Neuroprotection in Glaucoma
Glaucoma, a progressive optic neuropathy characterized by retinal ganglion cell degeneration and visual field loss, is a leading cause of irreversible blindness worldwide. Intraocular pressure (IOP) is currently the only modifiable risk factor for this disease. However, glaucomatous damage persists in almost 50% of patients, despite lowering IOP. Neuroprotection in glaucoma refers to non-IOP-related interventions that can prevent or delay glaucomatous neurodegeneration, independently of IOP. The current article reviews and discusses the various strategies for neuroprotection in glaucoma to date.
Brimonidine is an alpha-2 adrenergic agonist commonly used as an anti-glaucoma, IOP-lowering agent. Previous studies using animal models have shown enhanced survival of retinal ganglion cells (RGCs) independently of IOP. Brimonidine also protects RGCs from somatic, axonal, and dendritic degeneration in optic injuries involving ischemia, NMDA-induced neurotoxicity, ocular hypertension, optic crush, and optic neuritis.In its ophthalmic formulation, brimonidine must reach effective pharmacologic concentrations in the vitreous to have an effect on the retina. In a clinical study of phakic, aphakic, and pseudo-phakic patients undergoing pars plana vitrectomy, topical brimonidine 0.2% administered twice daily for 5 to 14 days prior to surgery yielded 2 nM in the vitreous, satisfying the threshold concentration for neuroprotection . Various mechanisms for brimonidine’s neuroprotective effects have been purported including neurotrophic factor activation, vasomodulation, glutamate inhibition, and cell-survival signal upregulation as well as apoptosis downregulation. Specifically, brimonidine increases the transcription of neurotrophic factors (e.g. brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF)) and their receptors (TrkB for BDNF and FGF receptor), which regulate various cellular functions including neuronal growth, plasticity, differentiation, and survival. Brimonidine has been shown to not only protect the retina from ischemic damage in a dose- and time-dependent manner, but also to support neural regeneration after injury. Brimonidine also mitigates neuronal death and promotes cell survival by decreasing Bax (pro-apoptotic) while increasing Bcl-2/xL (anti-apoptotic) expressions in injured cells, respectively. Brimonidine further provides anti-cytotoxic benefits by decreasing post-injury glutamate accumulation.
Mohamed et al. conducted a single-center, nonrandomized study evaluating brimonidine’s effects on visual field performance in 16 primary open-angle glaucoma (POAG) patients with medically controlled IOP. Visual fields were assessed at baseline, 6 months, and 12 months after administering 0.2% brimonidine twice daily. IOP significantly decreased at 6 and at 12 months. With respect to field field parameters, mean deviation significantly increased at 6 and at 12 months, whereas pattern standard deviation did not significantly improve for either time points. Overall, brimonidine improved visual field performance and also lowered IOP. Whether these neuroprotective effects were independent of IOP is not clear.
The Low-pressure Glaucoma Treatment Study (LoGTS) compared the effects of brimonidine and timolol on visual field progression in low-pressure glaucoma. In this multicenter, double-masked, randomized study, 99 patients were treated with brimonidine and 79 patients were treated with timolol. The incidence of visual field progression was significantly lower for patients receiving brimonidine monotherapy relative to the timolol group (9.1% and 39.2%, respectively), despite similar IOP-lowering effects. Notably, however, 55% of patients in the brimonidine cohort and about 30% of patients in the timolol cohort were lost to follow-up over the course of the study. Approximately half of those lost to follow up in the brimonidine group experienced ocular allergy, which may have potentially skewed the study’s findings. Additional clinical studies conducted by Tsai et al. reported a statistically significant reduction in retinal nerve fiber layer (RNFL) damage following the use of brimonidine 0.2% compared with timolol 0.5% in ocular hypertensive patients over 1 year, independently of IOP reduction.
