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excitotoxicity induced by excess glutamate. Notes: extensive stimulation of NMDARs by glutamate leads to high level of Ca 2+ to enter the cell, activating enzymes including phospholipases, endonucleases, and proteases. These enzymes may lead to apoptosis of the cell. Abbreviation: NMDAR, N-methyl-d-aspartic acid receptor.
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Glaucoma is the second leading cause for blindness worldwide. It is mainly caused by glaucomatous optic neuropathy (GON) characterized by retinal ganglion cell loss, which leads to visual field defect and blindness. Up to now, the main purpose of antiglaucomatous therapies has been to lower intraocular pressure (IOP) through surgeries and medicatio...
Context in source publication
Context 1
... extensive stimulation of NMDARs allows high level of Ca 2+ to enter the cell, activating enzymes including phos pholipases, endonucleases, and proteases such as calpain. These enzymes may lead to the damage of plasma mem brane, cytoskeleton, and DNA, and other cell components ( Figure 3). 27 Dreyer et al showed a twofold elevation in the glutamate level in the vitreous body of glaucoma patients, indicating the possibility of an excitotoxic mechanism resulting in RGC death. ...
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Glaucoma is a leading cause of irreversible blindness and characterized by progressive damage of retinal ganglion cells (RGCs). Growing evidences have linked impaired mitophagy with neurodegenerative diseases, while the E3 ubiquitin ligase parkin may play a key role. However, the pathophysiological relationship between parkin and glaucoma remains l...
Background
The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in neuronal pathophysiology. Using JNK inhibitors, we examined involvement of the JNK pathway in cultured rat retinal ganglion cell (RGC) death and in mouse retinal ischemia/reperfusion (I/R) injury of the visual axis. The in vitro effects of JNK inhibitors were...
Citations
... In recent years, several new treatment strategies have been proposed and investigated in preclinical models focusing on RGC neuroprotection through applying the pharmacological approach to protect against optic nerve damage and RGC apoptosis. This includes a variety of neuroprotectors such as anti-apoptotic agents [45], neurotrophic factors [46], Nitric oxide synthase antagonists [47], and antioxidants [48]. Most recently, gene therapy approaches [49], and stem cell transplantation therapy [50], have been attempted. ...
... The role of glial cells in supporting the RGCs is complex. Under normal physiological conditions, these cells protect the RGCs through providing metabolic and neuroprotective support as well as sustaining the homeostasis of the extracellular matrix of these cells [46,52]. However, upon exposure to high IOP injury, glial cells are activated and trigger RGCs apoptosis through a variety of mechanisms such as secreting elevated levels of tumor necrosis factor alpha (TNF-a) or nitric oxide (NO) which activate the apoptotic pathway in RGCs with resultant cell death [53]. ...
... The primary factor in permanent blindness, glaucoma is characterised by selective loss of retinal ganglion cells (RGC) [32] as a result of oxidative stress, apoptosis, and neuroinflammation [31] . Increased intraocular pressure (IOP), which can be brought on by either an increase in aqueous fluid production or a decrease in its outflow, results in optic nerve injury in this situation [33] . ...
... The main approach for therapeutic modalities is focused on trabecular meshwork and aqueous humor outflow pathways [6]. Treatment interventions for the same include topical use of anti-glaucoma drugs, laser surgery, and minimally invasive glaucoma surgery to reduce intraocular pressure [7]. It has been found that the risk of blindness among patients treated for OAG is high and estimated to be up to 27% [8]. ...
Glaucoma is a leading cause of irreversible blindness, and its prevalence has led to research into treatment modalities for glaucoma to prevent the progression of the disease. The primary treatment for glaucoma that has been extensively used is ocular hypotensives to reduce raised intraocular pressure. This treatment has its drawbacks due to the existence of other variants of glaucoma, such as normal-tension glaucoma, where the intraocular pressure is measured to be within regular levels. Hence, there is a need for new treatment interventions which can deliver a better prognosis for glaucoma. Neuroprotection is a new concept studied recently, and neuroprotective agents are being developed for glaucoma therapy. Rho kinase inhibitors are one such neuroprotective agent, and the most recent addition to the class of ocular hypotensives, where they function by reducing raised intraocular pressure. Its neuroprotective capabilities, such as cell survival and axon regeneration, are yet to be determined in detail. This literature review article aims to look into the need for new treatments such as neuroprotection to prevent the progression of glaucoma and the efficacy of rho kinase inhibitors in the treatment of glaucoma, with particular emphasis on its neuroprotective abilities. It also aims to identify the limitations that can occur while approaching neuroprotective therapy, as well as how it can enable future treatment modalities. By exploring this field, blindness caused by progressive glaucoma can be halted and managed by glaucoma therapy.
