Search

Glaucoma is a neuropathic disease that causes optic nerve damage, loss of retinal ganglion cells (RGCs), and visual field defects. Most glaucoma patients have no early signs or symptoms. Conventional pharmacological glaucoma medications and surgeries that focus on lowering intraocular pressure are not sufficient; RGCs continue to die, and the patient's vision continues to decline. Recent evidence has demonstrated that neuroprotective approaches could be a promising strategy for protecting against glaucoma. In the case of glaucoma, neuroprotection aims to prevent or slow down disease progression by mitigating RGCs death and optic nerve degeneration. Notably, new pharmacologic medications such as antiglaucomatous agents, antibiotics, dietary supplementation, novel neuroprotective molecules, neurotrophic factors, translational methods such as gene therapy and cell therapy, and electrical stimulation-based physiotherapy are emerging to attenuate the death of RGCs, or to make RGCs resilient to attacks. Understanding the roles of these interventions in RGC protection may offer benefits over traditional pharmacological medications and surgeries. In this review, we summarize the recent neuroprotective strategy for glaucoma, both in clinical trials and in laboratory research., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The purpose of this study was to evaluate the neuroprotective effects of omega-3 polyunsaturated fatty acid (ω3-PUFA) supplementation, alone or in combination with timolol eye drops, in a mouse model of hereditary glaucoma. DBA/2J mice (8.5-month-old) were assigned to an ω3-PUFAs + timolol, ω3-PUFAs only, timolol only, or an untreated group. Treated mice received a daily gavage administration of eicosapentaenoic acid (EPA) and docosahexaenoic acid and/or topical instillation of timolol (0.5%) once a day for 3 months. Blood was analysed regularly to determine ω3-PUFA levels and retinas were histologically analysed. Real-time PCR and Western blot were performed for retinal pro-inflammatory cytokines and macrophages. Blood arachidonic acid/EPA ratio gradually decreased and reached the desired therapeutic range (1-1.5) after 4 weeks of daily gavage with ω3-PUFAs in the ω3-PUFAs + timolol and ω3-PUFAs only groups. Retinal ganglion cell densities were significantly higher in the ω3-PUFAs + timolol (1303.77 ± 139.62/mm 2 ), ω3-PUFAs only (768.40 ± 52.44/mm 2 ) and timolol only (910.57 ± 57.28/mm 2 ) groups than in the untreated group (323.39 ± 95.18/mm 2 ). ω3-PUFA supplementation alone or timolol alone, significantly increased protein expression levels of M1 macrophage-secreted inducible nitric oxide synthase and M2 macrophage-secreted arginase-1 in the retina, which led to significant decreases in the expression levels of tumour necrosis factor-α (TNF-α). ω3-PUFA supplementation alone also resulted in significantly reduced expression of interleukin-18 (IL-18). ω3-PUFA + timolol treatment had no effect on the expression level of any of the aforementioned mediators in the retina. Supplementation with ω3-PUFAs has neuroprotective effect in the retinas of DBA/2J mice that is enhanced when combined with timolol eye drops. The continued inflammation following ω3-PUFAs + timolol treatment suggests that downregulation of IL-18 and TNF-α may not be the only factors involved in ω3-PUFA-mediated neuroprotection in the retina., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Interleukin (IL)-1β, a proinflammatory cytokine, is a key mediator in several acute and chronic neurological diseases. Thioredoxin-1 (TRX1) acts as an antioxidant and plays a protective role in certain neurons. We examined whether exogenous TRX1 exerts axonal protection and affects IL-1β levels in tumor necrosis factor (TNF)-induced optic nerve degeneration in rats. Immunoblot analysis showed that IL-1β was upregulated in the optic nerve after intravitreal injection of TNF. Treatment with recombinant human (rh) TRX1 exerted substantial protective effects against TNF-induced axonal loss. The increase in the IL-1β level in the optic nerve was abolished by rhTRX1. Treatment with rhTRX1 also significantly inhibited increased glial fibrillary acidic protein (GFAP) levels induced by TNF. Immunohistochemical analysis showed substantial colocalization of IL-1β and GFAP in the optic nerve after TNF injection. These results suggest that IL-1β is upregulated in astrocytes in the optic nerve after TNF injection and that exogenous rhTRX1 exerts axonal protection with an inhibitory effect on IL-1β., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Sodium channel blocking agents such as lamotrigine are potent agents for neuroprotection in several animal models of neurodegenerative and neuroinflammatory disease. We therefore explored whether lamotrigine therapy was neuroprotective in a rat model of ocular hypertension characterized by axonal injury and selective loss of retinal ganglion cells. Twenty-seven male Wistar rats were injected subcutaneously twice daily with either lamotrigine (14 mg/kg/day) or vehicle. Two weeks after the first injection, experimental ocular hypertension was induced in one eye by 532 nm trabecular laser treatment. Intraocular