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Open Access Review

Neuropathology and Therapeutics Addressing Glaucoma, a Prevalent Retina-Optic Nerve-Brain Disease that Causes Eyesight Impairment and Blindness

Najam A. Sharif 1,2,3,4,5,6,7,*

  1. Imperial College of Science and Technology, St. Mary's Campus, London, UK

  2. Singapore Eye Research Institute (SERI), Singapore

  3. Duke-National University of Singapore Medical School, Singapore

  4. Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas, USA

  5. Department of Pharmacy Sciences, Creighton University, Omaha, Nebraska, USA

  6. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA

  7. Global Alliances and External Research, Ophthalmology Innovation Center, Santen Incorporated, Emeryville, CA, USA

Correspondence: Najam A. Sharif

Academic Editor: Bart Ellenbroek

Received: January 24, 2022 | Accepted: March 20, 2022 | Published: March 22, 2022

OBM Neurobiology 2022, Volume 6, Issue 1, doi:10.21926/obm.neurobiol.2201116

Recommended citation: Sharif NA. Neuropathology and Therapeutics Addressing Glaucoma, a Prevalent Retina-Optic Nerve-Brain Disease that Causes Eyesight Impairment and Blindness. OBM Neurobiology 2022; 6(1): 116; doi:10.21926/obm.neurobiol.2201116.

© 2022 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Glaucomatous optic neuropathy (GON) associated with different forms of glaucoma and chronic ocular hypertension (cOHT) is characterized by progressive loss of retinal ganglion cells and their axons in the optic nerves that project to the brain to transmit visual information. The resultant thinning of the optic nerves cause loss of peripheral vision, which if not halted or slowed, can lead to irreversible blindness. Whilst the precise triggering insult(s) for the primary open angle glaucoma (POAG), the most prevalent of the glaucomas, remains unknown, the most prominent risk factors include elevated intraocular pressure, increasing age, African-American heritage (genetic predisposition), family history, low cerebral spinal/intracranial pressure, and vascular dysfunctions within the retina. However, whilst reduction of IOP by topical ocularly administered medications is the first-line therapeutic approach to address cOHT / POAG, surgical procedures and aqueous humor drainage devices are also useful means to lower IOP. It is hoped that the intense research into mechanisms underlying neurodegeneration has the potential to lead to discovery of potential neuroprotective and neuroregenerative agents s and technologies including novel sustained drug delivery platforms, gene therapy, cell therapy, physical support systems, food-derived nutrient treatments, neurostimulation via optogenetic, electrical and sonogenetic tools, yielding suitable treatments to treat cOHT / POAG and the attendant GON.

Keywords

Glaucoma; ocular hypertension; glaucomatous optic neuropathy; AQH drainage device; optic nerve degeneration; optic nerve head; retinal ganglion cells; nerve regeneration; neuroprotection

1. Introduction to the Eye and Visual System

As windows for the brain and providing vision, our eyes have a special place amongst the many organs within our bodies. Of the five senses, loss of sight is perceived as one of the most devastating and sorrowful event in the lives of those who experience such an unfortunate fate. Thus, preservation of vision is an extremely important and noble goal for mankind. The eye is indeed a very special organ with a complex structure composed of diverse cell-types with specific functions in the visual system (Figure 1A). At a gross level, compartmentalized into the anterior chamber (ANC) and posterior chamber (PSC) divided by the lens, the fluids within each segment are also unique with a watery nutritive fluid (aqueous humor; AQH [1]) bathing the ANC and a gelatinous material (vitreous humor) existing in the PSC. While cells lining the ANC are nourished by the AQH, a retinal blood supply provides nutrients to the retinal cells and which also removes metabolites and other substances from the retina, a very active energy-utilizing tissue. In that respect, the trabecular meshwork (TM) system [2,3,4,5], which is connected to the Schlemm’s canal (SC; [6,7,8]) which empties the AQH into the veinous circulation, is also an active tissue that filters the AQH and digests debris present in the AQH (Figure 1B). This activity helps maintain a homeostatic environment which permits the eyeball to retain a constant shape such that the clarity of the AQH provides light a clear unobstructed path to reach the lens and be focused onto the retina [9]. Obviously, any event or factor that compromises the normal functions of the TM and those of the various retinal cells and the optic nerve poses grave consequences for the visual system. Indeed, TM dysfunction causes chronic ocular hypertension (cOHT; [9]) and damages ganglion cells (which are of different types depending on their receptive field, dendritic branching and conduction velocities [10,11]) and their axons (that form the optic nerve [12]) through mechanical stretching and disruption of retinal tissue at the back of the eye which eventually leads to damage of retinal-optic nerve-brain connections resulting in various degrees of visual impairment.

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Figure 1 Anatomical location of various ocular tissues of the human eye are shown (A). AQH production and drainage from the anterior chamber of the eye via the conventional outflow pathway (via TM) and the uveoscleral (UVSC) pathway are also depicted (B).

Many specialized cells make up the retina including retinal ganglion cells (RGCs) [10,11], interneurons (e.g. amacrine cells, horizontal cells and bipolar cells), Muller glia, photoreceptors (rods and cones), and retinal pigmented epithelial (RPE) cells (Figure 2A, Figure 2B). At the back of the eye, RPE cells lie adjacent to an outer limiting Bruch’s membrane that separates the capillaries of the choroidal circulation from the RPE cells. At the anterior end of the retinal tissue is the inner limiting membrane that seperates the RGC axons from the vitreous humor (Figure 2B). Bundles of unmyelinated axons of RGCs, that form the retinal nerve fiber layer (RNFL) [13], gather from both sides of the retina towards the mid-line. The axon bundles make a 90-degree turn towards the back of the eye and make an exit from the eye at a site called the optic nerve head (ONH [13,14]). As these axons traverse the width of the retina they pass through a honey-combed structure, lamina cribosa (LC) (Figure 1A, Figure 2B [15,16,17]), and eventually become parts of the optic nerve. In order to optimally conduct the electrical signals generated by the RGCs, their axons are myelinated when they are bundled together to form the optic nerves as they exit the back of the eyeball. The optic nerves cross over at the optic chiasm to innervate the thalamic, pre-tectal and suprachiasmatic nuclei of the contralateral sides of the brain [18,19]. From there, relay axons project to different layers of the visual cortex [20] which are responsible for decoding the electrical signals from the RGCs for visual perception of the objects bein seen by the eyes (Figure 3).

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Figure 2 The elevated IOP-induced mechanical distortion affects all part of the eye and detrimentally impacts the back of the eye structures (A). In particular, the RGCs are injured through activation of resident and invading microglia (B) which release numerous toxic substances such as cytokines, glutamate, NO and endothelin. Note: these events do not necessarily occur sequentially. Also, since numerous types of RGCs exist with different levels of sensitivity to the toxins, not all RGCs are equally affected. Many types of interneurons in the retina are also subject to injury and damage by the deleterious factors in the extracellular space.

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Figure 3 This schematic illustrates as a top-view of the components of the visual system encompassing the eye, retina, optic nerves, thalamic and cortical connections. The various layers of the lateral geniculate nuclei (LGN) composed of the parvocellular and magnocellular cells are depicted in the inset.

2. Retinal and Brain Involvement in Visual Processes and Vision Loss

Retinal photoreceptor initate the process of vision, once light hits the eye by converting light to electrical impulses by a hyperpolarization response. At a high-level, a cascade of neurotransmitters are released amongst the retinal cells and neurons whose interactions with specific pre- and post-synaptic receptors initiate a multitude of biochemical and electrical signals. These are progressively relayed to the RGCs which code the visual information and transmit to the brain via the optic nerve. Signal transmission from the retina to the brain occurs in approximately 0.15 seconds, and information transfer happens at roughly 10 million bits per second and vision occurs. This makes the retina and the brain extremely high energy-consuming tissues. Specificity of the visual signals reside in the different types of RGCs that exist in the retina and to the many different neurons in different layers of the lateral geniculate nuclei (LGN) (Figure 3), superior colliculus (SC), pretectal and suprachiasmatic nuclei (SCN), and of course the many different nuclei within the many layers of the visual cortex [18,19,20]. Cells within the LGN and visual cortical layers have specialized functions that code information according to color, shape, contrast, resolution, movement, etc. Furthermore, these many structures receive and send out signals to other important brain regions such as cerebellum, hippocampus and striatum, thereby permitting further modulatory actions on the visual processes and the ultimate image processing and perception by the person.

Specifically, most optic nerve terminals project to specific neurons within the LGN which sorts retinal signals into parallel streams comprised of color, structure, motion and contrast. The top four parvocellular layers of LGN handle color and resolution, while the bottom two magnocellular layers process contrast and motion (Figure 4). The corresponding primary visual cortex (PVC) is also highly organized to receive LGN inputs from their long axons to maintain fidelity and complexity of the image information. Direct mapping of RGCs is precisely imprinted in the PVC on a point-by-point basis in a columnar pattern of connections alternating between the left and right eyes that places objects perceptually in the horizontal and vertical axes. Rapid comparison of the binocular signal inputs by V1-PVC cells allows perception of depth of vision and hence objects appear in three-dimensions. As V1 cells sharpen the lines and edges of images, the cells of V2 region of PVC refines their coloration. Visual perception encompassing form and color in V3 and V4 regions of PVC, recognition of face and object in the inferior temporal lobe, and motion and spatial awareness covered by the parietal lobe of the cortex completes the overall visual picture of the objects being viewed by the person. This is a highly simplified summary of a very intricate visual system and the processes involved in visual perception, and it is hoped that it is sufficient for the current contextual purpose (Figure 4).

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Figure 4 A high-level representation of the RGC-LGN-primary visual cortical layers and the related connections are shown in this diagram. The specificity of the connections covering color, contrast and resolution of images as perceived by the visual cortex neurons is described in more detail in the text.

3. Primary Open-Angle Glaucoma (POAG): Molecular and Cellular Pathology in the Retina-Optic Nerve-Brain Axis

The second leading cause of blindness worldwide is primary open-angle glaucoma (POAG) [21,22,23,24] which is often associated with abnormally and chronically high intraocular pressure (IOP) [21,22,23,24], and spontaneous IOP spikes [25], which is in turn caused by accumulation of excess AQH in the ANC of the eye [9,21,24]. AQH retention in the ANC primarily follows after deposition of aberrant collagen, fibronectin and extracellular matrix [26,27,28,29,30] in and adjacent to the TM, where TM cells that are susceptible to stress [31,32,33] and which have reduced capacity to phagocytose and digest such debris are killed [34]. Additional reduction and/or loss of autophagic mechanisms of TM cells [3,4,9,34] exacerbate the situation causing further elevation of IOP [21,22,23,24]. This elevated IOP (Figure 2A), coupled with low intracranial fluid pressure (ICFP) [35,36,37,38] leads to constriction of the RGC axons at the LC [39] which damages the unmyelinated part of the optic nerve at the ONH and LC. Increasing evidence indicates that the LC/ONH regions of the retina which are negatively impacted by the high IOP [13,14,40] and the RGC axons there are assaulted by a range of locally released inflammatory cytokines (e.g. tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6) due to inflammasome activation [41,42,43,44,45,46], and by other cytotoxic substances (e.g. glutamate [47,48,49,50,51], ATP [52], nitric oxide [53,54,55,56,57], endothelin [58,59,60], amyloid-β (AM-β) [61,62], phosphorylated-Tau [pTau]) and matrix metalloproteinases (MMPs) and other proteases [63,64] that degrade the structural matrix of the ONH and LC (Figure 5, Figure 6) [63,64]. Such damage severely reduces the strength and integrity of the RGC axons and the surrounding ECM holding them in place, and where lipofuscin [15,65] accumulate. Again, dysfunctional autophagic processes [19,66], at the ONH/LC regions allow cellular debris to accumulate resulting in scar formation. which leads to bending and stretching of the overall optic nerves resulting in atrophy and shrinkage of the RGC axons, reduction in axonal flow of mitochondria to the RGCs, and thus reduced energy production [67,68,69,70,71] to maintain cellular functions within the RGC somas], and reduced transport of vital growth factors [72,73,74,75] to the RGC bodies and ultimate RGC senescence. Thus, many potential sites of damage within the brain-optic nerve-retina visual system exist involving multiple deleterious neurotoxic and neuroinflammatory molecules and processes [76,77,78,79,80,81,82], reduced cerebral and retinal blood-flow [83,84], and abnormally diminished cerebral spinal/intracranial pressure [35,36,37,38,39] (Figure 5, Figure 6).

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Figure 5 The various loci of damage and the different insults and factors involved in causing cOHT/POAG resulting in GON are indicated in this schematic. Many of the inflammatory, immunologic and degenerative processes probably occur simultaneously but may last over different periods of time.