... Delivery of neurotrophic factors, inhibition of apoptosis signaling cascades by molecular methods, and suppression of oxidative stress and inflammation are the most important neuroprotective strategies that have already been studied in this regard. 2,3 However, these modalities have not been very successful to improve the clinical outcome, and new methods are needed to efficiently protect nerve cells and prevent them from progressive degeneration after the insult. 4 Stem cell-derived secretomes are increasingly being investigated as neuroprotective agents. ...
Purpose:
Retinal ganglion cells (RGCs) are one the most specialized neural tissues in the body. They transmit (and further process) chemoelectrical information originating in outer retinal layers to the central nervous system. In fact, the optic nerve is composed of RGC axons. Like other neural cells, RGCs will not completely heal after the injury, leading to irreversible vision loss from disorders such as glaucoma that primarily affect these cells. Several methods have been developed to protect or regenerate RGCs during or after the insult has occurred. This study aims to review the most recent clinical, animal and laboratory experiments designed for the regeneration of RGC that apply the stem cell-derived secretome.
Methods:
We extracted the studies from Web of Science (ISI), Medline (PubMed), Scopus, Embase, and Google scholar from the first record to the last report registered in 2022, using the following keywords; "secretome" OR "conditioned medium" OR "exosome" OR "extracellular vesicle" AND "stem cell" AND "RGC" OR "optic neuropathy". Any registered clinical trials related to the subject were also extracted from clinicaltrial.gov. All published original studies that express the effect of stem cell secretome on RGC cells in optic neuropathy, whether in vitro, in animal studies, or in clinical trials were included in this survey.
Results:
In this review, we provided an update on the existing reports, and a brief description of the details applied in the procedure. Compared to cell transplant, applying stem cell-derived secretome has the advantage of minimized immunogenicity yet preserving efficacy via its rich content of growth factors.
Conclusions:
Different sources of stem cell secretomes have distinct implications in the management of RGC injury, which is the main subject of the present article.
... The hallmark feature of glaucoma is axonal (optic nerve) degeneration with progressive loss of retinal ganglion cells (RGCs) somas (2). Currently, glaucoma management predominantly aims to lower the intraocular pressure (IOP) as it is considered the primary risk factor for the initiation and progression of glaucomatous optic neuropathy (3). Yet, a significant number of glaucoma cases continuously exhibit vision loss even when the IOP is controlled, and most IOP-dependent medications are accompanied by adverse effects (1). ...
Glaucoma is an irreversible sight-threatening disorder primarily due to elevated intraocular pressure (IOP), leading to retinal ganglion cell (RGC) death by apoptosis with subsequent loss of optic nerve fibers. A considerable amount of empirical evidence has shown the significant association between tumor necrosis factor cytokine (TNF; TNFα) and glaucoma; however, the exact role of TNF in glaucoma progression remains unclear. Total inhibition of TNF against its receptors can cause side effects, although this is not the case when using selective inhibitors. In addition, TNF exerts its antithetic roles via stimulation of two receptors, TNF receptor I (TNFR1) and TNF receptor II (TNFR2). The pro-inflammatory responses and proapoptotic signaling pathways predominantly mediated through TNFR1, while neuroprotective and anti-apoptotic signals induced by TNFR2. In this review, we attempt to discuss the involvement of TNF receptors (TNFRs) and their signaling pathway in ocular tissues with focus on RGC and glial cells in glaucoma. This review also outlines the potential application TNFRs agonist and/or antagonists as neuroprotective strategy from a therapeutic standpoint. Taken together, a better understanding of the function of TNFRs may lead to the development of a treatment for glaucoma.
... Glaucoma comprises a group of neurodegenerative diseases, leading to optic nerve damage and retinal ganglion cell death, which ultimately results in vision loss [11,12]. Most forms of glaucoma are associated with an increased intraocular pressure (IOP) [13]. ...
Topical drug delivery to the posterior segment of the eye is a very complex challenge. However, topical delivery is highly desired, to achieve an easy-to-use treatment option for retinal diseases. In this review, we focus on the drug characteristics that are relevant to succeed in this challenge. An overview on the ocular barriers that need to be overcome and some relevant animal models to study ocular pharmacokinetics are given. Furthermore, a summary of substances that were able to reach the posterior segment after eye drop application is provided, as well as an outline of investigated delivery systems to improve ocular drug delivery. Some promising results of substances delivered to the retina suggest that topical treatment of retinal diseases might be possible in the future, which warrants further research.
