawa
Publisher : Springer
ISBN 13 : 443154965X
Total Pages : 351 pages
Book Rating : 4.4/5 (315 download)

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Book Synopsis Neuroprotection and Neuroregeneration for Retinal Diseases by : Toru Nakazawa

Download or read book Neuroprotection and Neuroregeneration for Retinal Diseases written by Toru Nakazawa and published by Springer. This book was released on 2014-07-23 with total page 351 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides the latest findings on neuroprotection and neuroregeneration as potential therapeutic strategies for various eye diseases, namely, glaucoma, age-related macular degeneration (AMD), retinal detachment, and retinitis pigmentosa. Glaucoma is one of the main causes of blindness throughout the world, and other diseases such as AMD and retinitis pigmentosa also lead to loss of vision. All these conditions are characterized by degeneration of specific retinal cell types, making it essential to establish treatments to protect retinal neurons and the optic nerve. With that aim in mind, this book explains the mechanisms underlying aforementioned diseases and their experimental models. The novel strategy proposals for the treatment of retinal diseases based on the concept of neuroprotection are also discussed in the main body of the text, while the section on regenerative research discusses optic nerve regeneration, endothelial progenitor cells, and iPS cells. This book is recommended as a professional reference work for all doctors and trainees in the field of ophthalmology who are interested in neuroprotective and neuroregenerative treatments.

Neurodegeneration and Neuroprotection in Glaucoma Retinopathy-Probing the Role of Endothelin-1, Rage, A{221} and Lycium Barbarum

Author : Xuesong Mi
Publisher : Open Dissertation Press
ISBN 13 : 9781361302323
Total Pages : pages
Book Rating : 4.3/5 (23 download)

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Book Synopsis Neurodegeneration and Neuroprotection in Glaucoma Retinopathy-Probing the Role of Endothelin-1, Rage, A{221} and Lycium Barbarum by : Xuesong Mi

Download or read book Neurodegeneration and Neuroprotection in Glaucoma Retinopathy-Probing the Role of Endothelin-1, Rage, A{221} and Lycium Barbarum written by Xuesong Mi and published by Open Dissertation Press. This book was released on 2017-01-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Neurodegeneration and Neuroprotection in Glaucoma Retinopathy-probing the Role of Endothelin-1, RAGE, A{221} and Lycium Barbarum" by Xuesong, Mi, 米雪松, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: In order to understand the possible mechanisms in the glaucoma-related retinopathy, the role of the vasoconstrictor, endothelin-1 (ET-1), receptor for advanced glycation end-products (RAGE) as well as its ligand, Aβ in the degeneration of retinal ganglion cells (RGCs) were studied in experimental models. In addition, the relationship of ET-1, RAGE and Aβ for the RGC protective mechanism of Lycium Barbarum (LB) was also investigated. In the first part, ET-1 together with its receptors, ETA and ETB, were studied to understand their possible roles in chronic ocular hypertension (COH). The neuronal protective mechanism of LB was also determined by using a well established COH rat model. In normal rats, ET-1 and its receptors, ETA and ETB, were distributed in the retina, vasculature and optic nerve. Interestingly, ET-1 expression was up-regulated after COH. LB could decrease the expression of ET-1 and regulate its receptors (up-regulation of ETB and down-regulation of ETA in vasculature; up-regulation of ETA and down-regulation of ETB in RGCs) under the condition of COH. These data suggested that the RGC protective mechanism of LB might be related to its ability to regulate the biological effects of ET-1. To investigate the pathogenic effect of ET-1 in glaucoma, in the second part, we used transgenic mice with over-expression of ET-1 on endothelial cells (TET-1 mice). We found that beginning at 10-12 months, TET-1 mice showed a progressive retinal degeneration (loss of RGCs associated with neurons in the inner nuclear layer and outer nuclear layer of the retina) without elevation of the intraocular pressure (IOP). The data demonstrated that TET-1 mice may serve as a potential model to investigate the role of endothelial ET-1 in the pathogenesis of normal tension glaucoma and other degenerative retinopathy. To investigate whether LB plays a role on neuronal protection other than in COH, in the third part, we used an acute ocular hypertension (AOH)-induced ischemia mouse model. We found that LB could rescue RGCs under AOH insult, associating with blood vessel protection (decreasing the damage of blood-retinal-barriers and rescuing the survival of endothelial cells and pericytes) and inhibiting retinal gliosis. We also found the protective mechanism of LB was closely correlated with down-regulation of the expression of RAGE, ET-1, APP (amyloid precursor protein), AGE (advanced glycation end-product) as well as Aβ; therefore to reduce the damage effects of these RAGE-mediated reactions to the retinal neurons, blood vessels and glial cells involved in the ischemic insult. Taken together, the present study demonstrated that TET-1 mice may be a potential model for investigating the role of ET-1 in degenerative retinopathies, such as normal tension glaucoma. We also showed the neuronal protective mechanism of LB in vivo was associated with inhibiting the biological effect of ET-1 and down-regulating the damage signaling pathways mediated by the activation of RAGE and its ligands (AGE and Aβ). These results provided further understandings in the mechanism of the glaucoma-related retinopathy. In addition, LB could be a neuroprotective agent to the retina following both chronic and acute injuries. DOI: 10.5353/th_b4724392 Subjects: Neuroprotective agents Lycium chinense - Therapeutic use En