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Figure 6 This cartoon shows the multitude of events and damaging molecules involved in causing injury and death of RGCs, RGC axons and their terminals in the brain structures during the course of chronic OHT / POAG / NTG. Due to the heterogeneity of the RGCs and differential susceptibility and sensitivity to physical pressure and toxic agents, it is likely that not all patients will experience the same degree of visual impairment and their disease progression will also differ.

The cascade of damaging events described above, some happening sequentially and some in parallel, are responsible for the loss of many vulnerable RGCs and their axons [85,86,87,88,89,90]. The net result is reduced transmission of visual signals to the brain. Since the brain structures are reliant on electrical activity from the retina to also remain healthy, death signals from the RGC axons due to POAG/ GON may cause senolytic events in the thalamic and visual cortical tissues due to inducted neuroinflammation [91]. Apoptotic and neurodegenerative processes lead to death of neurons in the LGN, magnocellular and parvocellular layers of the thalamus [92,93,94,95,96], trans-neuronal degeneration and extensive brain network reorganization and disruption [97,98,99,100] culminating in reduction of visual acuity (including reduced contrast sensitivity), visual impairment (loss of peripheral vision), and if left undiagnosed and untreated, loss of central vision followed by total blindness.

What is disturbing to the POAG patient, and also to those patients with relatively normal IOPs (normotensive glaucoma [NTG]) [101,102,103,104,105], is that the disease is imperceptible, painless and continues unabated for multiple decades. Due to neuroplasticity, early defects in the retina-optic nerve-brain system are somewhat compensated and perception of suprathreshold contrast in patient’s vision is maintained despite loss of some visual sensitivity [106]. Patients first become aware of their POAG/NTG when their peripheral vision is reduced, black patches randomly intrude into their line of sight, and when this progresses over many decades to “tunnel vision” [107]. These insidious changes in visual perception indicate that now the tipping point has been reached and in fact 400,000 to 600,000 RGCs have been destroyed from the patient’s retina and an equal number of connections to the brain have been silenced. Hence, early diagnosis through regular eye exams is tantamount to receiving treatment close to the time of disease initiation and perhaps slowing down the demise of RGCs and thus reducing disease progression. Sadly, it is estimated that 53-58 million people will be afflicted with POAG by 2040 with the total glaucoma patient population reaching ~112 million by 2040 [108,109]. Therefore, there is an urgent need to diagnose patients at risk of chronic OHT (cOHT) / POAG earlier and discover and bring to the clinic novel IOP-lowering drugs and treatments that offer greater potency/efficacy and longer duration of action with a reduced side-effects profile to existing therapies. Furthermore, it is now well accepted that IOP reduction alone is insufficient to prevent visual defects in POAG/NTG, such that we need to directly protect the RGCs and their axons through some innovative rescue strategies. In addition to neuroprotection strategies to enhance the survival of RGCs, there is a need to repair RGC axons in order to more fully re-establish retino-thalamic connections. Clearly, GON being a multifactorial optic/brain disease will require a multifaceted treatment approach and these elements will be discussed below.

4. Treatment Options for cOHT / POAG: Drugs, Surgeries and AQH Microshunts

With advancing age and/or due to many other disease-initiating processes including loss of TM cells due to natural or abnormal senescence caused by endoplasmic reticular stress, poor autophagy, reduced phagocytic performance of remaining TM cells, the conventional AQH drainage system gets overwhelmed by the accumulating debris and becomes clogged [3,6]. Since the ciliary bodies continue to produce fresh AQH, the anterior chamber of the eye begins to expand and bulge thereby raising the IOP. This elevated IOP is transmitted through the eye and negatively impacts the weakest part of the visual system, the LC that lies just behind the ONH [13,14,19,45] where the unmyelinated axons of the RGCs gather and exit the back of the eye to form the optic nerve. This then initiates the detrimental cascade of events mentioned in the previous section above leading to visual impairment [91,94,98]. Clearly opening up of the TM outflow pathway and engaging the other non-conventional uveoscleral pathway would relieve some damaging effects of the raised IOP. To this end, numerous pharmaceutical drugs that reduce AQH formation (carbonic anhydrase inhibitors (e.g. dorzolamide; [110]), alpha-2-adrenergic agonists (e.g. brimonidine; [111]), beta-blockers (e.g. timolol and betaxolol; [112])), and those drugs that primarily promote AQH efflux via the conventional TM/SC outflow pathway (muscarinic agonists (e.g. pilocarpine; [113]); rho kinase inhibitors (e.g. ripasudil, netarsudil; [114,115]), and drugs that primarily stimulate AQH outflow via the uveoscleral pathway (prostaglandin (PG) FP-receptor agonists (e.g. latanoprost, travoprost and tafluprost; [116,117,118]), a novel non-PG EP2-receptor agonist (omidenepag isopropyl; [119,120,121,122,123]), and a conjugate of latanoprost and an nitric oxide releasing molecule (latanoprostene; [124])) have been discovered, developed and introduced into the clinical management of OHT / POAG (Table 1). The duality of mechanism of action of FP-PG agonists such as travoprost [117] and that of the non-PG EP2-receptor agonist, omidenepag isopropyl [120], inducing outflow of AQH via the uveoscleral and TM/SC pathways seems unique. Interestingly, the other unique property pertains to the rho kinase inhibitor, netarsudil, which lower IOP by stimulating AQH outflow via the TM/SC and by lowering episcleral veinous pressure in animals and human OHT/POAG patients [125,126]. Additionally, since netarsudil and omidenepag isopropyl lower IOP well in normotensive and OHT animals, they may have clinical utility in treating NTG. However, this remains to be demonstrated in additional clinical studies.

Table 1 Health agency-approved medications for treatment of cOHT / POAG / NTG.

Combinations of approved IOP-lowering medications, allowing engagement of multiple mechanisms of action to achieve higher efficacy, have also been developed for medical treatment of OHT/POAG [127,128]. Furthermore, the durability of the ocular hypotensive activity of drugs has been extended using polymer-based technology that permits the drug to be released into the ANC over time once the polymer rod is intracamerally injected into the ANC [129,130], or the drug is slowly eluted off from a silicon-ring-device placed around the eyeball and remains in contact with the conjunctiva/cornea [131], or the therapeutic drug is slowly released from punctal plugs [132], or via nanoparticles [133,134], polycaprolactones [135,136] or via port delivery systems akin to how antibodies are delivered to the eye [137]. Another recent important advent helping significantly lower and control IOP involves microshunts (e.g. Preserflo®) [138,139,140,141,142] which when placed into the ANC of the eye help drain the excess AQH to efficaciously lower IOP over many years, and improve visual acuity [140]. If needed, the patient can have the microshunt placed to drain the AQH and be treated topical ocularly with ocular hypotensive drugs to achieve the target IOP.

Even though the afore-mentioned therapeutic approaches tackle cOHT fairly well, new drugs with new mechanism(s) of action such as lowering IOP by decreasing episcleral venous pressure are needed. Similarly, lowering IOP through novel receptor or enzyme systems with a greater potency/efficacy and with lower side-effects potential [143,144] than existing drugs are continuing to be found and developed for use in the clinical setting (Table 2). Progression of these novel ocular hypotensives drugs targeting many different receptors, enzymes, and ion-channels at the level of TM/SC and UVSC outflow pathways [145,146,147,148,149,150,151,152,153,154,155][156,157,158,159,160,161,162,163,164,165,166,167,168,169] into formal development processes is eagerly awaited.

Table 2 List of compounds that lower IOP in various animal models of acute or chronic OHT / POAG.

5. Treatments Beyond IOP-Lowering:

5.1 Cyto- and Neuro-protective Therapies

In view of the multiplicity of damaging and destructive factors involved in the etiology and progression of cOHT/ POAG / NTG (Figure 5, Figure 6), it seems obvious that a singular preventative regimen is unlikely to be very successful. Rather a combinatorial approach [170] is necessitated with multiple interventional points [171,172,173,174,175,176] involving IOP reduction coupled with slowing/preventing local inflammation at the ONH/LC. However, as the ANC components strongly influence the pathological events at the back of the eye, it is imperative that some rescue strategies be directed there. Thus, means to stimulate autophagic activity of TM cells thus reduce their stress due to ECM accumulation and delivery of anti-oxidants to the ANC would be helpful [177,178,179,180,181,182]. Likewise, since inflammation is a one of the root causes of RGC death and destruction of their axons and of the associated brain neurons, dampening or eliminating such destructive elements is beneficial [183,184,185,186,187,188,189,190,191]. Preventing complement activation [192] and up-regulating protective endogenous genes and transcription factors [193,194] at the ONH/LC and thalamic and cortical regions is another useful strategy. Many other drugs and treatments [168,195,196,197,198,199,200,201,202,203,204] including senolytic drugs [195], glutamate receptor antagonists [197], delta-opioids [198], histone deacetylase inhibitors [199], vascular-specific phosphatase blockers [168], alpha-2 adrenergic agonists [200], sigma-receptor agonists [201], and various neurotrophic factors [202,203]. Furthermore, new conjugate/hybrid drugs with multi-pharmacophoric activities [205,206,207,208,209,210] directed at different intervention points of the RGC soma and axonal demise [170,171,172,173,174,175,176] are showing promise as neuroprotective agents.

5.2 Genetics, Cell Transplantation and Exosome-Based Therapies

Specific gene-therapy technologies are being utilized to curb the cyto-destructive and neurogenerative processes occurring during cOHT/POAG/GON. Some are addressing the reduced capacity of TM and other ANC cells to produce ECM-clearing MMPs [211] or modulating aquaporins to achieve AQH dynamic homeostasis [212]. Gene knock-out [213,214] or gene insertion [215,216,217] to promote delivery of various trophic factors such as brain-derived neurotrophic factor and ciliary neurotrophic factor to RGCs [218,219] that can rescue and preserve retinal and brain neurons are proving beneficial at least in animal models of POAG/GON. The advent and utility of cell replacement techniques and technologies to preserve retinal-optic nerve-brain connectivity and function involving stem cells for ANC pathologies [220,221,222,223,224], Schwann cells for optic nerve sheath replacement [225,226] and for RGC and Muller transplantation [227,228,229,230,231] are gaining prominence. Additionally, the experimental utility of extracellular vesicles and/or use of stem-cell-derived exosomes and secretomes [232,233,234,235] comprising many different protective proteins and micro-RNAs impart beneficial effects on the many cell-types that are integrally involved in the visual processes. Eventually, structural bio-materials may be needed to physically support the optic nerves to halt and prevent further damage of these vital structures [236,237,238,239].

5.3 Dietary Factors Providing Cellular Protection

It is well known that food-derived nutrients possess a multitude of health-promoting chemicals that positively impact bodily muscles, bones and cells of many organs, including the eye [240][241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258]. In this respect, a whole host of nutraceuticals possessing antioxidant, anti-inflammatory, anti-excitotoxic, and anti-apoptotic properties protect RGCs and brain neurons, including curcumin, ginkgo bilboba, lipoic acid, coenzyme Q10, saffron, vitamin B3, and urolithin from pomegranates. Although somewhat controversial, recent research appears to link the dietary intake of foods with resident microbes in the alimentary canal and as such the latter influencing the disease pathology and thus potential protective properties of the microbiota [259]. However, whilst giving us hope and encouragement, confirmatory clinical trials of the nicotinamide alone [256] and in combination with pyruvate [257], and with the urolithin [258] are needed.

5.4 Axonal and Cellular Regeneration Therapies

There are many limitations of successfully delivering, uptake, incorporation and functional integration of food-derived nutrients, gene- and cell-therapies for the protection and preservation of eyesight of cOHT/POAG/NTG and GON sufferers. To overcome such hurdles, new ways to activate intrinsic cyto- and neuro-protective factors and systems are being explored. These include gross or cell-directed in vitro and in vivo electrical stimulatory systems and devices. Indeed, some success has already been realized in this arena where low-level electrotherapy has helped regenerate RGC axons, promote Muller cell proliferation/differentiation through release of endogenous neurotrophins and other beneficial substances [260,261,262,263]. Translation of these findings to the human situation appear promising [260,263].

6. Novel Techniques and Technologies to Help Preserve Eyesight

As technologies progress, there is continuing hope that they would be applied to help glaucoma patients. Examples of these include the following: stem-cell-derived exosomal delivery of miRNAs and trophic factors [264,265,266], creation of artificial extracellular vesicles and stem cells with selective packaging of the cargos to be delivered [267,268]. Moreover, use of novel cell repair and regeneration methods [269,270,271,272,273,274,275,276,277,278], use of optic nerve and visual field magnetic resonance imaging and mapping [279,280] coupled with artificial intelligence technologies for earlier diagnosis of glaucoma [281,282], functional retinal oximetry to determine the metabolic status of the retinal cells [283] and adaptive optics to improve the cellular resolution to detect structural changes at the cell soma and dendrites before and after treatment for glaucoma [284] will undoubtedly help glaucoma patients in the future. Much progress has also been achieved using optogenetic technologies to restore vision in animals [285,286,287,288,289], and using chemical photoswitches [285] and retinal and brain implants [285,290]. Use of sonar technology to stimulate specific neuronal pathways to protect and enhance vision also holds great promise [291,292].