... This includes glutamate excitotoxicity (Weber et al., 1995;Perlman et al., 1996;Lagreze et al., 1998), protein misfolding (McKinnon et al., 2002;Goldblum et al., 2007;Kipfer-Kauer et al., 2010;Ito et al., 2012;Chiasseu et al., 2016), mitochondrial dysfunction (Abu-Amero et al., 2006;Kong et al., 2009;Osborne and del Olmo-Aguado, 2013), oxidative stress (Ferreira et al., 2004;Feilchenfeld et al., 2008;Gherghel et al., 2013;Goyal et al., 2014;Kimura et al., 2017), inflammation and autoimmune disorder (Wax et al., 1994;Tezel et al., 1998;Wax et al., 1998;Kremmer et al., 2004;Bell et al., 2013;Gramlich et al., 2013), and neurotrophic factors deprivation (Johnson et al., 2000;Quigley et al., 2000;Rudzinski et al., 2004;Knox et al., 2007). They can also be applied to intervene with the apoptotic cascade (Quigley et al., 1995;Song et al., 2015) and modulate glial responses (Tezel, 2009). Currently, none of these interventions have been approved for clinical use. ...
In recent years, the pharmacological benefits of herbal extracts have been revisited for their potential neuroprotective effects in glaucoma. The polysaccharides extracted from the fruits of Lycium barbarum L., or Lycium barbarum polysaccharides, exert their anti-aging effect through reducing oxidative stress, modulating the immune response, enhancing neuronal responses, and promoting cytoprotection. The therapeutic efficacy of Lycium barbarum polysaccharides in preserving retinal ganglion cells and their functions was demonstrated in a range of experimental models of optic neuropathies. These include the acute and chronic ocular hypertension models, the partial optic nerve transection model, and the ischemic-reperfusion injuries model. Based on these findings, Lycium barbarum polysaccharides appear to be a good candidate to be developed as a neuroprotective agent for treating multifactorial diseases. This review aims to present a comprehensive review on the latest preclinical evidence on the pre- and post-treatment benefits of Lycium barbarum polysaccharides in retinal ganglion cell neuroprotection. The possible mechanisms of Lycium barbarum polysaccharides mediating retinal ganglion cell neuroprotection will also be described. Moreover, the potential research gaps in the effective translation of Lycium barbarum polysaccharides treatment into clinical glaucoma management will be discussed.
... Most recent therapies are focused on lowering intraocular pressure (IOP) as it is considered the primary risk factor for the onset and progression of glaucomatous optic neuropathy (Song et al., 2015). However, recent evidence seems to suggest that glaucoma progression is not halted in all patients even after the lowering of IOP because numerous risk factors are involved in RGC apoptosis and elevated IOP is only one of them (Sihota et al., 2018). ...
Magnesium acetyltaurate (MgAT) has been shown to have a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal cell apoptosis. The current study investigated the involvement of nuclear factor kappa-B (NF-κB), p53 and AP-1 family members (c-Jun/c-Fos) in neuroprotection by MgAT against NMDA-induced retinal damage. In this study, Sprague-Dawley rats were randomized to undergo intravitreal injection of vehicle, NMDA or MgAT as pre-treatment to NMDA. Seven days after injections, retinal ganglion cells survival was detected using retrograde labelling with fluorogold and BRN3A immunostaining. Functional outcome of retinal damage was assessed using electroretinography, and the mechanisms underlying antiapoptotic effect of MgAT were investigated through assessment of retinal gene expression of NF-κB, p53 and AP-1 family members (c-Jun/c-Fos) using reverse transcription-polymerase chain reaction. Retinal phospho-NF-κB, phospho-p53 and AP-1 levels were evaluated using western blot assay. Rat visual functions were evaluated using visual object recognition tests. Both retrograde labelling and BRN3A immunostaining revealed a significant increase in the number of retinal ganglion cells in rats receiving intravitreal injection of MgAT compared with the rats receiving intravitreal injection of NMDA. Electroretinography indicated that pre-treatment with MgAT partially preserved the functional activity of NMDA-exposed retinas. MgAT abolished NMDA-induced increase of retinal phospho-NF-κB, phospho-p53 and AP-1 expression and suppressed NMDA-induced transcriptional activity of NF-κB, p53 and AP-1 family members (c-Jun/c-Fos). Visual object recognition tests showed that MgAT reduced difficulties in recognizing the visual cues (i.e. objects with different shapes) after NMDA exposure, suggesting that visual functions of rats were relatively preserved by pre-treatment with MgAT. In conclusion, pre-treatment with MgAT prevents NMDA induced retinal injury by inhibiting NMDA-induced neuronal apoptosis via downregulation of transcriptional activity of NF-κB, p53 and AP-1-mediated c-Jun/c-Fos. The experiments were approved by the Animal Ethics Committee of Universiti Teknologi MARA (UiTM), Malaysia, UiTM CARE No 118/2015 on December 4, 2015 and UiTM CARE No 220/7/2017 on December 8, 2017 and Ethics Committee of Belgorod State National Research University, Russia, No 02/20 on January 10, 2020.