Stem Cell Therapy
Mesenchymal Stromal Cells
Mesenchymal stromal cells (MSCs) have also been implicated in glaucoma neuroprotection. Studies using animal models and postmortem human tissues suggest an MSC association with neuroprotective factors, namely platelet-derived growth factor (PDGF). However, this neuroprotective approach is not without shortcomings as intravitreal injection of MSCs may similarly have adverse effects including reactive gliosis, vitreous clumping, and epiretinal membrane thickening. These unfavorable changes may be related to variability in cell preparation methodologies and standardized protocols are likely necessary to further elucidate the neuroprotective role of MSCs.
Human Embryonic Stem Cells
Human embryonic stem cells (hESCs) are pluripotent cells with the capacity to differentiate into all 3 embryonic layers. Experimental studies conducted by Sluch et al. have developed cell culture protocols for differentiating hESCs into RGCs. Previous preclinical studies (in mature uninjured rat and monkey eyes) have also demonstrated successful integration of hESCs and their mediation of light responses in the host retina. However, given the embryonic nature of hESCs, this technology is both an ethically controversial and scientifically challenging approach to neuroprotection in ocular disease.
Clinical trials currently investigating the role of stem cells in glaucoma include the following:
- The Intravitreal Mesenchymal Stem Cell Transplantation in Advanced Glaucoma Study: Phase I study evaluating the safety of intravitreally injecting autologous MSCs in 10 patients (NCT02330978).
- Stem Cell Ophthalmology Treatment Study and Stem Cell Ophthalmology Treatment Study II: Non-randomized, open-label, patient-funded studies assessing variability in patient outcomes according to different methods of MSC delivery including sub-Tenon’s, retrobulbar, intravitreal or intravenous route (NCT01920867, NCT03011541).
- The Effectiveness and Safety of Adipose-Derived Regenerative Cells for Treatment of Glaucomatous Neurodegeneration study: Single-arm, uncontrolled study evaluating the efficacy of stem cells delivered via the sub-Tenon’s route (NCT02144103).
Overall, the clinical utility of cell-based therapies is poorly understood. Despite the potential neuroprotective or neuroregenerative roles of stem cells, randomized and controlled clinical trials are necessary to sufficiently demonstrate the practical applications of stem cell therapy in glaucoma.
Ciliary Neurotrophic Factor
The hypothalamic neuropeptide, ciliary neurotrophic factor (CNTF), is a neuronal survival factor that may potentially confer neuroprotection in glaucoma. Currently, Neurotech Pharmaceuticals is conducting a randomized, sham-controlled, masked Phase II clinical trial using NT-501, an implantable polymeric device, to deliver encapsulated CNTF in 54 glaucoma patients. Following intravitreal implantation, the semi-permeable membrane encasement enables sustained CNTF release by retinal pigment epithelial cells targeting the retinal ganglion cells (NCT02862938).
Recombinant Human Nerve Growth Factor
Recombinant human nerve growth factor (rhNGF) is an effective neuroprotective agent with a favorable safety and efficacy profile. Notably, ophthalmic formulations of rhNGF are FDA-approved for treating neurotrophic keratitis. Clinical trials investigating the role of rhNGF in glaucoma are currently underway. The NGF-Glaucoma trial is a Phase 1b, monocentric, double-masked randomized study, which aims to assess the safety and tolerability of rhNGF ophthalmic solution compared to a vehicle control in chronic POAG patients. Structural and functional evaluations using optical coherence tomography, visual field, and electroretinography (ERG) are secondary objectives (NCT02855450).
Brain‑derived Neurotrophic Factor
Oddone et al. reported decreased brain‑derived neurotrophic factor (BDNF) and NGF levels in early glaucoma, and therefore proposed these growth factors as biomarkers for detecting early disease. Additional evidence has shown that administering trophic factors in combination (neurturin, GDNF, and BDNF) more effectively enhances RGC survival relative to administering these factors alone.