Characterization of a Cholinergic Synapse in a Model of Glaucoma

Author : Cynthia Anne Cooley-Themm
Publisher :
ISBN 13 :
Total Pages : 179 pages
Book Rating : 4.:/5 (114 download)

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Book Synopsis Characterization of a Cholinergic Synapse in a Model of Glaucoma by : Cynthia Anne Cooley-Themm

Download or read book Characterization of a Cholinergic Synapse in a Model of Glaucoma written by Cynthia Anne Cooley-Themm and published by . This book was released on 2018 with total page 179 pages. Available in PDF, EPUB and Kindle. Book excerpt: This research analyzes changes that occur at a retinal cholinergic synapse in a rat glaucoma model. Using this glaucoma model, evidence is presented to suggest a novel neuroprotective role for the release of acetylcholine (ACh) in the adult mammalian retina. Specifically, evidence is presented for changes at the synapse between two groups of neuronal cells within the adult mammalian retina, the starburst amacrine cells (SACs) and the retinal ganglion cells (RGCs). This synapse was analyzed under glaucomatous conditions and after inducing neuroprotection. The studies presented in this thesis will show that ACh released from SACs initiates neuroprotection against insult in RGCs in retinas induced with glaucoma-like conditions using a hypertonic saline injection to the episcleral vein. We believe our studies will demonstrate that cholinergic communication between these two cell types is reduced prior to the loss of RGCs in an in vivo glaucoma model but can be restored with the use of ACh enhancing pharmacological agents. Lastly, we propose a potential cell-survival signaling cascade triggered by an ACh-activated mechanism. These results can provide valuable insight into neuroprotective treatments for diseases involving neuronal cell death such as glaucoma.

Characterization of Ng2 Macrophage in Glaucoma

Author : Qian Feng
Publisher : Open Dissertation Press
ISBN 13 : 9781361337967
Total Pages : pages
Book Rating : 4.3/5 (379 download)

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Book Synopsis Characterization of Ng2 Macrophage in Glaucoma by : Qian Feng