... Oxidative stress is also a likely contributing factor in the pathogenesis of glaucoma. Studies have shown that antioxidants such as Coenzyme Q10, alpha-lipoic acid, superoxide dismutase, ginkgo biloba leaf extract, and bilberry leaf extract decrease RGC loss in rat models of glaucoma (88). ...
Purpose: To investigate the trends and progresses in glaucoma research by searching two major clinical trial registries; clinicaltrials.gov , and Australianclinicaltrials.gov.au .
Methods: All clinical trials with glaucoma covered by Clinicaltrials.gov , and Australianclinicaltrials.gov.au starting the study before 1 January 2021 were included. Trials evaluating glaucoma treatment were separated from non-treatment trials and divided into three major categories: “laser treatment,” “surgical treatment,” and “medical treatment.” In the category of “medical treatment,” new compounds and their individual targets were identified and subcategorized according to treatment strategy; intraocular pressure (IOP)-lowering, neuroprotective or vascular. The phase transition success rates were calculated.
Results: One-thousand five hundred and thirty-seven trials were identified. Sixty-three percent ( n = 971) evaluated glaucoma treatment, of which medical treatment accounted for the largest proportion (53%). The majority of medical trials evaluated IOP-lowering compounds, while trials with neuroprotective or vascular compounds accounted for only 5 and 3%, respectively. Eighty-eight new compounds were identified. Phase I, II, and III transition success rates were 63, 26, and 47%, respectively.
Conclusion: The number of clinical trials in glaucoma research has increased significantly over the last 30 years. Among the most recently evaluated compounds, all three main treatment strategies were represented, but clinical trials in neuroprotection and vascular modalities are still sparse. In addition to traditional medicines, dietary supplements and growth factors are assessed for a potential anti-glaucomatous effect. Phase II and III success rates were below previously reported success rates for all diseases and ophthalmology in general. A stricter phenotyping of patients can improve the success rates in glaucoma and ophthalmological research and gain a better understanding of responders and non-responders.
... Glaucoma is the leading cause of irreversible blindness in the world, and it is estimated that in 2020, approximately 80 million people had glaucoma, of which 11.2 million had a bilateral form [1,2]. This condition causes selective damage to retinal ganglion cells (RGC) [3], resulting in oxidative stress, apoptosis, and neuroinflammation [4]. For this reason, glaucoma should be considered a neuropathy characterized by specific structural degenerative alterations of the optic nerve, leading to visual impairments [5]. ...
Background:
Glaucoma is currently the leading cause of irreversible blindness; it is a neuropathy characterized by structural alterations of the optic nerve, leading to visual impairments. The aim of this work is to develop a new oral formulation able to counteract the early changes connected to glaucomatous degeneration. The composition is based on gastrodin and vitamin D3 combined with vitamin C, blackcurrant, and lycopene.
Methods:
Cells and tissues of the retina were used to study biological mechanisms involved in glaucoma, to slow down the progression of the disease. Experiments mimicking the conditions of glaucoma were carried out to examine the etiology of retinal degeneration.
Results:
Our results show a significant ability to restore glaucoma-induced damage, by counteracting ROS production and promoting cell survival by inhibiting apoptosis. These effects were confirmed by the intracellular mechanism that was activated following administration of the compound, either before or after the glaucoma induction. In particular, the main results were obtained as a preventive action of glaucoma, showing a beneficial action on all selected markers, both on cells and on eyecup preparations. It is therefore possible to hypothesize both the preventive and therapeutic use of this formulation, in the presence of risk factors, and due to its ability to inhibit the apoptotic cycle and to stimulate cell survival mechanisms, respectively.
Conclusion:
This formulation has exhibited an active role in the prevention or restoration of glaucoma damage for the first time.