Gene therapy strategies for glaucoma neuroprotection are rising of interested, although currently limited in clinical applications. Experimental studies conducted by Jain et al. in juvenile open angle glaucoma effectively lowered IOP and inhibited glaucomatous damage by inducing loss-of-function mutations in the myocilin gene in mouse models of myocilin-associated POAG. Human cell-cultures similarly exhibited decreased trabecular meshwork myocilin mRNA following myocilin gene mutations. Various investigators are also studying tunica interna endothelial cell kinase (TEK) as a genetic target. Given its role as an angiopoietin receptor involved in Schlemm’s canal development, disruption of this gene is associated with various phenotypes of congenital glaucoma. Therefore, inducing gain-of-function mutations in TEK may have potential value in gene therapy.
Additional strategies include genetically delivering neuroprotective factors to mitigate retinal ganglion cell loss. In particular, genetic constructs designed by Astellas Pharmaceuticals enable the overexpression of BDNF and TrkB. This dual delivery of both the neuroprotective ligand and its receptor allows for the prolonged activation of ganglion cell survival pathways and may prove to be a reliable therapeutic approach to POAG in the planned Phase I/IIa trials.
Ocular Blood Flow Regulating Agents
Aside from IOP, vascular dysregulation has also been suggested in glaucoma pathogenesis. Notably, anti-glaucoma medications including carbonic anhydrase inhibitors, such as dorzolamide, and prostaglandin analogs, such as latanoprost, have been shown to improve ocular perfusion in addition to lowering IOP. Experimental studies in animal models of retinal ischemia have also demonstrated the neuroprotective effects of betaxolol, a selective beta-2 adrenergic antagonist. However, the precise mechanisms of neuroprotection conferred by these agents or whether these effects occur independently of IOP are unclear and further investigations are necessary.
Ginkgo biloba extract (GBE) has various antioxidant effects and has been suggested as a neuroprotective agent in neurodegenerative diseases including cognitive impairment and Alzheimer’s Disease (AD). Mitochondrial dysfunction and oxidative stress have both been purported in dementia and glaucoma pathogenesis. Not surprisingly, given this mechanistic overlap, researchers have similarly explored the potential therapeutic benefits of GBE in glaucoma. A crossover randomized clinical trial comprising 27 normal tension glaucoma (NTG) patients evaluated the effects of GBE on visual field performance in patients receiving 40 mg GBE three times daily for 4 weeks followed by 4 weeks of placebo (separated by an 8-week washout period) compared to patients receiving the placebo treatment first followed by GBE. NTG patients receiving GBE showed significant improvements in visual field indices. In a 4-year longitudinal study conducted by Lee et al., NTG patients treated with GBE also showed marked improvement in visual field performance and without significant IOP changes. Alternatively, a crossover, placebo‑controlled, clinical trial showed no improvement in visual field performance or contrast sensitivity in Chinese NTG cohorts treated with GBE. In addition to its anti-oxidant effects, GBE also has vascular regulatory effects and has been shown to improve ocular blood flow. Color Doppler studies have demonstrated increased blood flow velocity and decreased vascular resistance in the retrobulbar as well as peripapillary vascular networks of NTG patients. A clinical trial is currently underway to further establish the effects of GBE on ocular blood flow in POAG (NCT02376114).
Memantine is a non-competitive NMDA antagonist with anti-glutamate excitotoxicity effects. Though typically indicated in moderate to severe AD, memantine has also been shown to protect against RGC loss in animal models of glaucoma. Despite these potentially promising neuroprotective findings, large-scale multicenter, randomized double-masked placebo-controlled Phase III clinical trials failed to demonstrate significant benefits with memantine therapy in patients with glaucoma (NCT00141882, NCT00168350).