The early and accurate detection and diagnosis of cOHT / POAG/ NTG is key to helping patients with visual impairment and as such 24-hr monitoring of IOP is essential. A contact lens-based IOP recording device has been developed to aid in this endeavor [293]. Fluid drainage via the traditional pathways from the eye are damaged during development of cOHT/POAG, and thus the ability to engage lymphatic drainage in the eye and brain may be useful [294,295]. Similarly, development of new diagnostic/ biomarker techniques are critical for starting treatment to preserve and slow down GON, and recent reports are encouraging in this respect [296,297,298,299].

Use of single cell transcriptomics [300], anti-sense oligonucleotides [152], antibodies directed at inflammatory mediators [301], and use of specific micro-RNAs to lower IOP and perhaps provide neuroprotection [149] by exploiting recently discovered cellular nanotubes [302] are exciting new developments worthy of further pursuit. Last but not least, novel imaging technologies using 2-photon-excited fluorescence and flood-illumination adaptive optics [303,304], coupled with proteostasis drugs to eliminate excess phosphorylated proteins and misfolded proteins [305,306] from the ANC and from the retina/optic nerve/brain offer new treatment paradigms for cOHT/POAG/NTG/GON, especially if the combinatorial treatments [257,307] are reproduced in other clinical trials across the world.

7. Conclusions

Apart from causing visual impairment in the early stages of GON development, the disease progression robs patients of their ability to perform daily tasks such as reading, driving, and clearly recognizing objects and faces. These difficulties translate into various disabilities associated with visual field deterioration resulting in POAG patients bumping into objects-, falling down and sustaining injuries, and as the situation worsens can then cause anxiety and depression (Figure 7). Thankfully, as described above, significant progress has been made in the last dozen years towards a better understanding of the factors and pathologies involved in the GON disease processes endured by patients that suffer from cOHT / POAG/ NTG. Advancements in early and more accurate diagnosis of these ocular ailments is still lagging behind expectations although new biomarkers and devices hold great promise. The multifactorial nature of the damaging agents, insults and pathways involved in causing the sight-threatening diseases will certainly require a multicomponent treatment regimen. This will also necessitate varied permutations and combinations of drugs/devices/nutraceuticals/regenerative medicines designed to account for genetic, structural and functional elements impacted and experienced by each patient. Such personalized medicine will come to fruition in due course if we collectively continue to forge ahead discovering and developing new treatment modalities in a multidisciplinary manner to help the POAG/NTG patients preserve and protect their eyesight.

Click to view original image

Figure 7 The negative impact of glaucomatous optic neuropathy as a result of cOHT / POAG causing visual field loss and various consequences of death of thalamic, cerebellar, and cortical neurons is highlighted in this schematic. Patients suffering from GON not only lose peripheral vision but also experience a whole host of other neurological disturbances which lowers their quality of life due to many types of disabilities listed in this figure.

Author Contributions

The author is solely responsible for conceptualizing, researching and writing this article.

Competing Interests

The author declares that there is no competing interest in writing this article. The only intention is to gather, collate and disseminate the high-level information about the pathological aspects of glaucoma and ocular hypertension with the hope that it will enhance multidisciplinary awareness about these sight threatening eye diseases. In time, I hope further research will be stimulated and innovation will lead to new and improved therapies for the patients who live with these ocular disorders.