pressure (IOP) was monitored by rebound tonometry and four weeks after the elevation of IOP the loss of optic nerve axons was quantified relative to eyes without either IOP elevation or lamotrigine exposure. In other animals with ocular hypertension, the optic nerves were examined by immunohistochemistry for the expression of the inducible form of nitric oxide synthase (iNOS) at 7 and 28 days. Four weeks after initiation of IOP elevation, no significant difference in axonal loss was observed between rats treated with lamotrigine (30.8% ± 10.5%) or vehicle (17.8% ± 5.7%) (P = 0.19, T-test). There was no significant difference in mean IOP, peak IOP and integral IOP exposure. Furthermore, optic nerve axon counts per unit integral IOP exposure were similar in both groups (P = 0.44). The optic nerves were not positive for the expression of iNOS. In conclusion, this study provides no evidence that lamotrigine is neuroprotective for RGC axons after four weeks of experimental ocular hypertension in the rat, in a model where axonal degeneration occurs in the absence of iNOS expression., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Injury to retinal ganglion cell (RGC) axons within the optic nerve causes apoptosis of the soma. We previously demonstrated that in vivo axotomy causes elevation of superoxide anion within the RGC soma, and that this occurs 1-2 days before annexin-V positivity, a marker of apoptosis. Pegylated superoxide dismutase delivery to the RGC prevents the superoxide elevation and rescues the soma. Together, these results imply that superoxide is an upstream signal for apoptosis after axonal injury in RGCs. We then studied metallocorroles, potent superoxide dismutase mimetics, which we had shown to be neuroprotective in vitro and superoxide scavengers in vivo for RGCs. RGCs were retrograde labeled with the fluorescent dye 4Di-10Asp, and then axotomized by intraorbital optic nerve transection. Iron(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole (Fe(tpfc)(SO(3)H)(2)) (Fe-corrole) was injected intravitreally. Longitudinal imaging of RGCs was performed and the number of surviving RGCs enumerated. There was significantly greater survival of labeled RGCs with Fe-corrole, but the degree of neuroprotection was relatively less than that predicted by their ability to scavenge superoxide-This implies an unexpected complexity in signaling of apoptosis by reactive oxygen species., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

To determine if the absence of c-Jun N-terminal kinase 3 (JNK3) in the mouse retina would reduce retinal ganglion cell (RGC) loss in mice with experimental glaucoma. C57BL/6 mice underwent experimental intraocular pressure (IOP) elevation with a bead/viscoelastic injection into one eye. One-half of the mice were Jnk3 homozygous knockouts (KO) and were compared to wild type (WT) mice. IOP was measured under anesthesia with the TonoLab, axial length was measured post-mortem with calipers after inflation to 15mmHg, and RGC layer counts were performed on retinal whole mount images stained with DAPI, imaged by confocal microscopy, and counted by masked observers in an image analysis system. Axon counts were performed in optic nerve cross-sections by semi-automated image analysis. Both WT and Jnk3(-/-) mice had mean elevations of IOP of more than 50% after bead injection. Both groups underwent the expected axial globe elongation due to chronic IOP elevation. The absence of JNK3 in KO retina was demonstrated by Western blots. RGC layer neuron counts showed modest loss in both WT and Jnk3(-/-) animals; local differences by retinal eccentricity were detected, in each case indicating greater loss in KO animals than in WT. The baseline number of RGC layer cells in KO animals was 10% higher than in WT, but the number of optic nerve axons was identical in KO and WT controls. A slightly greater loss of RGC in Jnk3(-/-) mice compared to controls was detected in experimental mouse glaucoma by RGC layer counting and there was no protective effect shown in axon counts. Counts of RGC layer cells and optic nerve axons indicate that Jnk3(-/-) mice have an increased number of amacrine cells compared to WT controls., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In glaucoma, the major cause of global irreversible blindness, there is an urgent need for treatment modalities that directly target the RGCs. The discovery of an alternative therapeutic approach, independent of IOP reduction, is highly sought after, due to the indirect nature and limited effectiveness of IOP lowering therapy in preventing RGC loss. Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma. These mechanisms and their potential treatment include excitotoxicity, protein misfolding, mitochondrial dysfunction, oxidative stress, inflammation and neurotrophin deprivation. All of these mechanisms ultimately lead to programmed cell death with loss of RGCs. In this article we summarize the mechanisms involved in glaucomatous disease, highlight the rationale for neuroprotection in glaucoma management and review current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic., (Copyright © 2010 Elsevier Ltd. All rights reserved.)