Citicoline (cytidine 5’-diphosphocholine) is an endogenous compound and an emerging therapeutic agent for glaucoma. Clinical studies have recently investigated the neuroprotective effects of citicoline in glaucoma in its intramuscular (IM), oral, and topical eye drop formulations. Giraldi et al. first described the neurotrophic properties of citicoline for treating POAG in 1989, whereby patients treated with IM citicoline 1 g daily for 10 days all showed significant improvement in visual field testing, despite well-controlled IOP. These therapeutic effects continued for at least 3 months and were maintained with retreatment. Giraldi and investigators also evaluated citicoline’s protective effects with repeated cycles of therapy every 6 months and found that the perimetric benefits persisted for over 10 years. Visual field worsening fractions in treated patients and controls were 10% and 50%, respectively. Placebo-controlled studies have also demonstrated significant improvements in retinocortical function with IM citicoline as measured by visual evoked potentials (VEP) and pattern ERG (PERG)
Rejdak et al. was the first to evaluate the neuroprotective effects of oral citicoline in glaucoma. VEP significantly normalized in amplitude and implicit time in glaucomatous eyes treated with 2, bi-weekly courses of 500 mg tablets containing citicoline. Studies have similarly reported improved VEP amplitude and retinocortical time in chronic POAG patients treated with oral citicoline. Longitudinal investigations have further evaluated the benefits of oral citicoline in patients with progressing POAG, despite controlled IOP. Patients treated with oral citicoline 500 mg daily (4-month cycles separated by 2-month wash-out periods) over 2 years showed a significant reduction in glaucomatous progression rate, averaging -0.15 +/- 0.3 dB/year. Additional studies have reported delayed glaucomatous damage in retinal morphology, whereby OCT thickness measurements of the RNFL and the ganglion cells complex markedly improved with oral citicoline therapy. Intriguingly, however, the significance of these results was not apparent until after 1-year of citicoline therapy, suggesting that extended treatment is needed to achieve clinically meaningful effects. Parisi et al. compared the efficacies of oral and IM citicoline and reported similar improvements in retinal function and neural conduction along visual pathways for both formulations. Continued therapy for up to 8 years stabilized or further improved visual dysfunction in glaucoma patients, suggesting the need for repeated dosing to achieve optimal results.
Topical administration of citicoline eye drops has also been shown to improve retinal function and neural conduction along the visual pathway, as measured by PERG and VEP. Although these effects are similar to that of oral citicoline, enhanced penetration for reaching therapeutic levels of topical citicoline in the vitreous is associated with increasingly probable adverse effects. In contrast, oral citicoline has very minimal or absent side effects as well as improved compliance and is the preferred route of administration. In fact, citicoline is authorized as a food supplement in the European Union (EU), Italian Ministry of Health, and the United States. Citicoline is approved in the EU and Italian Ministry of Health, as a novel food ingredient in food supplements and in dietary foods for special medical purposes in glaucoma patients.
Calcium Channel Blockers
Calcium channel blockers (CCBs) have been implicated in glaucoma neuroprotection by preventing calcium-mediated apoptosis and improving ocular blood flow. In particular, brovincamine and nilvadipine are 2 CCB’s that permeate the blood-brain barrier and, thus, selectively influence the optic nerve circulation without appreciably affecting systemic circulation. Randomized clinical trials have demonstrated the therapeutic effects of brovincamine and nilvadipine, whereby NTG patients treated with CCBs showed improved ocular blood flow and delayed progression of visual field defects. Despite their selectivity, however, these CCBs may impair ocular blood flow autoregulation, especially during acute increases in IOP. In addition, non-selective CCBs should be prescribed with caution since reduced systemic blood pressure can compromise blood flow to the optic nerve and potentially contribute to glaucoma pathogenesis.
Decreased antioxidant levels in conjunction with increased oxidative free radical damage have been implicated in glaucoma pathogenesis. In fact, studies have demonstrated trabecular meshwork (TM) degeneration followed by IOP elevation and subsequent glaucomatous damage in human tissues. Additional studies have reported significant correlations between oxidative damage in TM gene expression and increased IOP as well as visual field loss. Among the various antioxidants, Coenzyme Q10 (CoQ10), a cofactor of the mitochondrial respiratory chain, may be useful in scavenging free radicals and minimizing oxidative stress. A 12-month clinical trial evaluated the efficacy of Coqun (CoQ10 plus vitamin E) ophthalmic solution along with beta-blockers in glaucoma patients compared to patients treated with beta-blockers alone. Glaucoma patients receiving the combined regimen featured improved inner retinal function and visual cortical responses, as determined by PERG and VEP, respectively.