Download or read book Characterization of Ng2 Macrophage in Glaucoma written by Qian Feng and published by Open Dissertation Press. This book was released on 2017-01-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Characterization of NG2 Macrophage in Glaucoma: an Investigation Focusing on Its Origin and Potential Roles in Ischemic Retina" by Qian, Feng, 馮茜, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Macrophage manipulation as immunomodulatory intervention in glaucoma, a leading cause to blindness characterized by retinal ganglion cell (RGC) loss, has been proposed as a promising strategy to protect RGCs from dying. Three types of macrophage in damaged retinas, microglia-derived macrophage, monocyte-derived macrophage and perivascular macrophage, together consist a highly heterogeneous population with both beneficial and detrimental functions partly resulted from their distinct origins. NG2 (Nerve/glial antigen 2) positive macrophage, a subtype of macrophage, has been considered to fulfill specific functions with neuroprotective and neurogenic potentials. Whether NG2+ macrophage can be a possible target for treatment in glaucoma is unknown. Basic information of this subtype of macrophage in ischemic retinas of a mouse glaucomatous model called acute ocular hypertension (AOH) model was obtained in this study to answer three questions. First, do NG2+ macrophage exist in mouse retina, if so, what do they like? In normal mouse retinas, NG2+ macrophage did not exist. After AOH, NG2 could be induced on macrophage. And they are unevenly distributed in the whole retina while reside in the ganglion cell layer, inner plexiform layer or inner nuclear layer. Moreover, NG2+ macrophage all contained two nuclei with typical amoeboid-like morphologies of macrophage in activation state except the rounded type. Secondly, are they associated with the surrounding cells, if so, how? Close association of RGCs and Muller cells with NG2+ macrophage was found due to their co-localization. To know how they functioned, potential roles regarding its proliferating and phagocytic abilities were revealed by its co-localization with proliferating and phagocytic markers. However, unlike NG2+ macrophage in ischemic brain, NG2+ macrophage in ischemic retina did not express neurotrophic factors while some of them were found to express interlukin-10, an anti-inflammatory cytokine. Possible neurogenic potential was also observed by its co-localization with Nestin, a neural stem cell marker. Thirdly, where do they come from? To know their origins, bone marrow chimeras combined with specific markers were used to distinguish microglia-derived macrophage, monocyte-derived macrophage and perivascular macrophage. And it was found that majority of NG2+ macrophage was originated from resident microglia, rather than monocyte-derived macrophage or perivascular macrophage. Taken together, the present study showed the basic profile of a subtype of macrophage in a mouse model of glaucoma, more accurately, NG2+ macrophage in AOH mouse retinas. NG2 expression was induced mostly in resident microglia in AOH retina as a proliferating population with phagocytic, anti-inflammatory functions, and possible neurogenic potentials. Therefore, NG2+ macrophage may be a potential candidate target for treatment of glaucoma. DOI: 10.5353/th_b5185941 Subjects: Glaucoma Macrophages

Glaucoma

Author : Jihan Salame
Publisher :
ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (134 download)

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Book Synopsis Glaucoma by : Jihan Salame

Download or read book Glaucoma written by Jihan Salame and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Glaucoma is a degenerative optic nerve disease that causes retinal ganglion cell loss and visual field loss. Current glaucoma therapy focuses on decreasing intraocular pressure with in the eye as it is one of the main risk factor, however in some patients, retinal ganglion cell death continues despite the intraocular pressure reduction. Treatment needs to shift from therapies that only control intraocular pressure to ones that focus on neuroprotection. Nerve Growth Factor (NGF) and its two receptors Trk A and p75 are expressed in the human eye and have shown a role in maintaining neuroprotection and normal eye health and vision. Growing evidence has shown a decline of NGF and its receptors in several ocular diseases, including glaucoma. This literature review examines the applicability of NGF as a treatment for glaucoma by acting as a protector of retinal ganglion cells and the optic nerve. This literature review shows NGF can exert neuroprotective effects on retinal ganglion cell (RGC) degeneration occuring in glaucoma subjects.

Endothelin-1 Mediated Decline in Mitochondrial Function Contributes to Neurodegeneration in Glaucoma

Author : Renuka M. Chaphalkar
Publisher :
ISBN 13 :
Total Pages : 137 pages
Book Rating : 4.:/5 (125 download)

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Book Synopsis Endothelin-1 Mediated Decline in Mitochondrial Function Contributes to Neurodegeneration in Glaucoma by : Renuka M. Chaphalkar