References

  1. Civan M, Macknight AD. The ins and outs of aqueous humor secretion. Exp Eye Res. 2004; 78: 625-631. [CrossRef]
  2. Abu-Hassan DW, Acott TS, Kelley MJ. The trabecular meshwork: A basic review of form and function. J Ocul Biol. 2014; 2. Doi: 10.13188/2334-2838.1000017. [CrossRef]
  3. Sacca SC, Pulliero A, Izzotti A. The dysfunction of the trabecular meshwork during glaucoma course. J Cell Physiol. 2015; 230: 510-525. [CrossRef]
  4. Carreon T, van der Merwe E, Fellman RL, Johnstone M, Bhattacharya SK. Aqueous outflow-a continuum from trabecular meshwork to episcleral veins. Prog Retin Eye Res. 2017; 57: 108-133. [CrossRef]
  5. Buffault J, Labbé A, Hamard P, Brignole-Baudouin F, Baudouin C. The trabecular meshwork: Structure, function and clinical implications. A review of the literature. J Fr Ophtalmol. 2020; 43: e217-e230. [CrossRef]
  6. Overby DR, Zhou EH, Vargas-Pinto R, Pedrigi RM, Fuchshofer R, Braakman ST, et al. Altered mechanobiology of Schlemm’s canal endothelial cells in glaucoma. Proc Natl Acad Sci USA. 2014; 111: 13876-13881. [CrossRef]
  7. Stamer WD, Braakman ST, Zhou EH, Ethier CR, Fredberg JJ, Overby DR, et al. Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction. Prog Retin Eye Res. 2015; 44: 86-98. [CrossRef]
  8. Wang LY, Su GY, Wei ZY, Zhang ZJ, Liang QF. Progress in the basic and clinical research on the Schlemm's canal. Int J Ophthalmol. 2020; 13: 816-821. [CrossRef]
  9. Acott TS, Vranka JA, Keller KE, Raghunathan V, Kelley MJ. Normal and glaucomatous outflow regulation. Prog Retin Eye Res. 2021; 82: 100897. [CrossRef]
  10. Sanes JR, Masland RH. The types of retinal ganglion cells: Current status and implications for neuronal classification. Annu Rev Neurosci. 2015; 38: 221-246. [CrossRef]
  11. Grünert U, Martin PR. Cell types and cell circuits in human and non-human primate retina. Prog Retin Eye Res. 2020; 5:100844. [CrossRef]
  12. Yohannan J, Boland MV. The evolving role of the relationship between optic nerve structure and function in glaucoma. Ophthalmology. 2017; 124: S66-S70. [CrossRef]
  13. Xu G, Weinreb RN, Leung CK. Optic nerve head deformation in glaucoma: The temporal relationship between optic nerve head surface depression and retinal nerve fiber layer thinning. Ophthalmology. 2014; 121: 2362-2370. [CrossRef]
  14. Burgoyne CF, Downs JC, Bellezza AJ, Suh JK, Hart RT. The optic nerve head as a biomechanical structure: A new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res. 2005; 24: 39-73. [CrossRef]
  15. Lee EJ, Kim TW, Weinreb RN, Kim H. Reversal of lamina cribrosa displacement after intraocular pressure reduction in open-angle glaucoma. Ophthalmology. 2013; 120: 553-559. [CrossRef]
  16. Coudrillier B, Campbell IC, Read AT, Geraldes DM, Vo NT, Feola A, et al. Effects of peripapillary scleral stiffening on the deformation of the lamina cribrosa. Investig Ophthalmol Vis Sci. 2016; 57: 2666-2677. [CrossRef]
  17. Daguman IJ, Delfin MS. Correlation of lamina cribosa and standard automated perimeter findings in glaucoma and non-glaucoma patients. J Ophthalmic Stud. 2019; 2. Doi: 10.16966/2639-152X.110. [CrossRef]
  18. Masri RA, Grünert U, Martin PR. Analysis of parvocellular and magnocellular visual pathways in human retina. J Neurosci. 2020; 40: 8132-8148. [CrossRef]
  19. Van Hook MJ, Monaco C, Bierlein ER, Smith JC. Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma. Front Cell Neurosci. 2021; 14: 626056. [CrossRef]
  20. Lam D, Jim J, To E, Rasmussen C, Kaufman PL, Matsubara J. Astrocyte and microglial activation in the lateral geniculate nucleus and visual cortex of glaucomatous and optic nerve transected primates. Mol Vis. 2009; 15: 2217-2229.
  21. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: A review. JAMA. 2014; 311: 1901-1911. [CrossRef]
  22. Sharif NA. Ocular hypertension and glaucoma: A review and current perspectives. Int J Ophthalmol Vis Sci. 2017; 2: 22-36.
  23. Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. Lancet. 2017; 390: 2183-2193. [CrossRef]
  24. Sharif NA. Therapeutic drugs and devices for tackling ocular hypertension and glaucoma, and need for neuroprotection and cytoprotective therapies. Front Pharmacol. 2021; 12: 729249. [CrossRef]
  25. Kim JH, Caprioli J. Intraocular pressure fluctuation: Is it important? J Ophthalmic Vis Res. 2018; 3: 170-174. [CrossRef]
  26. De Groef L, Andries L, Siwakoti A, Geeraerts E, Bollaerts I, Noterdaeme L, et al. Aberrant collagen composition of the trabecular meshwork results in reduced aqueous humor drainage and elevated IOP in MMP-9 null mice. Investig Ophthalmol Vis Sci. 2016; 57: 5984-5995. [CrossRef]
  27. Kasetti RB, Maddineni P, Millar JC, Clark AF, Zode GS. Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork. Sci Rep. 2017; 7: 14951. [CrossRef]
  28. Lynch JM, Li B, Katoli P, Xiang C, Leehy B, Rangaswamy N, et al. Binding of a glaucoma-associated myocilin variant to the αB-crystallin chaperone impedes protein clearance in trabecular meshwork cells. J Biol Chem. 2018; 293: 20137-20156. [CrossRef]
  29. Von Zee CL, Langert KA, Stubbs EB. Transforming growth factor-β2 induces synthesis and secretion of endothelin-1 in human trabecular meshwork cells. Investig Ophthalmol Vis Sci. 2012; 53: 5279-5286. [CrossRef]
  30. Rao VR, Stubbs EB Jr. TGF-β2 promotes oxidative stress in human trabecular meshwork cells by selectively enhancing NADPH oxidase 4 expression. Investig Ophthalmol Vis Sci. 2021; 62: 4. [CrossRef]
  31. Yemanyi F, Vranka J, Raghunathan VK. Crosslinked extracellular matrix stiffens human trabecular meshwork cells via dysregulating β-catenin and YAP/TAZ signaling pathways. Investig Ophthalmol Vis Sci. 2020; 61: 41. [CrossRef]
  32. Calkins DJ, Horner PJ. The cell and molecular biology of glaucoma: Axonopathy and the brain. Investig Ophthalmol Vis Sci. 2012; 53: 2482-2484. [CrossRef]
  33. Borrás T. A single gene connects stiffness in glaucoma and the vascular system. Exp Eye Res. 2017; 158: 13-22. [CrossRef]
  34. Porter K, Hirt J, Stamer WD, Liton PB. Autophagic dysregulation in glaucomatous trabecular meshwork cells. Biochim Biophys Acta. 2015; 1852: 379-385. [CrossRef]
  35. Berdahl JP, Allingham RR, Johnson DH. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology. 2008; 115: 763-768. [CrossRef]
  36. Wostyn P, De Groot V, Van Dam D, Audenaert K, Killer HE, De Deyn PP. Glaucoma and the role of cerebrospinal fluid dynamics. Investig Ophthalmol Vis Sci. 2015; 56: 6630-6631. [CrossRef]
  37. Jóhannesson G, Eklund A, Lindén C. Intracranial and intraocular pressure at the lamina cribrosa: Gradient effects. Curr Neurol Neurosci Rep. 2018; 18: 25. [CrossRef]
  38. Price DA, Harris A, Siesky B, Mathew S. The influence of translaminar pressure gradient and intracranial pressure in glaucoma: A review. J Glaucoma. 2020; 29: 141-146. [CrossRef]
  39. Hollander H, Makarov F, Stefani FH, Stone J. Evidence of constriction of optic axons at the lamina cribrosa in the normotensive eye in humans and other mammals. Ophthalmic Res. 1995; 127: 296-309. [CrossRef]
  40. Tu S, Li K, Ding X, Hu D, Li K, Ge J. Relationship between intraocular pressure and retinal nerve fibre thickness loss in a monkey model of chronic ocular hypertension. Eye. 2019; 33: 1833-1841. [CrossRef]
  41. Yuan L, Neufeld AH. Tumor necrosis factor‐α: A potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia. 2000; 32: 42-50. [CrossRef]
  42. Yang X, Luo C, Cai J. Neurodegenerative and inflammatory pathway components linked to TNF-alpha/TNFR1 signaling in the glaucomatous human retina. Investig Ophthalmol Vis Sci. 2011; 52: 8442-8454. [CrossRef]
  43. Chi W, Li F, Chen H, Wang Y, Zhu Y, Yang X, et al. Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma. Proc Natl Acad Sci USA. 2014; 111: 11181-11186. [CrossRef]
  44. Wilson GN, Inman DM, Dengler-Crish CM, Smith MA, Crish SD. Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma. J Neuroinflammation. 2015; 12: 176. [CrossRef]
  45. Yerramothu P, Vijay AK, Willcox MDP. Inflammasomes, the eye and anti-inflammasome therapy. Eye. 2018; 32: 491-505. [CrossRef]
  46. Coyle S, Khan MN, Chemaly M, Callaghan B, Doyle C, Willoughby CE, et al. Targeting the NLRP3 Inflammasome in Glaucoma. Biomolecules. 2021; 11: 1239. [CrossRef]
  47. Ju WK, Lindsey JD, Angert M, Patel A, Weinreb RN. Glutamate receptor activation triggers OPA1 release and induces apoptotic cell death in ischemic rat retina. Mol Vis. 2008; 14: 2629-2638.
  48. Fu CT, Sretavan DW. Ectopic vesicular glutamate release at the optic nerve head and axon loss in mouse experimental glaucoma. J Neurosci. 2012; 32: 15859-15876. [CrossRef]
  49. Ju WK, Kim KY, Noh YH, Hoshijima M, Lukas TJ, Ellisman MH, et al. Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes. Glia. 2015; 63: 736-753. [CrossRef]
  50. Wamsley S, B’Ann TG, Dahl DB, Case GL, Sherwood RW, May CA, et al. Vitreous glutamate concentration and axon loss in monkeys with experimental glaucoma. Arch Ophthalmol. 2005; 123: 64-70. [CrossRef]
  51. Nguyen D, Alavi MV, Kim KY, Kang T, Scott RT, Noh YH, et al. A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics. Cell Death Dis. 2011; 2: e240. [CrossRef]
  52. Resta V, Novelli E, Vozzi G, Scarpa C, Caleo M, Ahluwalia A, et al. Acute retinal ganglion cell injury caused by intraocular pressure spikes is mediated by endogenous extracellular ATP. Eur J Neurosci. 2007; 25: 2741-2754. [CrossRef]
  53. Neufeld AH. Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma. Arch Ophthalmol. 1999; 117: 1050-1056. [CrossRef]
  54. Yuan L, Neufeld AH. Activated microglia in the human glaucomatous optic nerve head. J Neurosci Res. 2001; 64: 523-532. [CrossRef]
  55. Cho KJ, Kim JH, Park HY, Park CK. Glial cell response and iNOS expression in the optic nerve head and retina of the rat following acute high IOP ischemia-reperfusion. Brain Res. 2011; 1403: 67-77. [CrossRef]
  56. Quillen S, Schaub J, Quigley H, Pease M, Korneva A, Kimball E. Astrocyte responses to experimental glaucoma in mouse optic nerve head. PLoS One. 2020; 15: e0238104. [CrossRef]
  57. Hernandez MR, Luo XX, Andrzejewska W, Neufeld AH. Age-related changes in the extracellular matrix of the human optic nerve head. Am J Ophthalmol. 1989; 107: 476-484. [CrossRef]
  58. Stokely ME, Brady ST, Yorio T. Effects of endothelin-1 on components of anterograde axonal transport in optic nerve. Investig Ophthalmol Vis Sci. 2002; 43: 3223-3230.
  59. Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest. 2011; 121: 1429-1444. [CrossRef]
  60. Chaphalkar RM, Stankowska DL, He S, Kodati B, Phillips N, Prah J, et al. Endothelin-1 mediated decrease in mitochondrial gene expression and bioenergetics contribute to neurodegeneration of retinal ganglion cells. Sci Rep. 2020; 10: 3571. [CrossRef]
  61. Orwig SD, Perry CW, Kim LY, Turnage KC, Zhang R, Vollrath D, et al. Amyloid fibril formation by the glaucoma-associated olfactomedin domain of myocilin. J Mol Biol. 2012; 421: 242-255. [CrossRef]
  62. Wang L, Mao X. Role of retinal amyloid-β in neurodegenerative diseases: Overlapping mechanisms and emerging clinical applications. Int J Mol Sci. 2021; 22: 2360. [CrossRef]
  63. Chintala SK. The emerging role of proteases in retinal ganglion cell death. Exp Eye Res. 2006; 82: 5-12. [CrossRef]
  64. Downs JC, Roberts MD, Sigal IA. Glaucomatous cupping of the lamina cribrosa: A review of the evidence for active progressive remodeling as a mechanism. Exp Eye Res. 2011; 93: 133-140. [CrossRef]
  65. McElnea EM, Hughes E, McGoldrick A, McCann A, Quill B, Docherty N, et al. Lipofuscin accumulation and autophagy in glaucomatous human lamina cribrosa cells. BMC Ophthalmol. 2014; 14: 153. [CrossRef]
  66. Gunawan M, Low C, Neo K, Yeo S, Ho C, Barathi VA, et al. The role of autophagy in chemical proteasome inhibition model of retinal degeneration. Int J Mol Sci. 2021; 22: 7271. [CrossRef]
  67. Thomas D, Papadopoulo O, Doshi R, Kapin MA, Sharif NA. Retinal ATP and phosphorus metabolites: Reduction by hypoxia and recovery with MK-801 and diltiazem. Med Sci Res. 2000; 28: 87-91.
  68. Abu-Amero KK, Morales J, Bosley TM. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Investig Ophthalmol Vis Sci. 2006; 47: 2533-2541. [CrossRef]