Nicotinamide (vitamin B3 or NAM), an important precursor for nicotinamide adenine dinucleotide (NAD), has a favorable neuroprotective profile in glaucoma given its integral roles in calcium homeostasis, endothelin-mediated vascular regulation, and maintenance of mitochondrial function. NAM neuroprotection in glaucoma has largely been demonstrated in animal models and independently of IOP. However, Nzoughet et al. recently reported significantly reduced plasma NAM levels in POAG patients relative to controls, which further support NAM’s neuroprotective properties. In addition, the safety and efficacy of oral NAM have already been demonstrated in a Phase III randomized clinical trial (UTN U1111-1131-4069). In light of these reassuring preliminary findings, the Center for Eye Research in Australia is currently conducting the first clinical trial to assess the short-term therapeutic effects of NAM supplementation in POAG patients (Trial ID ACTRN12617000809336).
- ↑ Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 2002. Bulletin of the World Health Organization 2004;82:844-51.
- ↑ Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48-56.
- ↑ Guymer C, Wood JP, Chidlow G, Casson RJ. Neuroprotection in glaucoma: recent advances and clinical translation. Clin Experiment Ophthalmol. 2019;47(1):88-105.
- ↑ Hernández M, Urcola JH, Vecino E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp Eye Res. 2008;86 (5):798–806.
- ↑ 5.0 5.1 Woldemussie E, Ruiz G, Wijono M, Wheeler LA. Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Vis Sci. 2001;42:2849–55.
- ↑ Aviles-Trigueros M, Mayor-Torroglosa S, Garcıa-Aviles A, et al. Transient ischemia of the retina results in massive degeneration of the retinotectal projection: long-term neuroprotection with brimonidine. Experimental Neurology 2003;184:767-77.
- ↑ Galindo-Romero C, Harun-Or-Rashid M, Jiménez-López M, et al. Neuroprotection by α2-Adrenergic Receptor Stimulation after Excitotoxic Retinal Injury: A Study of the Total Population of Retinal Ganglion Cells and Their Distribution in the Chicken Retina. PLoS One 2016;11(9).
- ↑ Lambert W, Ruiz L, Crish S, et al. Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons. Molecular Neurodegeneration 2011;6(4).
- ↑ Marangoz D, Guzel E, Eyuboglu S, et al. Comparison of the neuroprotective effects of brimonidine tartrate and melatonin on retinal ganglion cells. Int Ophthalmol 2017.
- ↑ Kim K, Jang I, Moon H, et al. Neuroprotective Effects of Human Serum Albumin Nanoparticles Loaded With Brimonidine on Retinal Ganglion Cells in Optic Nerve Crush Model. Investigative Ophthalmology & Visual Science 2015;56:5641-9.
- ↑ Lindsey J, Duong-Polk K, Hammond D, et al. Differential Protection of Injured Retinal Ganglion Cell Dendrites by Brimonidine. Investigative Ophthalmology & Visual Science 2015;56(3):1789-804.
- ↑ 12.0 12.1 Guo X, Namekata K, Kimura A, et al. Brimonidine suppresses loss of retinal neurons and visual function in a murine model of optic neuritis. Neuroscience Letters 2015;592:27-31.
- ↑ Kent A, Nussdorf J, David R, et al. Vitreous concentration of topically applied brimonidine tartrate 0.2%. Ophthalmology 2001;108(4).
- ↑ 14.0 14.1 Gao H, Qiao X, Cantor LB, WuDunn D. Upregulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells. Arch Ophthalmol. 2002;120(6):797–803.
- ↑ Feke GT, Bex PJ, Taylor CP, et al. Effect of brimonidine on retinal vascular autoregulation and short-term visual function in normal tension glaucoma. Am J Ophthalmol. 2014;158(1):105–112.e1.