Download or read book Endothelin-1 Mediated Decline in Mitochondrial Function Contributes to Neurodegeneration in Glaucoma written by Renuka M. Chaphalkar and published by . This book was released on 2020 with total page 137 pages. Available in PDF, EPUB and Kindle. Book excerpt: Glaucoma is an optic neuropathy with multifactorial etiologies, commonly associated with elevated intraocular pressure (IOP) and characterized by degeneration of the optic nerve, loss of retinal ganglion cells (RGC), cupping of optic disc and visual field deficits, which could ultimately lead to vision loss. In most cases, glaucoma is a chronic, asymptomatic and gradually progressing neurodegenerative disease, sometimes referred to as the "silent thief of sight," hence, routine eye examinations by an ophthalmologist are critical to determine if there is a likelihood of developing the disease. Elevated IOP is a primary and the only modifiable risk factor in glaucoma. Currently, reducing IOP remains the only proven treatment to delay the progression of RGC death; however, some patients continue to have neurodegenerative effects despite lowering IOP. Therefore, development of novel neuroprotection strategies as an adjunct therapy to IOP-lowering agents will provide a valuable therapeutic strategy in glaucoma. One of the promising targets for neuroprotection is the endothelin system of peptides and their receptors. The endothelin (ET) system comprises of three vasoactive peptides (ET-1, ET-2 and ET-3), which act through two types of G-protein coupled receptors, namely, ETA and ETB receptors. Originally discovered in the cardiovascular system, the diverse expression pattern of endothelin peptides and their receptors implicate their involvement in a variety of physiological processes in the body. A growing body of evidence suggests that endothelins and their receptors are associated with neurodegeneration in glaucoma. Previous studies have demonstrated that ET-1 levels are elevated in aqueous humor (AH) and plasma of glaucoma patients. Our lab previously demonstrated that in an ocular hypertension model in rats, there was an increase in ETB as well as ETA receptor expression primarily in RGCs compared to contralateral eyes. Following IOP elevation, RGC loss was significantly attenuated in the ETB receptor-deficient rats, pointing to a causative role of the ETB receptor in glaucomatous neurodegeneration. However, the precise cellular and molecular mechanisms by which ET-1 promotes neurodegeneration through its actions on the endothelin receptors are not completely understood. Previous studies have shown that ETB receptor stimulation increases the oxidative stress and production of superoxide anions, in sympathetic neurons. Several studies point to the role of mitochondrial dysfunction and oxidative stress as contributors to glaucomatous damage in animal models of glaucoma. To investigate various molecular events contributing to the ET-1 mediated RGC loss in glaucoma, we carried out RNA-seq analysis of the translatome in rat primary RGCs following ET-1 treatment. We identified several key mitochondrial and neurodegenerative gene candidates including Atp5h, Cox17, Foxo1, Moap1 and Map3k11 that were differentially expressed in the translatome by ET-1 treatment in RGCs. Based on our RNA-seq findings, we hypothesized that ET-1 causes an increase in reactive oxygen species (ROS) by acting through the ETB receptor that produces a subsequent decline in mitochondrial function and bioenergetics ultimately predisposing RGCs to cell death. To test this hypothesis, we used an in vitro approach by utilizing rat primary culture of RGCs treated with ET-1 as well as an in vivo approach by intravitreal ET-1 injections in rodents and the Morrison's model of glaucoma in rats. Our data showed that there is a significant decrease in the expression of cytochrome c oxidase 17 copper chaperone (COX17) and ATP synthase, H+ transporting, mitochondrial F0 complex, subunit D (ATP5H), both of which are critical components of the electron transport chain and oxidative phosphorylation pathway. Using a Seahorse mitostress assay, we also found a significant decline of several mitochondrial parameters following ET-1 treatment in primary RGCs, which indicated the possibility of a disruption in the mitochondrial quality control machinery. Hence, we also explored the effect of the ET-1 treatment on the mitophagy pathway, specifically in RGCs. Our findings suggest that there is a decrease in mitophagosome formation in RGCs in the Morrison ocular hypertensive model as well as in GFP-LC3 mice injected with ET-1, indicating an impairment in the mitochondrial quality control mechanism. Our studies reveal several novel candidates that could be targeted for the development of neuroprotective approaches to treat glaucoma.

Novel Molecular Mechanisms of Neuronal and Vascular Protection in Experimental Glaucoma

Author : Mohammadali Almasieh
Publisher :
ISBN 13 : 9780494789346
Total Pages : pages
Book Rating : 4.7/5 (893 download)

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Book Synopsis Novel Molecular Mechanisms of Neuronal and Vascular Protection in Experimental Glaucoma by : Mohammadali Almasieh

Download or read book Novel Molecular Mechanisms of Neuronal and Vascular Protection in Experimental Glaucoma written by Mohammadali Almasieh and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Endothelin Receptor-mediated Neurodegeneration in Glaucoma

Author : Nolan McGrady
Publisher :
ISBN 13 :
Total Pages : 155 pages
Book Rating : 4.:/5 (13 download)

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Book Synopsis Endothelin Receptor-mediated Neurodegeneration in Glaucoma by : Nolan McGrady