  69. McElnea EM, Quill B, Docherty NG, Irnaten M, Siah WF, Clark AF, et al. Oxidative stress, mitochondrial dysfunction and calcium overload in human lamina cribrosa cells from glaucoma donors. Mol Vis. 2011; 17: 1182-1189.
  70. Coughlin L, Morrison RS, Horner PJ, Inman DM. Mitochondrial morphology differences and mitophagy deficits in murine glaucomatous optic nerve. Investig Ophthalmol Vis Sci. 2015; 56: 1437-1446. [CrossRef]
  71. Eells JT. Mitochondrial dysfunction in the aging retina. Biology. 2019; 8: 31. [CrossRef]
  72. Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA, Zack DJ. Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Investig Ophthalmol Vis Sci. 2000; 41: 764-774.
  73. Sposato V, Bucci MG, Coassin M, Russo MA, Lambiase A, Aloe L. Reduced NGF level and TrkA protein and TrkA gene expression in the optic nerve of rats with experimentally induced glaucoma. Neurosci Lett. 2008; 446: 20-24. [CrossRef]
  74. Dengler-Crish CM, Smith MA, Inman DM, Wilson GN, Young JW, Crish SD. Anterograde transport blockade precedes deficits in retrograde transport in the visual projection of the DBA/2J mouse model of glaucoma. Front Neurosci. 2014; 8: 290. [CrossRef]
  75. Fahy ET, Chrysostomou V, Crowston JG. Impaired axonal transport in glaucoma. Curr Eye Res. 2016; 41: 273-283.
  76. Ha Y, Liu H, Xu Z, Yokota H, Narayanan SP, Lemtalsi T, et al. Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma. Cell Death Dis. 2015; 6: e1900. [CrossRef]
  77. Slater BJ, Vilson FL, Guo Y, Weinreich D, Hwang S, Bernstein SL. Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy. Investig Ophthalmol Vis Sci. 2013; 54: 7952-7961. [CrossRef]
  78. Wei X, Cho KS, Thee EF, Jager MJ, Chen DF. Neuroinflammation and microglia in glaucoma: Time for a paradigm shift. J Neurosci Res. 2019; 97: 70-76. [CrossRef]
  79. Evangelho K, Mogilevskaya M, Losada-Barragan M, Vargas-Sanchez JK. Pathophysiology of primary open-angle glaucoma from a neuroinflammatory and neurotoxicity perspective: A review of the literature. Int Ophthalmol. 2019; 39: 259-271. [CrossRef]
  80. Adornetto A, Russo R, Parisi V. Neuroinflammation as a target for glaucoma therapy. Neural Regen Res. 2019; 14: 391-394. [CrossRef]
  81. Vernazza S, Tirendi S, Bassi AM, Traverso CE, Saccà SC. Neuroinflammation in primary open-angle glaucoma. J Clin Med. 2020; 9: 3172. [CrossRef]
  82. Soto I, Howell GR. The complex role of neuroinflammation in glaucoma. Cold Spring Harb Perspect Med. 2014; 4: a017269. [CrossRef]
  83. Flammer J, Konieczka K, Flammer AJ. The primary vascular dysregulation syndrome: Implications for eye diseases. EPMA J. 2013; 4: 14. [CrossRef]
  84. Pasquale LR. Vascular and autonomic dysregulation in primary open-angle glaucoma. Curr Opinion Ophthalmol. 2016; 27: 94-101. [CrossRef]
  85. Ou Y, Jo RE, Ullian EM, Wong RO, Della Santina L. Selective vulnerability of specific retinal ganglion cell types and synapses after transient ocular hypertension. J Neurosci. 2016; 36: 9240-9252. [CrossRef]
  86. Della Santina L, Ou Y. Who's lost first? Susceptibility of retinal ganglion cell types in experimental glaucoma. Exp Eye Res. 2017; 158: 43-50. [CrossRef]
  87. Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, et al. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biology. 2007; 179: 1523-1537. [CrossRef]
  88. Maddineni P, Kasetti RB, Patel PD, Millar JC, Kiehlbauch C, Clark AF, et al. CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma. Mol Neurodegener. 2020; 15: 48. [CrossRef]
  89. Risner ML, Pasini S, McGrady NR, Calkins DJ. Bax contributes to retinal ganglion cell dendritic degeneration during glaucoma. Mol Neurobiol. 2022; 59: 1366-1380. [CrossRef]
  90. Bhandari A, Smith JC, Zhang Y, Jensen AA, Reid L, Goeser T, et al. Early-stage ocular hypertension alters retinal ganglion cell synaptic transmission in the visual thalamus. Front Cell Neurosci. 2019; 13: 426. [CrossRef]
  91. Sapienza A, Raveu AL, Reboussin E, Roubeix C, Boucher C, Dégardin J, et al. Bilateral neuroinflammatory processes in visual pathways induced by unilateral ocular hypertension in the rat. J Neuroinflammation. 2016; 13: 44. [CrossRef]
  92. Yücel YH, Zhang Q, Gupta N, Kaufman PL, Weinreb RN. Loss of neurons in magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch Ophthalmol. 2000; 118: 378-384. [CrossRef]
  93. Dai Y, Sun X, Yu X, Guo W, Yu D. Astrocytic responses in the lateral geniculate nucleus of monkeys with experimental glaucoma. Vet Ophthalmol. 2012; 15: 23-30. [CrossRef]
  94. Gupta N, Ly T, Zhang Q, Kaufman PL, Weinreb RN, Yücel YH. Chronic ocular hypertension induces dendrite pathology in the lateral geniculate nucleus of the brain. Exp Eye Res. 2007; 84: 176-184. [CrossRef]
  95. Sasaoka M, Nakamura K, Shimazawa M, Ito Y, Araie M, Hara H. Changes in visual fields and lateral geniculate nucleus in monkey laser-induced high intraocular pressure model. Exp Eye Res. 2008; 86: 770-782. [CrossRef]
  96. Abdulhussein D, Kanda M, Aamir A, Manzar H, Yap TE, Cordeiro MF. Apoptosis in health and diseases of the eye and brain. Adv Protein Chem Struct Biol. 2021; 126: 279-306. [CrossRef]
  97. Trivedi V, Bang JW, Parra C, Colbert MK, O’Connell C, Arshad A, et al. Widespread brain reorganization perturbs visuomotor coordination in early glaucoma. Sci Rep. 2019; 9: 14168. [CrossRef]
  98. Martucci A, Cesareo M, Toschi N, Garaci F, Bagetta G, Nucci C. Brain networks reorganization and functional disability in glaucoma. Prog Brain Res. 2020; 257: 65-76. [CrossRef]
  99. You M, Rong R, Zeng Z, Xia X, Ji D. Transneuronal degeneration in the brain during glaucoma. Front Aging Neurosci. 2021; 13: 643685. [CrossRef]
  100. Yu L, Xie L, Dai C, Xie B, Liang M, Zhao L, et al. Progressive thinning of visual cortex in primary open-angle glaucoma of varying severity. PLoS One. 2015; 10: e0121960. [CrossRef]
  101. Group CN. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998; 126: 487-497. [CrossRef]
  102. Group CN. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998; 126: 498-505. [CrossRef]
  103. Park HY, Lee KI, Lee K, Shin HY, Park CK. Torsion of the optic nerve head is a prominent feature of normal-tension glaucoma. Investig Ophthalmol Vis Sci. 2015; 56: 156-163. [CrossRef]
  104. Mallick J, Devi L, Malik PK, Mallick J. Update on normal tension glaucoma. J Ophthalmic Vis Res. 2016; 11: 204-208. [CrossRef]
  105. Zhang HJ, Mi XS, So KF. Normal tension glaucoma: From the brain to the eye or the inverse? Neural Regen Res. 2019; 14: 1845-1850. [CrossRef]
  106. Bham HA, Dewsbery SD, Denniss J. Unaltered perception of suprathreshold contrast in early glaucoma despite sensitivity loss. Investig Ophthalmol Vis Sci. 2020; 61: 23. [CrossRef]
  107. Crabb DP. A view on glaucoma-are we seeing it clearly? Eye. 2016; 30: 304-313. [CrossRef]
  108. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis. Ophthalmology. 2014; 121: 2081-2090. [CrossRef]
  109. Flaxman SR, Bourne RR, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al. Global causes of blindness and distance vision impairment 1990-2020: A systematic review and meta-analysis. Lancet Glob Health. 2017; 5: e1221-e1234.
  110. Sugrue MF. The preclinical pharmacology of dorzolamide hydrochloride, a topical carbonic anhydrase inhibitor. J Ocul Pharmacol Ther. 1996; 12: 363-376. [CrossRef]
  111. Duru Z, Ozsaygili C. Preservative-free versus preserved brimonidine %0.15 preparations in the treatment of glaucoma and ocular hypertension: Short term evaluation of efficacy, safety, and potential advantages. Cutan Ocul Toxicol. 2020; 39: 21-24. [CrossRef]
  112. Negri L, Ferreras A, Iester M. Timolol 0.1% in glaucomatous patients: Efficacy, tolerance, and quality of life. J Ophthalmol. 2019; 2019: 4146124. [CrossRef]
  113. Naveh-Floman N, Stahl V, Korczyn AD. Effect of pilocarpine on intraocular pressure in ocular hypertensive subjects. Ophthalmic Res. 1986; 18: 34-37. [CrossRef]
  114. Futakuchi A, Morimoto T, Ikeda Y, Tanihara H, Inoue T. Intraocular pressure-lowering effects of ripasudil in uveitic glaucoma, exfoliation glaucoma, and steroid-induced glaucoma patients: ROCK-S, a multicentre historical cohort study. Sci Rep. 2020; 10: 10308. [CrossRef]
  115. Lin CW, Sherman B, Moore LA, Laethem CL, Lu DW, Pattabiraman PP, et al. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J Ocul Pharmacol Ther. 2018; 34: 40-51. [CrossRef]
  116. Hellberg MR, McLaughlin MA, Sharif NA, DeSantis L, Dean TR, Kyba EP, et al. Identification and characterization of the ocular hypotensive efficacy of travoprost, a potent and selective FP prostaglandin receptor agonist, and AL-6598, a DP prostaglandin receptor agonist. Surv Ophthalmol. 2002; 47: S13-S33. [CrossRef]
  117. Toris CB, Gabelt BT, Kaufman PL. Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction. Surv Ophthalmol. 2008; 53: S107-S120. [CrossRef]
  118. Klimko PG, Sharif NA. Discovery, characterization and clinical utility of prostaglandin agonists for the treatment of glaucoma. Br J Pharmacol. 2019; 176: 1051-1058. [CrossRef]
  119. Kirihara T, Taniguchi T, Yamamura K, Iwamura R, Yoneda K, Odani-Kawabata N, et al. Pharmacologic characterization of omidenepag isopropyl, a novel selective EP2 receptor agonist, as an ocular hypotensive agent. Investig Ophthalmol Vis Sci. 2018; 59: 145-153. [CrossRef]
  120. Fuwa M, Toris CB, Fan S, Taniguchi T, Ichikawa M, Odani-Kawabata N, et al. Effects of a novel selective EP2 receptor agonist, omidenepag isopropyl, on aqueous humor dynamics in laser-induced ocular hypertensive monkeys. J Ocul Pharmacol Ther. 2018; 34: 531-537. [CrossRef]
  121. Aihara M, Lu F, Kawata H, Iwata A, Odani-Kawabata N, Shams NK. Omidenepag isopropyl versus latanoprost in primary open-angle glaucoma and ocular hypertension: The phase 3 AYAME study. Am J Ophthalmol. 2020; 220: 53-63. [CrossRef]
  122. Fuwa M, Shimazaki A, Odani-Kawabata N, Kirihara T, Taniguchi T, Iwamura R, et al. Additive intraocular pressure-lowering effects of a novel selective EP2 receptor agonist, Omidenepag isopropyl, combined with existing antiglaucoma agents in conscious ocular normotensive monkeys. J Ocul Pharmacol Ther. 2021; 37: 223-229. [CrossRef]
  123. Sakata R, Fujishiro T, Saito H, Nakamura N, Honjo M, Shirato S, et al. Recovery of deepening of the upper eyelid sulcus after switching from prostaglandin FP receptor agonists to EP2 receptor agonist: A 3-month prospective analysis. Jpn J Ophthalmol. 2021; 65: 591-597. [CrossRef]
  124. Addis VM, Miller-Ellis E. Latanoprostene bunod ophthalmic solution 0.024% in the treatment of open-angle glaucoma: Design, development, and place in therapy. Clin Ophthalmol. 2018; 12: 2649-2657. [CrossRef]
  125. Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther. 2015; 31: 146-151. [CrossRef]
  126. Sit AJ, Gupta D, Kazemi A, McKee H, Challa P, Liu KC, et al. Netarsudil improves trabecular outflow facility in patients with primary open angle glaucoma or ocular hypertension: A phase 2 study. Am J Ophthalmol. 2021; 226: 262-269. [CrossRef]
  127. Hollo G, Topouzis F, Fechtner RD. Fixed-combination intraocular pressure-lowering therapy for glaucoma and ocular hypertension: Advantages in clinical practice. Expert Opin Pharmacother. 2014; 15: 1737-1747. [CrossRef]
  128. Asrani S, Bacharach J, Holland E, McKee H, Sheng H, Lewis RA, et al. Fixed-dose combination of netarsudil and latanoprost in ocular hypertension and open-angle glaucoma: Pooled efficacy/safety analysis of phase 3 MERCURY-1 and-2. Adv Ther. 2020; 37: 1620-1631. [CrossRef]
  129. Navratil T, Garcia A, Tully J, Maynor B, Ahmed II, Budenz DL, et al. Preclinical evaluation of ENV515 (travoprost) intracameral implant-clinical candidate for treatment of glaucoma targeting six-month duration of action. Investig Ophthalmol Vis Sci. 2014; 55: 3548.
  130. Lewis RA, Christie WC, Day DG, Craven ER, Walters T, Bejanian M, et al. Bimatoprost sustained-release implants for glaucoma therapy: 6-month results from a phase I/II clinical trial. Am J Ophthalmol. 2017; 175: 137-147. [CrossRef]