- ↑ Wheeler LA, Lai R, WoldeMussie E. From the lab to the clinic: activation of an alpha-2 agonist pathway is neuroprotective in models of retinal and optic nerve injury. Eur J Ophthalmol. 1999;9(Suppl.1):17.
- ↑ Dong CJ, Guo Y, Agey P, et al. Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity. Invest Ophthalmol Vis Sci. 2008;49(10):4515–22.
- ↑ Kent AR, Nussdorf JD, David R, et al. Vitreous concentration of topically applied brimonidine tartrate 0.2%. Ophthalmology. 2001;108(4):784–87.
- ↑ Lai R, Chun T, Hasson D, et al. Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat. Visual Neuroscience 2002;19:175-85.
- ↑ Lonngren U, Napankangas U, Lafuente M, et al. The growth factor response in ischemic rat retina and superior colliculus after brimonidine pre-treatment. Brain Research Bulletin 2006;71:208-18.
- ↑ Donello J, Padillo E, Webster M, et al. α2-Adrenoceptor Agonists Inhibit Vitreal Glutamate and Aspartate Accumulation and Preserve Retinal Function after Transient Ischemia. The Journal of Pharmacology and Experimental Therapeutics 2001;296(1):216-23.
- ↑ Lee D, Kim K-Y, Noh Y, et al. Brimonidine Blocks Glutamate Excitotoxicity-Induced Oxidative Stress and Preserves Mitochondrial Transcription Factor A in Ischemic Retinal Injury. PLoS One 2012;7(10).
- ↑ Lee K, Nakayama M, Aihara M, et al. Brimonidine is neuroprotective against glutamate-induced neurotoxicity, oxidative stress, and hypoxia in purified rat retinal ganglion cells. Molecular Vision 2010;16:246-51.
- ↑ Tatton W, Chalmers-Redman R, Sud A, et al. Maintaining Mitochondrial Membrane Impermeability: An Opportunity for New Therapy in Glaucoma? Survey of Ophthalmology 2001;45.
- ↑ Wheeler L, WoldeMussie E, Lai R. Role of Alpha-2 Agonists in Neuroprotection. Survey of Ophthalmology 2003;48:S47-S51.
- ↑ 26.0 26.1 Mohamed J, Abo-Elkhei O. The Role of Brimonidine Eye Drops as an Adjunctive Therapy for Optic Nerve Protection in Patients with Controlled Open Angle Glaucoma. The Egyptian Journal of Hospital Medicine 2017;68(3):1418-24.
- ↑ Krupin T, Liebmann J, Greenfield D, et al. A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. Am J Ophthalmol 2011;151(6).
- ↑ Tsai J-C, Chang H-W. Comparison of the effects of brimonidine 0.2% and timolol 0.5% on retinal nerve fiber layer thickness in ocular hypertensive patients: a prospective, unmasked study. J Ocul Pharmacol Ther 2005; 21: 475–82.
- ↑ Johnson TV, Bull ND, Hunt DP, et al. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 2010;51(4):2051–59.
- ↑ Emre E, Yüksel N, Duruksu G, et al. Neuroprotective effects of intravitreally transplanted adipose tissue and bone marrow-derived mesenchymal stem cells in an experimental ocular hypertension model. Cytotherapy. 2015;17(5):543–59.
- ↑ Yu S, Tanabe T, Dezawa M, et al. Effects of bone marrow stromal cell injection in an experimental glaucoma model. Biochem Biophys Res Commun. 2006;344(4):1071–79.
- ↑ Johnson TV, Dekorver NW, Levasseur VA, et al. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain. 2014;137 (2):503–19.
- ↑ Osborne A, Sanderson J, Martin KR. Neuroprotective effects of human mesenchymal stem cells and platelet-derived growth factor on human retinal ganglion cells. Stem Cells. 2018;36(1):65–78.
- ↑ Tassoni A, Gutteridge A, Barber AC, et al. Molecular mechanisms mediating retinal reactive stem cell transplantation. Stem Cells. 2015;33:3006–16.