Download or read book Endothelin Receptor-mediated Neurodegeneration in Glaucoma written by Nolan McGrady and published by . This book was released on 2018 with total page 155 pages. Available in PDF, EPUB and Kindle. Book excerpt: Primary open-angle glaucoma (POAG) is a complex set of optic neuropathies which are characterized by the degeneration of the optic nerve, cupping of the optic disk and loss of retinal ganglion cells (RGCs). There are approximately 3 million Americans who currently suffer from this disease although this is most likely an underestimation since many individuals with glaucoma are unaware that they have the disease. POAG is an age-related disease progressing slowly over the course of several decades and is most commonly associated with an elevation in intraocular pressure (IOP). Currently available treatments for glaucoma, both surgical and pharmacological, are solely focused on the regulation of IOP; nevertheless, some individuals continue to show progressive damage despite being on available therapies. In recent years, there has been increased momentum towards the development of neuroprotective strategies for POAG, particularly in preclinical models of glaucoma. Despite these efforts, there is still no neuroprotective treatment currently available for glaucoma patients. A potential target for the development of a neuroprotective approach is the endothelin system of peptides and their receptors. The endothelin (ET) system is composed of three vasoactive peptides (ET-1, ET-2 and ET-3) which are comprised of 21-amino acids. The peptides bind to two G-protein coupled receptors (ETA and ETB receptors) leading to activation of numerous signal transduction pathways. Although originally described for its role in the vasculature, all components of the ET system has been shown to be expressed in multiple tissues and cell types and are responsible for diverse cellular effects. Clinical studies have demonstrated an increase in ET-1 concentrations both in the aqueous humor and plasma of glaucoma patients. A previous study by our lab, using a rodent model of ocular hypertension, showed that endothelin B (ETB) receptor expression is increased when compared to control eyes and contributes to neurodegeneration (Minton et al., 2012). Preliminary data in the current study, using Brown Norway rats, demonstrated that ETA expression is also increased in the IOP elevated eyes, suggesting the possibility that the ETA receptor might also have a degenerative role during ocular hypertension. We hypothesize that the ETA expression increases following IOP elevation and contributes to the neurodegeneration of retinal ganglion cells and their axons. To test this hypothesis we employed a well-characterized in vivo model of glaucoma as well as multiple cellular and molecular approaches to understand the role of the ETA receptor in glaucomatous degeneration. Our data suggest that overexpression of the ETA receptor promotes cell death in cultured RGCs. Since both ETA and ETB receptors appear to contribute to neurodegeneration, we tested the ability of an FDA approved medication, macitentan, for neuroprotection in the Morrison model of glaucoma in rats and found it to promote RGC survival. Our studies raise the possibility of testing macitentan as a neuroprotective treatment for glaucoma patients.

Glaucoma-induced Cell Loss in the Retinal Ganglion Cell Layer Can be Prevented Using Nicotine in an in Vivo Rat Model

Author : P. J. Birkholz
Publisher :
ISBN 13 :
Total Pages : 142 pages
Book Rating : 4.:/5 (746 download)

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Book Synopsis Glaucoma-induced Cell Loss in the Retinal Ganglion Cell Layer Can be Prevented Using Nicotine in an in Vivo Rat Model by : P. J. Birkholz

Download or read book Glaucoma-induced Cell Loss in the Retinal Ganglion Cell Layer Can be Prevented Using Nicotine in an in Vivo Rat Model written by P. J. Birkholz and published by . This book was released on 2011 with total page 142 pages. Available in PDF, EPUB and Kindle. Book excerpt: Previous in-vitro studies have demonstrated that ACh has a neuroprotective effect against glutamate-induced excitotoxicity in retinal ganglion cells (ECGs) through activation of nicotinic ACh receptors (Wehrwein et al., 2004, Thompson et al., 2006, Asomugha et al., 2009). However, any physiological role of ACh as a neuroprotective agent in the intact retina is unknown. To address this issue, we propose to analyze the neuroprotective effect of the ACh agonist, nicotine, in an in-vivo model of glaucoma using adult Long Evans rats. In these experiments, the left eye in each adult rat was left untreated and used as an internal control. In the right eye, hypertonic saline (0.5 ml of 2 mM NaCl) was injected into the episcleral vein to induce glaucoma (Morrison et al., 1997). After one month, the rats were sacrificed and the retinas were removed, flat mounted, fixed and nuclei were stained with Cresyl Violet. Stained cells in the RGC layer in gaucoma-induced retinas were counted and compared to the number of cells counted in the RCG layer under untreated conditions. This model of glaucoma was used to determine if nicotine could prevent loss of RGCs using an intravitreal injection, eye drops, and transdermal patches. These results support the hypothesis that hypertonic saline injections into the episcleral vein leads to loss of cells from the EGC layer and can be used as a robust in-vivo model of glaucoma. Results from these studies suggest that nicotine, or other nicotinic agents, could be used in future therapeutic treatment for glaucoma.