  131. Brandt JD, Sall K, DuBiner H, Benza R, Alster Y, Walker G, et al. Six-month intraocular pressure reduction with a topical bimatoprost ocular insert: Results of a phase II randomized controlled study. Ophthalmology. 2016; 123: 1685-1694. [CrossRef]
  132. Perera SA, Ting DS, Nongpiur ME, Chew PT, Aquino MC, Sng CC, et al. Feasibility study of sustained-release travoprost punctum plug for intraocular pressure reduction in an Asian population. Clin Ophthalmol. 2016; 10: 757-764. [CrossRef]
  133. Wong TT, Novack GD, Natarajan JV, Ho CL, Htoon HM, Venkatraman SS. Nanomedicine for glaucoma: Sustained release latanoprost offers a new therapeutic option with substantial benefits over eyedrops. Drug Deliv Transl Res. 2014; 4: 303-309. [CrossRef]
  134. Natarajan JV, Darwitan A, Barathi VA, Ang M, Htoon HM, Boey F, et al. Sustained drug release in nanomedicine: A long-acting nanocarrier-based formulation for glaucoma. ACS Nano. 2014; 8: 419-429. [CrossRef]
  135. Kim J, Kudisch M, da Silva NR, Asada H, Aya-Shibuya E, Bloomer MM, et al. Long-term intraocular pressure reduction with intracameral polycaprolactone glaucoma devices that deliver a novel anti-glaucoma agent. J Control Release. 2018; 269: 45-51. [CrossRef]
  136. Aref AA. Sustained drug delivery for glaucoma: Current data and future trends. Curr Opin Ophthalmol. 2017; 28: 169-174. [CrossRef]
  137. Khanani AM, Aziz AA, Weng CY, Lin WV, Vannavong J, Chhablani J, et al. Port delivery system: A novel drug delivery platform to treat retinal diseases. Expert Opin Drug Deliv. 2021; 18: 1571-1576. [CrossRef]
  138. Richter GM, Coleman AL. Minimally invasive glaucoma surgery: Current status and future prospects. Clin Ophthalmol. 2016; 10: 189-206. [CrossRef]
  139. Ansari E. An update on implants for minimally invasive glaucoma surgery (MIGS). Ophthalmol Ther. 2017; 6: 233-241. [CrossRef]
  140. Sadruddin O, Pinchuk L, Angeles R, Palmberg P. Ab externo implantation of the MicroShunt, a poly (styrene-block-isobutylene-blockstyrene) surgical device for the treatment of primary open-angle glaucoma: A review. Eye Vis. 2019; 6: 36. [CrossRef]
  141. Collar B, Shah J, Cox A, Simon G, Irazoqui PP. Parylene-C microbore tubing: A simpler shunt for reducing intraocular pressure. IEEE Trans Biomed Eng. 2021; 69: 1264-1272. [CrossRef]
  142. Le PH, Nguyen M, Humphrey KA, Klifto MR. Ahmed and Baerveldt drainage implants in the treatment of juvenile open-angle glaucoma. J Glaucoma. 2021; 30: 276-280. [CrossRef]
  143. Alm A, Grierson I, Shields MB. Side effects associated with prostaglandin analog therapy. Surv Ophthalmol. 2008; 53: S93-S105. [CrossRef]
  144. Yeh PH, Cheng YC, Shie SS, Lee YS, Shen SC, Chen HS, et al. Brimonidine related acute follicular conjunctivitis: Onset time and clinical presentations, a long-term follow-up. Medicine. 2021; 100: e26724. [CrossRef]
  145. Savinainen A, Prusakiewicz JJ, Oswald J, Spencer E, Lou Z, Cohen ML, et al. Pharmacokinetics and intraocular pressure-lowering activity of TAK-639, a novel C-type natriuretic peptide analog, in rabbit, dog, and monkey. Exp Eye Res. 2019; 189: 107836. [CrossRef]
  146. Dismuke WM, Sharif NA, Ellis DZ. Human trabecular meshwork cell volume decrease by NO-independent soluble guanylate cyclase activators YC-1 and BAY-58-2667 involves the BKCa ion channel. Investig Ophthalmol Vis Sci. 2009; 50: 3353-3359. [CrossRef]
  147. Ohia SE, Robinson J, Mitchell L, Ngele KK, Heruye S, Opere CA, et al. Regulation of aqueous humor dynamics by hydrogen sulfide: Potential role in glaucoma pharmacotherapy. J Ocul Pharmacol Ther. 2018; 34: 61-69. [CrossRef]
  148. Stacy R, Huttner K, Watts J, Peace J, Wirta D, Walters T, et al. A randomized, controlled phase I/II study to evaluate the safety and efficacy of MGV354 for ocular hypertension or glaucoma. Am J Ophthalmol. 2018; 192: 113-123. [CrossRef]
  149. Luna C, Li G, Huang J, Qiu J, Wu J, Yuan F, et al. Regulation of trabecular meshwork cell contraction and intraocular pressure by miR-200c. PloS One. 2012; 7: e51688. [CrossRef]
  150. Mayama C. Calcium channels and their blockers in intraocular pressure and glaucoma. Eur J Pharmacol. 2014; 739: 96-105. [CrossRef]
  151. Moreno-Montañés J, Sádaba B, Ruz V, Gómez-Guiu A, Zarranz J, González MV, et al. Phase I clinical trial of SYL040012, a small interfering RNA targeting β-adrenergic receptor 2, for lowering intraocular pressure. Mol Ther. 2014; 22: 226-232. [CrossRef]
  152. Pfeiffer N, Voykov B, Renieri G, Bell K, Richter P, Weigel M, et al. First-in-human phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in subjects with open-angle glaucoma undergoing glaucoma filtration surgery. PloS One. 2017; 12: e0188899. [CrossRef]
  153. Sharif NA, Katoli P, Scott D, Li L, Kelly C, Xu S, et al. FR-190997, a nonpeptide bradykinin b 2-receptor partial agonist, is a potent and efficacious intraocular pressure lowering agent in ocular hypertensive cynomolgus monkeys. Drug Dev Res. 2014; 75: 211-223. [CrossRef]
  154. May JA, Sharif NA, McLaughlin MA, Chen HH, Severns BS, Kelly CR, et al. Ocular hypotensive response in nonhuman primates of (8 R)-1-[(2 S)-2-aminopropyl]-8, 9-dihydro-7 H-pyrano [2, 3-g] indazol-8-ol a selective 5-HT2 receptor agonist. J Med Chem. 2015; 58: 8818-8833. [CrossRef]
  155. Miller S, Leishman E, Hu SS, Elghouche A, Daily L, Murataeva N, et al. Harnessing the endocannabinoid 2-arachidonoylglycerol to lower intraocular pressure in a murine model. Investig Ophthalmol Vis Sci. 2016; 57: 3287-3296. [CrossRef]
  156. Patil RV, Xu S, van Hoek AN, Rusinko A, Feng Z, May J, et al. Rapid identification of novel inhibitors of the human aquaporin-1 water channel. Chem Biol Drug Des. 2016; 87: 794-805. [CrossRef]
  157. Miller E, Berlin MS, Ward CL, Sharpe JA, Jamil A, Harris A. Ocular hypotensive effect of the novel EP3/FP agonist ONO-9054 versus xalatan: Results of a 28-day, double-masked, randomised study. Br J Ophthalmol. 2017; 101: 796-800. [CrossRef]
  158. Furlotti G, Alisi MA, Cazzolla N, Ceccacci F, Garrone B, Gasperi T, et al. Targeting serotonin 2A and adrenergic α1 receptors for ocular antihypertensive agents: Discovery of 3, 4-dihydropyrazino [1, 2-b] indazol-1 (2H)-one derivatives. ChemMedChem. 2018; 13: 1597-1607. [CrossRef]
  159. Spadoni G, Bedini A, Furiassi L, Mari M, Mor M, Scalvini L, et al. Identification of bivalent ligands with melatonin receptor agonist and fatty acid amide hydrolase (FAAH) inhibitory activity that exhibit ocular hypotensive effect in the rabbit. J Med Chem. 2018; 61: 7902-7916. [CrossRef]
  160. Ellis DA, Scheibler L, Sharif NA. Prostaglandin conjugates and derivatives for treating glaucoma and ocular hypertension. Washington: United States patent; 2017; US9604949B2.
  161. Park MH, Park KH, Choi BJ, Han WH, Yoon HJ, Jung HY, et al. Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice. Proc Natl Acad Sci USA. 2022; 119: e2115082119. [CrossRef]
  162. Li G, Torrejon KY, Unser AM, Ahmed F, Navarro ID, Baumgartner RA, et al. Trabodenoson, an adenosine mimetic with A1 receptor selectivity lowers intraocular pressure by increasing conventional outflow facility in mice. Investig Ophthalmol Vis Sci. 2018; 59: 383-392. [CrossRef]
  163. Honjo M, Igarashi N, Kurano M, Yatomi Y, Igarashi K, Kano K, et al. Autotaxin-lysophosphatidic acid pathway in intraocular pressure regulation and glaucoma subtypes. Investig Ophthalmol Vis Sci. 2018; 59: 693-701. [CrossRef]
  164. Nagano N, Honjo M, Kawaguchi M, Nishimasu H, Nureki O, Kano K, et al. Development of a novel intraocular-pressure-lowering therapy targeting ATX. Biol Pharm Bull. 2019; 42: 1926-1935. [CrossRef]
  165. Roy Chowdhury U, Dosa PI, Fautsch MP. ATP sensitive potassium channel openers: A new class of ocular hypotensive agents. Exp Eye Res. 2017; 158: 85-93. [CrossRef]
  166. Ibrahim MM, Maria DN, Mishra SR, Guragain D, Wang X, Jablonski MM. Once daily pregabalin eye drops for management of glaucoma. ACS Nano. 2019; 13: 13728-13744. [CrossRef]
  167. Uchida T, Shimizu S, Yamagishi R, Tokuoka SM, Kita Y, Sakata R, et al. TRPV4 is activated by mechanical stimulation to induce prostaglandins release in trabecular meshwork, lowering intraocular pressure. Plos One. 2021; 16: e0258911. [CrossRef]
  168. Thomson BR, Carota IA, Souma T, Soman S, Vestweber D, Quaggin SE. Targeting the vascular-specific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma. Elife. 2019; 8: e48474. [CrossRef]
  169. Brigell M, Withers B, Buch A, Peters KG. Tie2 activation via VE-PTP inhibition with razuprotafib as an adjunct to latanoprost in patients with open angle glaucoma or ocular hypertension. Transl Vis Sci Technol. 2022; 11: 7. [CrossRef]
  170. Howell GR, MacNicoll KH, Braine CE, Soto I, Macalinao DG, Sousa GL, et al. Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol Dis. 2014; 71: 44-52. [CrossRef]
  171. Williams PA, Marsh-Armstrong N, Howell GR, Bosco A, Danias J, Simon J, et al. Neuroinflammation in glaucoma: A new opportunity. Exp Eye Res. 2017; 157: 20-27. [CrossRef]
  172. Levin LA, Crowe ME, Quigley HA, Cordeiro MF, Donoso LA, Liao YJ, et al. Neuroprotection for glaucoma: Requirements for clinical translation. Exp Eye Res. 2017; 157: 34-37. [CrossRef]
  173. He S, Stankowska DL, Ellis DZ, Krishnamoorthy RR, Yorio T. Targets of neuroprotection in glaucoma. J Ocul Pharmacol Ther. 2018; 34: 85-106. [CrossRef]
  174. Sharif NA. Glaucomatous optic neuropathy treatment options: The promise of novel therapeutics, techniques and tools to help preserve vision. Neural Regen Res. 2018; 13: 1145-1150. [CrossRef]
  175. Guymer C, Wood JP, Chidlow G, Casson RJ. Neuroprotection in glaucoma: Recent advances and clinical translation. Clin Exp Ophthalmol. 2019; 47: 88-105. [CrossRef]
  176. Lusthaus J, Goldberg I. Current management of glaucoma. Med J Aust. 2019; 210: 180-187. [CrossRef]
  177. Stothert AR, Fontaine SN, Sabbagh JJ, Dickey CA. Targeting the ER-autophagy system in the trabecular meshwork to treat glaucoma. Exp Eye Res. 2016; 144: 38-45. [CrossRef]
  178. He JN, Zhang SD, Qu Y, Wang HL, Tham CC, Pang CP, et al. Rapamycin removes damaged mitochondria and protects human trabecular meshwork (TM-1) cells from chronic oxidative stress. Mol Neurobiol. 2019; 56: 6586-6593. [CrossRef]
  179. Zhu X, Wu S, Zeng W, Chen X, Zheng T, Ren J, et al. Protective effects of rapamycin on trabecular meshwork cells in glucocorticoid-induced glaucoma mice. Front Pharmacol. 2020; 11: 1006. [CrossRef]
  180. Chen M, Liu B, Gao Q, Zhuo Y, Ge J. Mitochondria-targeted peptide MTP-131 alleviates mitochondrial dysfunction and oxidative damage in human trabecular meshwork cells. Investig Ophthalmol Vis Sci. 2011; 52: 7027-7037. [CrossRef]
  181. Ammar DA, Hamweyah KM, Kahook MY. Antioxidants protect trabecular meshwork cells from hydrogen peroxide-induced cell death. Transl Vis Sci Technol. 2012; 1: 4. [CrossRef]
  182. Rao VR, Lautz JD, Kaja S, Foecking EM, Lukács E, Stubbs EB. Mitochondrial-targeted antioxidants attenuate TGF-β2 signaling in human trabecular meshwork cells. Investig Ophthalmol Vis Sci. 2019; 60: 3613-3624. [CrossRef]
  183. Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M. A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. J Neuroinflammation. 2019; 16: 184. [CrossRef]
  184. Baya Mdzomba J, Joly S, Rodriguez L, Dirani A, Lassiaz P, Behar-Cohen F, et al. Nogo-A-targeting antibody promotes visual recovery and inhibits neuroinflammation after retinal injury. Cell Death Dis. 2020; 11: 101. [CrossRef]
  185. Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC, Vavvas DG, et al. Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma. PloS One. 2012; 7: e40065. [CrossRef]
  186. Yang X, Zeng Q, Barış M, Tezel G. Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma. J Neuroinflammation. 2020; 17: 252. [CrossRef]
  187. Trost A, Motloch K, Koller A, Bruckner D, Runge C, Schroedl F, et al. Inhibition of the cysteinyl leukotriene pathways increases survival of RGCs and reduces microglial activation in ocular hypertension. Experimental Eye Research. 2021; 213: 108806. [CrossRef]
  188. Aksar AT, Yuksel N, Gok M, Cekmen M, Caglar Y. Neuroprotective effect of edaravone in experimental glaucoma model in rats: A immunofluorescence and biochemical analysis. Int J Ophthalmol. 2015; 8: 239-244.