- ↑ Tzameret A, Sher I, Belkin M, et al. Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy. Exp Eye Res. 2014;118:135–44.
- ↑ Kim JY, You YS, Kim SH, et al. Epiretinal membrane formation after intravitreal autologous stem cell implantation in a retinitis pigmentosa patient. Retin Cases Brief Rep. 2016.
- ↑ 37.0 37.1 Khatib TZ, Martin KR. Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine. Curr Eye Res. 2020;45(3):327-338.
- ↑ Lopez Sanchez MIG, Crowston JG, Mackey DA, et al. Emerging mitochondrial therapeutic targets in optic neuropathies. Pharmacol Ther 2016; 165:132–52.
- ↑ Sluch VM, Davis CO, Ranganathan V, et al. Differentiation of human ESCs to retinal ganglion cells using a CRISPR engineered reporter cell line. Sci Rep 2015; 5:1–17.
- ↑ Venugopalan P, Wang Y, Nguyen T, et al. Transplanted neurons integrate into adult retinas and respond to light. Nat Commun 2016; 7:1–9.
- ↑ Chao JR, Lamba DA, Klesert TR, et al. Transplantation of human embryonic stem cell-derived retinal cells into the subretinal space of a non-human primate. Transl Vis Sci Technol 2017; 6:1–13.
- ↑ Pease ME, Zack DJ, Berlinicke C, et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci. 2009;50(5):2194–200.
- ↑ Lambiase A, Rama P, Bonini S, et al. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998;338(17):1174–80.
- ↑ Cukras C, Wiley HE, Jeffrey BG, et al. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase I/IIa trial by intravitreal delivery. Mol Ther. 2018;26(9):2282–94.
- ↑ Bartel M, Schaffer D, Büning H. Enhancing the clinical potential of AAV vectors by capsid engineering to evade pre-existing immunity. Front Microbiol. 2011;2:204.
- ↑ Jain A, Zode G, Kasetti RB, et al. CRISPR-Cas9–based treatment of myocilin-associated glaucoma. Proc Natl Acad Sci. 2017;114(42):11199–204.
- ↑ Thomson BR, Heinen S, Jeansson M, et al. A lymphatic defect causes ocular hypertension and glaucoma in mice. J Clin Invest. 2014;124(10):4320–24.
- ↑ Souma T, Tompson SW, Thomson BR, et al. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest. 2016;126(7):2575–87.
- ↑ Osborne A, Wang AXZ, Tassoni A, et al. Design of a novel gene therapy construct to achieve sustained brain-derived neurotrophic factor signaling in neurons. Hum Gene Ther. 2018;29(7):828–41.
- ↑ Osborne A, Khatib TZ, Songra L, et al. Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-- related kinase receptor-B signaling. Cell Death Dis. 2018;9(10).
- ↑ Mozaffarieh M, Flammer J. New insights in the pathogenesis and treatment of normal tension glaucoma. Curr Opin Pharmacol 2013;13:43‑49.
- ↑ Martinez A, Gonzalez F, Capeans C, Perez R, Sanchez‑Salorio M. Dorzolamide effect on ocular blood flow. Invest Ophthalmol Vis Sci 1999;40:1270‑1275.
- ↑ Boltz A, Schmidl D, Weigert G, et al. Effect of latanoprost on choroidal blood flow regulation in healthy subjects. Invest Ophthalmol Vis Sci 2011;52:4410‑4415.
- ↑ McKibbin M, Menage MJ. The effect of once‑daily latanoprost on intraocular pressure and pulsatile ocular blood flow in normal tension glaucoma. Eye (Lond) 1999;13(Pt 1):31‑34.
- ↑ Osborne NN, Cazevieille C, Carvalho AL, et al. In vivo and in vitro experiments show that betaxolol is a retinal neuroprotective agent. Brain Res 1997;751:113‑123.