Webvision

Author : Helga Kolb
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (53 download)

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Book Synopsis Webvision by : Helga Kolb

Download or read book Webvision written by Helga Kolb and published by . This book was released on 2007 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Neuroprotective Effects of Brn3b in PC12 Cells and Retinal Ganglion Cells Under Glaucomatous Conditions

Author : Nitasha R. Phatak
Publisher :
ISBN 13 :
Total Pages : 152 pages
Book Rating : 4.:/5 (964 download)

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Book Synopsis Neuroprotective Effects of Brn3b in PC12 Cells and Retinal Ganglion Cells Under Glaucomatous Conditions by : Nitasha R. Phatak

Download or read book Neuroprotective Effects of Brn3b in PC12 Cells and Retinal Ganglion Cells Under Glaucomatous Conditions written by Nitasha R. Phatak and published by . This book was released on 2016 with total page 152 pages. Available in PDF, EPUB and Kindle. Book excerpt: Glaucoma is a group of chronic progressive optic neuropathies commonly characterized by elevated intraocular pressure (IOP) (a subset of glaucoma patients display neurodegenerative effects at ‘normal’ IOP) leading to axonal degeneration, optic nerve head cupping and apoptosis of retinal ganglion cell death (RGCs), which result in visual field defects and blindness. While there are medications available to lower IOP, there is an unmet need for neuroprotective treatments for glaucoma, since some neurodegenerative effects persist despite lowering IOP. The main focus of this study was on the class 4 POU domain transcription factor, Brn3b, which has been shown to play a key role in the development of RGCs. Two previous studies from other labs showed that a decrease in Brn3b expression occurs in animal model of glaucoma. A recent publication from our laboratory demonstrated neuroprotective effects of adeno-associated virus (AAV) mediated expression of Brn3b in a rat model of ocular hypertension. This research project identified some mechanisms of Brn3b-mediated neuroprotection in cultured PC12 cells (under the condition of hypoxia) and also in vivo in the Morrison's model of ocular hypertension in rats. In the first part of the study, we demonstrated the effect of overexpression of Brn3b on various markers of synaptic plasticity in PC12 cells under conditions of normoxia as well as hypoxia. Immunoblot as well as immunocytochemical analyses revealed an increase in expression of neurite growth markers, GAP-43 and ac-TUBA, by Brn3b upregulation both under conditions of normoxia as well as hypoxia. . This suggests that transcription factor Brn3b has the ability to upregulate expression genes contributing to synaptic plasticity genes both under ‘normal’ conditions and during a glaucomatous insult (hypoxia). In the concluding part of this study, cell survival factors including, Bcl-2, Bcl-xL and p-AKT were studied as potential targets of Brn3b-mediated neuroprotection. Adeno-associated virus-mediated expression of Brn3b in rat eyes with elevated IOP promoted an upregulation of Bcl-2, Bcl-xL and p-AKT in RGCs, as determined by immunohistochemistry. Taken together, the evidence suggests that Brn3b has the potential to be developed as a therapeutic agent for neuroprotection during ocular neurodegenerative diseases like glaucoma.