  189. Yu PA, Chao WA, Ling YU. Mitochondria-targeted antioxidant SS-31 is a potential novel ophthalmic medication for neuroprotection in glaucoma. Med Hypothesis Discov Innovation Ophthalmol. 2015; 4: 120-126.
  190. Yang L, Li S, Miao L, Huang H, Liang F, Teng X, et al. Rescue of glaucomatous neurodegeneration by differentially modulating neuronal endoplasmic reticulum stress molecules. J Neurosci. 2016; 36: 5891-5903. [CrossRef]
  191. Schnichels S, Joachim SC. The inducible nitric oxide synthase-inhibitor 1400W as a potential treatment for retinal diseases. Neural Regen Res. 2021; 16: 1221-1222. [CrossRef]
  192. Williams PA, Tribble JR, Pepper KW, Cross SD, Morgan BP, Morgan JE, et al. Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol Neurodegener. 2016; 11: 26. [CrossRef]
  193. Kole C, Brommer B, Nakaya N, Sengupta M, Bonet-Ponce L, Zhao T, et al. Activating transcription factor 3 (ATF3) protects retinal ganglion cells and promotes functional preservation after optic nerve crush. Investig Ophthalmol Vis Sci. 2020; 61: 31. [CrossRef]
  194. Ying Y, Xue R, Yang Y, Zhang SX, Xiao H, Zhu H, et al. Activation of ATF4 triggers trabecular meshwork cell dysfunction and apoptosis in POAG. Aging. 2021; 13: 8628-8642. [CrossRef]
  195. El-Nimri NW, Moore SM, Zangwill LM, Proudfoot JA, Weinreb RN, Skowronska-Krawczyk D, et al. Evaluating the neuroprotective impact of senolytic drugs on human vision. Sci Rep. 2020; 10: 21752. [CrossRef]
  196. Wang X, Lin J, Arzeno A, Choi JY, Boccio J, Frieden E, et al. Intravitreal delivery of human NgR-Fc decoy protein regenerates axons after optic nerve crush and protects ganglion cells in glaucoma models. Investig Ophthalmol Vis Sci. 2015; 56: 1357-1366. [CrossRef]
  197. Weinreb RN, Liebmann JM, Cioffi GA, Goldberg I, Brandt JD, Johnson CA, et al. Oral memantine for the treatment of glaucoma: Design and results of 2 randomized, placebo-controlled, phase 3 studies. Ophthalmology. 2018; 125: 1874-1885. [CrossRef]
  198. Husain S, Zaidi SAH, Singh S, Guzman W, Mehrotra S. Reduction of neuroinflammation by δ-opioids via STAT3-dependent pathway in chronic glaucoma model. Front Pharmacol. 2021; 12: 601404. [CrossRef]
  199. Zaidi SA, Thakore N, Singh S, Guzman W, Mehrotra S, Gangaraju V, et al. Histone deacetylases regulation by δ-opioids in human optic nerve head astrocytes. Investig Ophthalmol Vis Sci. 2020; 61: 17. [CrossRef]
  200. Lindsey JD, Duong-Polk KX, Hammond D, Chindasub P, Leung CK, Weinreb RN. Differential protection of injured retinal ganglion cell dendrites by brimonidine. Investig Ophthalmol Vis Sci. 2015; 56: 1789-1804. [CrossRef]
  201. Ellis DZ, Li L, Park Y, He S, Mueller B, Yorio T. Sigma-1 receptor regulates mitochondrial function in glucose-and oxygen-deprived retinal ganglion cells. Investig Ophthalmol Vis Sci. 2017; 58: 2755-2764. [CrossRef]
  202. Flachsbarth K, Jankowiak W, Kruszewski K, Helbing S, Bartsch S, Bartsch U. Pronounced synergistic neuroprotective effect of GDNF and CNTF on axotomized retinal ganglion cells in the adult mouse. Exp Eye Res. 2018; 176: 258-265. [CrossRef]
  203. Al Hussein Al Awamlh S, Wareham LK, Risner ML, Calkins DJ. Insulin signaling as a therapeutic target in glaucomatous neurodegeneration. Int J Mol Sci. 2021; 22: 4672. [CrossRef]
  204. Johnson MA, Mehrabian Z, Guo Y, Ghosh J, Brigell MG, Bernstein SL. Anti-NOGO antibody neuroprotection in a rat model of NAION. Transl Vis Sci Technol. 2021; 10: 12. [CrossRef]
  205. Buendia I, Navarro E, Michalska P, Gameiro I, Egea J, Abril S, et al. New melatonin-cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection. Future Med Chem. 2015; 7: 1961-1969. [CrossRef]
  206. Buendia I, Tenti G, Michalska P, Méndez-López I, Luengo E, Satriani M, et al. ITH14001, a CGP37157-nimodipine hybrid designed to regulate calcium homeostasis and oxidative stress, exerts neuroprotection in cerebral ischemia. ACS Chem Neurosci. 2017; 8: 67-81. [CrossRef]
  207. Michalska P, Tenti G, Satriani M, Cores A, Ramos MT, García AG, et al. Aza-CGP37157-lipoic hybrids designed as novel Nrf2-inducers and antioxidants exert neuroprotection against oxidative stress and show neuroinflammation inhibitory properties. Drug Dev Res. 2020; 81: 283-294. [CrossRef]
  208. Gontijo VS, Viegas FP, Ortiz CJ, de Freitas Silva M, Damasio CM, Rosa MC, et al. Molecular hybridization as a tool in the design of multi-target directed drug candidates for neurodegenerative diseases. Curr Neuropharmacol. 2020; 18: 348-407. [CrossRef]
  209. Esteruelas G, Halbaut L, García-Torra V, Espina M, Cano A, Ettcheto M, et al. Development and optimization of Riluzole-loaded biodegradable nanoparticles incorporated in a mucoadhesive in situ gel for the posterior eye segment. Int J Pharm. 2022; 612: 121379. [CrossRef]
  210. Boia R, Ruzafa N, Aires ID, Pereiro X, Ambrósio AF, Vecino E, et al. Neuroprotective strategies for retinal ganglion cell degeneration: Current status and challenges ahead. Int J Mol Sci. 2020; 21: 2262. [CrossRef]
  211. O’Callaghan J, Crosbie D, Cassidy P, Sherwood JM, Flügel-Koch C, Lütjen-Drecoll E, et al. Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma. Hum Mol Genet. 2017; 26: 1230-1246. [CrossRef]
  212. Wu J, Bell OH, Copland DA, Young A, Pooley JR, Maswood R, et al. Gene therapy for glaucoma by ciliary body aquaporin 1 disruption using CRISPR-Cas9. MolTher. 2020; 28: 820-829. [CrossRef]
  213. Mak HK, Ng SH, Ren T, Ye C, Leung CK. Impact of PTEN/SOCS3 deletion on amelioration of dendritic shrinkage of retinal ganglion cells after optic nerve injury. Exp Eye Res. 2020; 192: 107938. [CrossRef]
  214. Huang Z, Hu Z, Xie P, Liu Q. Tyrosine-mutated AAV2-mediated shRNA silencing of PTEN promotes axon regeneration of adult optic nerve. PLoS One. 2017; 12: e0174096. [CrossRef]
  215. Wan X, Pei H, Zhao MJ, Yang S, Hu WK, He H, et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy. Sci Rep. 2016; 6: 21587. [CrossRef]
  216. Ratican SE, Osborne A, Martin KR. Progress in gene therapy to prevent retinal ganglion cell loss in glaucoma and Leber’s hereditary optic neuropathy. Neural Plast. 2018; 2018: 7108948. [CrossRef]
  217. Yuan J, Zhang Y, Liu H, Wang D, Du Y, Tian Z, et al. Seven-year follow-up of gene therapy for Leber’s hereditary optic neuropathy. Ophthalmology. 2020; 127: 1125-1127. [CrossRef]
  218. Khatib TZ, Osborne A, Yang S, Ali Z, Jia W, Manyakin I, et al. Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axonal transport with functional recovery. Sci Adv. 2021; 7: eabd2590. [CrossRef]
  219. Hu Y, Leaver SG, Plant GW, Hendriks WT, Niclou SP, Verhaagen J, et al. Lentiviral-mediated transfer of CNTF to schwann cells within reconstructed peripheral nerve grafts enhances adult retinal ganglion cell survival and axonal regeneration. Mol Ther. 2005; 11: 906-915. [CrossRef]
  220. Limoli PG, Limoli C, Vingolo EM, Franzone F, Nebbioso M. Mesenchymal stem and non-stem cell surgery, rescue, and regeneration in glaucomatous optic neuropathy. Stem Cell Res Ther. 2021; 12: 275. [CrossRef]
  221. Zhu W, Gramlich OW, Laboissonniere L, Jain A, Sheffield VC, Trimarchi JM, et al. Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo. Proc Natl Acad Sci USA. 2016; 113: E3492-E3500. [CrossRef]
  222. Zhu W, Jain A, Gramlich OW, Tucker BA, Sheffield VC, Kuehn MH. Restoration of aqueous humor outflow following transplantation of iPSC-derived trabecular meshwork cells in a transgenic mouse model of glaucoma. Investig Ophthalmol Vis Sci. 2017; 58: 2054-2062. [CrossRef]
  223. Yun H, Wang Y, Zhou Y, Kumar A, Wang K, Sun M, et al. Human stem cells home to and repair laser-damaged trabecular meshwork in a mouse model. Commun Biol. 2018; 1: 216. [CrossRef]
  224. Mallick S, Sharma M, Kumar A, Du Y. Cell-based therapies for trabecular meshwork regeneration to treat glaucoma. Biomolecules. 2021; 11: 1258. [CrossRef]
  225. Guo L, Davis B, Nizari S, Normando EM, Shi H, Galvao J, et al. Direct optic nerve sheath (DONS) application of Schwann cells prolongs retinal ganglion cell survival in vivo. Cell Death Dis. 2014; 5: e1460. [CrossRef]
  226. Smedowski A, Liu X, Pietrucha-Dutczak M, Matuszek I, Varjosalo M, Lewin-Kowalik J. Predegenerated Schwann cells-a novel prospect for cell therapy for glaucoma: Neuroprotection, neuroregeneration and neuroplasticity. Sci Rep. 2016; 6: 23187. [CrossRef]
  227. Johnson TV, Martin KR. Cell transplantation approaches to retinal ganglion cell neuroprotection in glaucoma. Curr Opin Pharmacol. 2013; 13: 78-82. [CrossRef]
  228. Chamling X, Sluch SM, Zack DJ. The potential of human stem cells for the study and treatment of glaucoma. 2016; 57: ORSFi1-ORSFi6. [CrossRef]
  229. Nascimento-dos-Santos G, de-Souza-Ferreira E, Lani R, Faria CC, Araújo VG, Teixeira-Pinheiro LC, et al. Neuroprotection from optic nerve injury and modulation of oxidative metabolism by transplantation of active mitochondria to the retina. Biochim Biophys Acta Mol Basis Dis. 2020; 1866: 165686. [CrossRef]
  230. Liu Y, Lee RK. Cell transplantation to replace retinal ganglion cells faces challenges-the switchboard dilemma. Neural Regen Res. 2021; 16: 1138-1143. [CrossRef]
  231. Eastlake K, Lamb WD, Luis J, Khaw PT, Jayaram H, Limb GA. Prospects for the application of Müller glia and their derivatives in retinal regenerative therapies. Prog Retin Eye Res. 2021; 28: 100970. [CrossRef]
  232. Mead B, Ahmed Z, Tomarev S. Mesenchymal stem cell-derived small extracellular vesicles promote neuroprotection in a genetic DBA/2J mouse model of glaucoma. Investig Ophthalmol Vis Sci. 2018; 59: 5473-5480. [CrossRef]
  233. Harrell CR, Fellabaum C, Arsenijevic A, Markovic BS, Djonov V, Volarevic V. Therapeutic potential of mesenchymal stem cells and their secretome in the treatment of glaucoma. Stem Cells Int. 2019; 2019: 7869130. [CrossRef]
  234. Tabak S, Feinshtein V, Schreiber-Avissar S, Beit-Yannai E. Non-pigmented ciliary epithelium-derived extracellular vesicles loaded with SMAD7 siRNA attenuate Wnt signaling in trabecular meshwork cells in vitro. Pharmaceuticals. 2021; 14: 858. [CrossRef]
  235. Chen M, Ren C, Ren B, Fang Y, Li Q, Zeng Y, et al. Human retinal progenitor cells derived small extracellular vesicles delay retinal degeneration: A paradigm for cell-free therapy. Front Pharmacol. 2021; 12: 748956. [CrossRef]
  236. Behtaj S, Öchsner A, Anissimov YG, Rybachuk M. Retinal tissue bioengineering, materials and methods for the treatment of glaucoma. Tissue Eng Regen Med. 2020; 17: 253-269. [CrossRef]
  237. Topuz B, Aydin HM. Preparation of decellularized optic nerve grafts. Artif Organs. 2021. Doi: 10.1111/aor.14098. [CrossRef]
  238. Luo Z, Xian B, Li K, Li K, Yang R, Chen M, et al. Biodegradable scaffolds facilitate epiretinal transplantation of hiPSC-Derived retinal neurons in nonhuman primates. Acta Biomater. 2021; 134: 289-301. [CrossRef]
  239. McGrady NR, Pasini S, Baratta RO, Del Buono BJ, Schlumpf E, Calkins DJ. Restoring the extracellular matrix: A neuroprotective role for collagen mimetic peptides in experimental glaucoma. Front Pharmacol. 2021; 12: 764709. [CrossRef]
  240. Morrone LA, Rombola L, Adornetto A, Corasaniti MT, Russo R. Rational basis for nutraceuticals in the treatment of glaucoma. Curr Neuropharmacol. 2018; 16: 1004-1017. [CrossRef]
  241. Saccà SC, Corazza P, Gandolfi S, Ferrari D, Sukkar S, Iorio EL, et al. Substances of interest that support glaucoma therapy. Nutrients. 2019; 11: 239. [CrossRef]
  242. Chaudhry S, Dunn H, Carnt N, White A. Nutritional supplementation in the prevention and treatment of Glaucoma. Surv Ophthalmol. 2021. Doi: 10.1016/j.survophthal.2021.12.001. [CrossRef]
  243. Shim SH, Kim JM, Choi CY, Kim CY, Park KH. Ginkgo biloba extract and bilberry anthocyanins improve visual function in patients with normal tension glaucoma. J Med Food. 2012; 15: 818-823. [CrossRef]
  244. Manthey AL, Chiu K, So KF. Effects of Lycium barbarum on the visual system. Int Rev Neurobiol. 2017; 135: 1-27. [CrossRef]
  245. Lindsey JD, Duong-Polk KX, Hammond D, Leung CK, Weinreb RN. Protection of injured retinal ganglion cell dendrites and unfolded protein response resolution after long-term dietary resveratrol. Neurobiol Aging. 2015; 36: 1969-1981. [CrossRef]