The Neuroprotective Effect of Lycium Barbarum Polysaccharides on Retinal Neurons in a Novel Acute Glaucoma Attack Animal Model

Author : Yuk-Fan Silvania Lau
Publisher : Open Dissertation Press
ISBN 13 : 9781361286593
Total Pages : pages
Book Rating : 4.2/5 (865 download)

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Book Synopsis The Neuroprotective Effect of Lycium Barbarum Polysaccharides on Retinal Neurons in a Novel Acute Glaucoma Attack Animal Model by : Yuk-Fan Silvania Lau

Download or read book The Neuroprotective Effect of Lycium Barbarum Polysaccharides on Retinal Neurons in a Novel Acute Glaucoma Attack Animal Model written by Yuk-Fan Silvania Lau and published by Open Dissertation Press. This book was released on 2017-01-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "The Neuroprotective Effect of Lycium Barbarum Polysaccharides on Retinal Neurons in a Novel Acute Glaucoma Attack Animal Model" by Yuk-fan, Silvania, Lau, 劉玉芬, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Acute glaucoma is an ocular emergency and sight -threatening disease which is caused by a sudden increase in intraocular ocular pressure (IOP) due to blockage of aqueous humor outflow. Acute glaucoma can result in permanent loss of visual acuity and visual field (VF). Prophylactic or therapeutic medicine is rare for acute glaucoma. In animal studies, a well-established model to investigate this acute IOP spike is by fluid infusion and adjustment of the fluid level to induce high IOP within a few seconds. However, there is no blockage of aqueous outflow and the increase in intraocular pressure is unrealistically rapid. To mimic the IOP profile in human acute glaucoma attack, we propose the use of an ophthalmic viscosurgical device (OVD), Healon 5 (AMO, Santa Ana, CA, USA) which is injected intracamerally to block aqueous outflow. The IOP is allowed to increase naturally inside the globe. We found that Healon 5 can induce an acute elevation in IOP with very similar characteristics to those observed in humans. For example, the IOP profile during the attack, changes in the anterior segment and retinal nerve fibre layer (RNFL) thinning are all consistent with findings in human acute angle closure glaucoma (AACG). We believed that our new model can more accurately reflect acute glaucoma than other animal models. Based on these findings we further tested the neuroprotective effect of Lycium barbarum polysaccharides (LBP) on retinal neurons against an acute rise in IOP (attack) with the new model. L. barbarum is an herb that has been used in Chinese medicine for thousands of years. The fruit of this plant is believed to be good for the health of the eyes. In our study we found that oral administration of LBP preceding an acute glaucoma attack can preserve the visual function of the animals despite the loss of neurons in the retinal ganglion cell layer (RGCL). L. barbarum intake seems to inhibit secondary cell death and progression of the disease. In conclusion, we had successfully established a new acute glaucoma attack animal model by intracameral injection of Healon 5. This model more closely resembles the condition observed in human acute glaucoma. We also found that LBP has a prophylactic neuroprotective effect against an acute glaucoma attack in animals. It can protect the visual function and possibly inhibit secondary cell death. Oral consumption of LBP as a health supplement may provide extra benefit to people who are at high risk of developing acute glaucoma, in addition to the protective effects of LBP against other diseases. DOI: 10.5353/th_b4730932 Subjects: Neuroprotective agents Lycium chinense - Therapeutic use Glaucoma

Perspective on Gene Therapy for Glaucoma

Author : Hilda Petrs-Silva
Publisher :
ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (139 download)

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Book Synopsis Perspective on Gene Therapy for Glaucoma by : Hilda Petrs-Silva

Download or read book Perspective on Gene Therapy for Glaucoma written by Hilda Petrs-Silva and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Glaucoma is a chronic and multifactorial neurodegenerative disease marked by structural damage to the optic nerve with axonal loss, progressive retinal ganglion cell degeneration, and optic disc excavation. Both high intraocular pressure and aging are important risk factors, but not essential to the progression of glaucomatous neurodegeneration. Current treatments are based on controlling intraocular pressure, which is not always effective in avoiding the progression of visual loss. In this sense, novel therapeutic strategies to glaucoma should aim to promote the neuroprotection of both the cell soma of retinal ganglion cells and the axons of the optic nerve. Gene therapy is a new therapeutical approach to glaucoma with a great capacity to overcome neurodegeneration. It consists of the transfer of exogenous genetic material to target cells with a therapeutic purpose. Gene therapy strategies for glaucoma include both the neuroprotection aiming to prevent cell soma and axonal loss and the regeneration of optic nerve axons. In this chapter, we review the most promising current gene therapies for glaucoma that address the various aspects of glaucoma pathology. We also discuss the potential of combining neuroprotective and regenerative strategies to reach a synergic effect for the treatment of glaucoma.