  246. Zhang WH, Chen Y, Gao LM, Cao YN. Neuroprotective role of epigallocatechin-3-gallate in acute glaucoma via the nuclear factor-κB signaling pathway. Exp Ther Med. 2021; 22: 1235. [CrossRef]
  247. Cammalleri M, Dal Monte M, Amato R, Bagnoli P, Rusciano D. A dietary combination of forskolin with homotaurine, spearmint and B vitamins protects injured retinal ganglion cells in a rodent model of hypertensive glaucoma. Nutrients. 2020; 12: 1189. [CrossRef]
  248. Inman DM, Lambert WS, Calkins DJ, Horner PJ. α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction. PLoS One. 2013; 8: e65389. [CrossRef]
  249. Liu R, Wang Y, Pu M, Gao J. Effect of alpha lipoic acid on retinal ganglion cell survival in an optic nerve crush model. Mol Vis. 2016; 22: 1122-1136.
  250. Lambert WS, Carlson BJ, Formichella CR, Sappington RM, Ahlem C, Calkins DJ. Oral delivery of a synthetic sterol reduces axonopathy and inflammation in a rodent model of glaucoma. Front Neurosci. 2017; 11: 45. [CrossRef]
  251. Davis BM, Tian K, Pahlitzsch M, Brenton J, Ravindran N, Butt G, et al. Topical coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension. Mitochondrion. 2017; 36: 114-123. [CrossRef]
  252. Davis BM, Pahlitzsch M, Guo L, Balendra S, Shah P, Ravindran N, et al. Topical curcumin nanocarriers are neuroprotective in eye disease. Sci Rep. 2018; 8: 11066. [CrossRef]
  253. Fernández-Albarral JA, Martínez-López MA, Marco EM, de Hoz R, Martín-Sánchez B, San Felipe D, et al. Is saffron able to prevent the dysregulation of retinal cytokines induced by ocular hypertension in mice? J Clin Med. 2021; 10: 4801. [CrossRef]
  254. Williams PA, Harder JM, Foxworth NE, Cochran KE, Philip VM, Porciatti V, et al. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science. 2017; 355: 756-760. [CrossRef]
  255. Chou TH, Romano GL, Amato R, Porciatti V. Nicotinamide-rich diet in DBA/2J mice preserves retinal ganglion cell metabolic function as assessed by PERG adaptation to flicker. Nutrients. 2020; 12: 1910. [CrossRef]
  256. Hui F, Tang J, Williams PA, McGuinness MB, Hadoux X, Casson RJ, et al. Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial. Clin Experiment Ophthalmol. 2020; 48: 903-914. [CrossRef]
  257. De Moraes CG, John SW, Williams PA, Blumberg DM, Cioffi GA, Liebmann JM. Nicotinamide and pyruvate for neuroenhancement in open-angle glaucoma: A phase 2 randomized clinical trial. JAMA Ophthalmol. 2022; 140: 11-18. [CrossRef]
  258. Liu S, D’Amico D, Shankland E, Bhayana S, Garcia JM, Aebischer P, et al. Effect of urolithin a supplementation on muscle endurance and mitochondrial health in older adults: A randomized clinical trial. JAMA Netw Open. 2022; 5: e2144279. [CrossRef]
  259. Napolitano P, Filippelli M, Davinelli S, Bartollino S, dell’Omo R, Costagliola C. Influence of gut microbiota on eye diseases: An overview. Ann Med. 2021; 53: 750-761. [CrossRef]
  260. Pardue MT, Ciavatta VT, Hetling JR. Neuroprotective effects of low-level electrical stimulation therapy on retinal degeneration. Adv Exp Med Biol. 2014; 801: 845-851. [CrossRef]
  261. Lim JH, Stafford BK, Nguyen PL, Lien BV, Wang C, Zukor K, et al. Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat Neurosci. 2016; 19: 1073-1084. [CrossRef]
  262. Enayati S, Chang K, Achour H, Cho KS, Xu F, Guo S, et al. Electrical stimulation induces retinal müller cell proliferation and their progenitor cell potential. Cells. 2020; 9: 781. [CrossRef]
  263. Cheng H, Huang Y, Yue H, Fan Y. Electrical stimulation promotes stem cell neural differentiation in tissue engineering. Stem Cells Int. 2021; 2021: 6697574. [CrossRef]
  264. Moss LD, Sode D, Patel R, Lui A, Hudson C, Patel NA, et al. Intranasal delivery of exosomes from human adipose derived stem cells at forty-eight hours post injury reduces motor and cognitive impairments following traumatic brain injury. Neurochem Int. 2021; 150: 105173. [CrossRef]
  265. Fayazi N, Sheykhhasan M, Soleimani Asl S, Najafi R. Stem cell-derived exosomes: A new strategy of neurodegenerative disease treatment. Mol Neurobiol. 2021; 58: 3494-3514. [CrossRef]
  266. Seyedrazizadeh SZ, Poosti S, Nazari A, Alikhani M, Shekari F, Pakdel F, et al. Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury. Stem Cell Res Ther. 2020; 11: 203. [CrossRef]
  267. Shah S, Esdaille CJ, Bhattacharjee M, Kan HM, Laurencin CT. The synthetic artificial stem cell (SASC): Shifting the paradigm of cell therapy in regenerative engineering. Proc Natl Acad Sci USA. 2022; 119: e2116865118. [CrossRef]
  268. Staufer O, Dietrich F, Rimal R, Schröter M, Fabritz S, Boehm H, et al. Bottom-up assembly of biomedical relevant fully synthetic extracellular vesicles. Sci Adv. 2021; 7: eabg6666. [CrossRef]
  269. Laha B, Stafford BK, Huberman AD. Regenerating optic pathways from the eye to the brain. Science. 2017; 356: 1031-1034. [CrossRef]
  270. Gokoffski KK, Peng M, Alas B, Lam P. Neuro-protection and neuro-regeneration of the optic nerve: recent advances and future directions. Curr Opin Neurol. 2020; 33: 93-105. [CrossRef]
  271. Roska B, Sahel JA. Restoring vision. Nature. 2018; 557: 359-367. [CrossRef]
  272. Apara A, Galvao J, Wang Y, Blackmore M, Trillo A, Iwao K, et al. KLF9 and JNK3 interact to suppress axon regeneration in the adult CNS. J Neurosci. 2017; 37: 9632-9644. [CrossRef]
  273. Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature. 2000; 403: 434-439. [CrossRef]
  274. Zhou B, Yu P, Lin MY, Sun T, Chen Y, Sheng ZH. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J Cell Biol. 2016; 214: 103-119. [CrossRef]
  275. Van de Velde S, De Groef L, Stalmans I, Moons L, Van Hove I. Towards axonal regeneration and neuroprotection in glaucoma: Rho kinase inhibitors as promising therapeutics. Prog Neurobiol. 2015; 131: 105-119. [CrossRef]
  276. Nieuwenhuis B, Eva R. ARF6 and Rab11 as intrinsic regulators of axon regeneration. Small GTPases. 2020; 11: 392-401. [CrossRef]
  277. Nieuwenhuis B, Barber AC, Evans RS, Pearson CS, Fuchs J, MacQueen AR, et al. PI 3-kinase delta enhances axonal PIP 3 to support axon regeneration in the adult CNS. EMBO Mol Med. 2020; 12: e11674. [CrossRef]
  278. Tsai JC. Innovative IOP-independent neuroprotection and neuroregeneration strategies in the pipeline for glaucoma. J Ophthalmol. 2020; 2020: 9329310. [CrossRef]
  279. Chow LS, Paley MN. Recent advances on optic nerve magnetic resonance imaging and post-processing. Magn Reson Imaging. 2021; 79: 76-84. [CrossRef]
  280. Prabhakaran GT, Al-Nosairy KO, Tempelmann C, Thieme H, Hoffmann MB. Mapping visual field defects with fMRI-impact of approach and experimental conditions. Front Neurosci. 2021; 15: 745886. [CrossRef]
  281. Zheng C, Johnson TV, Garg A, Boland MV. Artificial intelligence in glaucoma. Curr Opin Ophthalmol. 2019; 30: 97-103. [CrossRef]
  282. Han X, Steven K, Qassim A, Marshall HN, Bean C, Tremeer M, et al. Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA. Am J Hum Genet. 2021; 108: 1204-1216. [CrossRef]
  283. Garg AK, Knight D, Lando L, Chao DL. Advances in retinal oximetry. Transl Vis Sci Technol. 2021; 10: 5. [CrossRef]
  284. Bower AJ, Liu T, Aguilera N, Li J, Liu J, Lu R, et al. Integrating adaptive optics-SLO and OCT for multimodal visualization of the human retinal pigment epithelial mosaic. Biomed Opt Express. 2021; 12: 1449-1466. [CrossRef]
  285. Marc R, Pfeiffer R, Jones B. Retinal prosthetics, optogenetics, and chemical photoswitches. ACS Chem Neurosci. 2014; 5: 895-901. [CrossRef]
  286. Tochitsky I, Kramer RH. Optopharmacological tools for restoring visual function in degenerative retinal diseases. Curr Opin Neurobiol. 2015; 34: 74-78. [CrossRef]
  287. Gu L, Uhelski ML, Anand S, Romero-Ortega M, Kim YT, Fuchs PN, et al. Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons. PloS One. 2015; 10: e0117746. [CrossRef]
  288. Batabyal S, Kim S, Wright W, Mohanty S. Layer-specific nanophotonic delivery of therapeutic opsin-encoding genes into retina. Exp Eye Res. 2021; 205: 108444. [CrossRef]
  289. Sridharan A, Shah A, Kumar SS, Kyeh J, Smith J, Blain-Christen J, et al. Optogenetic modulation of cortical neurons using organic light emitting diodes (OLEDs). Biomed Phys Eng Express. 2020; 6: 025003. [CrossRef]
  290. Fernández E, Alfaro A, Soto-Sánchez C, Gonzalez-Lopez P, Lozano AM, Peña S, et al. Visual percepts evoked with an intracortical 96-channel microelectrode array inserted in human occipital cortex. J Clin Invest. 2021; 131: e151331. [CrossRef]
  291. Qiu Z, Kala S, Guo J, Xian Q, Zhu J, Zhu T, et al. Targeted neurostimulation in mouse brains with non-invasive ultrasound. Cell Rep. 2021; 34: 108595. [CrossRef]
  292. Provansal M, Marazova K, Sahel JA, Picaud S. Vision restoration by optogenetic therapy and developments toward sonogenetic therapy. Transl Vis Sci Technol. 2022; 11: 18. [CrossRef]
  293. De Moraes CG, Mansouri K, Liebmann JM, Ritch R. Association between 24-hour intraocular pressure monitored with contact lens sensor and visual field progression in older adults with glaucoma. JAMA Ophthalmol. 2018; 136: 779-785. [CrossRef]
  294. Tam ALC, Gupta N, Zhang Z, Yucel YH. Latanoprost stimulates ocular lymphatic drainage: An in vivo nanotracer study. Transl Vis Sci Technol. 2013; 2: 3. [CrossRef]
  295. Kasi A, Liu C, Faiq MA, Chan KC. Glymphatic imaging and modulation of the optic nerve. Neural Regen Res. 2022; 17: 937-947. [CrossRef]
  296. Leung CK, Lam AK, Weinreb RN, Garway-Heath DF, Yu M, Guo PY, et al. Diagnostic assessment of glaucoma and non-glaucomatous optic neuropathies via optical texture analysis of the retinal nerve fibre layer. Nat Biomed Eng. 2022. Doi: 10.1038/s41551-021-00813-x. [CrossRef]
  297. Rabiolo A, Fantaguzzi F, Sacconi R, Gelormini F, Borrelli E, Triolo G, et al. Combining structural and vascular parameters to discriminate among glaucoma patients, glaucoma suspects, and healthy subjects. Transl Vis Sci Technol. 2021; 10: 20. [CrossRef]
  298. Cordeiro MF, Hill D, Patel R, Corazza P, Maddison J, Younis S. Detecting retinal cell stress and apoptosis with DARC: Progression from lab to clinic. Prog Retin Eye Res. 2021; 86: 100976. [CrossRef]
  299. Tsuda S, Tanaka Y, Kunikata H, Yokoyama Y, Yasuda M, Ito A, et al. Real-time imaging of RGC death with a cell-impermeable nucleic acid dyeing compound after optic nerve crush in a murine model. Exp Eye Res. 2016; 146: 179-188. [CrossRef]
  300. Li H, Li T, Horns F, Li J, Xie Q, Xu C, et al. Single-cell transcriptomes reveal diverse regulatory strategies for olfactory receptor expression and axon targeting. Curr Biol. 2020; 30: 1189-1198.e5. [CrossRef]
  301. Thiel MA, Wild A, Schmid MK, Job O, Bochmann F, Loukopoulos V, et al. Penetration of a topically administered anti–tumor necrosis factor alpha antibody fragment into the anterior chamber of the human eye. Ophthalmology. 2013; 120: 1403-1408. [CrossRef]
  302. Keller KE, Bradley JM, Sun YY, Yang YF, Acott TS. Tunneling nanotubes are novel cellular structures that communicate signals between trabecular meshwork cells. Investig Ophthalmol Vis Sci. 2017; 58: 5298-5307. [CrossRef]
  303. Boguslawski J, Palczewska G, Tomczewski S, Milkiewicz J, Kasprzycki P, Stachowiak D, et al. In vivo imaging of the human eye using a 2-photon-excited fluorescence scanning laser ophthalmoscope. J Clin Invest. 2022; 132: e154218. [CrossRef]
  304. Rossi EA, Norberg N, Eandi C, Chaumette C, Kapoor S, Le L, et al. A new method for visualizing drusen and their progression in flood-illumination adaptive optics ophthalmoscopy. Transl Vis Sci Technol. 2021; 10: 19. [CrossRef]
  305. Huard DJ, Lieberman RL. Progress toward development of a proteostasis drug for myocilin-associated glaucoma. Future Med Chem. 2018; 10: 1391-1393. [CrossRef]
  306. Lieberman RL, Ma MT. Molecular insights into myocilin and its glaucoma-causing misfolded olfactomedin domain variants. Acc Chem Res. 2021; 54: 2205-2215. [CrossRef]
  307. Tribble JR, Hui F, Jöe M, Bell K, Chrysostomou V, Crowston JG, et al. Targeting diet and exercise for neuroprotection and neurorecovery in glaucoma. Cells. 2021; 10: 295. [CrossRef]
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