- ↑ Osborne NN, DeSantis L, Bae JH, et al. Topically applied betaxolol attenuates NMDA‑induced toxicity to ganglion cells and ischemic effects on the retina. Exp Eye Res 1999;69:331‑342.
- ↑ Ghiso JA, Doudevski I, Ritch R, et al. Alzheimer’s disease and glaucoma: Mechanistic similarities and differences. J Glaucoma 2013;22 Suppl 5:S36‑S38.
- ↑ Ritch R. Potential role for Ginkgo biloba extract in the treatment of glaucoma. Med Hypotheses 2000;54:221‑235.
- ↑ 59.0 59.1 Saccà SC, Pascotto A, Camicione P, et al. Oxidative DNA damage in the human trabecular meshwork: Clinical correlation in patients with primary open‑angle glaucoma. Arch Ophthalmol 2005;123:458‑463.
- ↑ Eckert A, Keil U, Scherping I, et al. Stabilization of mitochondrial membrane potential and improvement of neuronal energy metabolism by Ginkgo biloba extract EGb 761. Ann N Y Acad Sci 2005;1056:474‑485.
- ↑ Quaranta L, Bettelli S, Uva MG, et al. Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma. Ophthalmology 2003;110:359‑362.
- ↑ Lee J, Sohn SW, Kee C. Effect of Ginkgo biloba extract on visual field progression in normal tension glaucoma. J Glaucoma. 2013;22:780–784.
- ↑ Guo X, Kong X, Huang R, et al. Effect of Ginkgo biloba on visual field and contrast sensitivity in Chinese patients with normal tension glaucoma: A randomized, crossover clinical trial. Invest Ophthalmol Vis Sci 2014;55:110‑116.
- ↑ Chung HS, Harris A, Kristinsson JK, et al. Ginkgo biloba extract increases ocular blood flow velocity. J Ocul Pharmacol Ther. 1999;15:233–240.
- ↑ Harris A, Gross J, Moore N, et al. The effects of antioxidants on ocular blood flow in patients with glaucoma. Acta Ophthalmol. 2018;96:e237–e241.
- ↑ Park JW, Kwon HJ, Chung WS, et al. Short-term effects of Ginkgo biloba extract on peripapillary retinal blood flow in normal tension glaucoma. Korean J Ophthalmol. 2011;25:323–328.
- ↑ Vorwerk CK, Lipton SA, Zurakowski D, et al. Chronic low-dose glutamate is toxic to retinal ganglion cells: toxicity blocked by memantine. Invest Ophthalmol Vis Sci. 1996;37:1618–24.
- ↑ Hare WA, WoldeMussie E, Lai RK, et al. Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: functional measures. Invest Ophthalmol Vis Sci. 2004;45 (8):2625.
- ↑ 69.0 69.1 Pecori Giraldi J, Virno M, Covelli G, et al. Therapeutic value of citicoline in the treatment of glaucoma (computerized and automated perimetric investigation). Int. Ophthalmol. 1989;13:109–112.
- ↑ Virno M, Pecori-Giraldi J, Liguori A, et al. The protective effect of citicoline on the progression of the perimetric defects in glaucomatous patients (perimetric study with a 10-year follow-up). Acta Ophthalmol. Scand. Suppl. 2000;78:56–57.
- ↑ Parisi V, Manni, G, Colacino G, et al. Cytidine-50-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma. Ophthalmology 1999;106:1126–1134.
- ↑ Parisi V. Electrophysiological assessment of glaucomatous visual dysfunction during treatment with cytidine-50-diphosphocholine (citicoline): A study of 8 years of follow-up. Doc. Ophthalmol. 2005;110:91–102.
- ↑ 73.0 73.1 Rejdak R, Toczolowski J, Kurkowski, J, et al. Oral citicoline treatment improves visual pathway function in glaucoma. Med. Sci. Monit. 2003;9:PI24–PI28.
- ↑ Bubella RM, Carità S, Badalamenti R, et al. Neuroprotezione del paziente con glaucoma cronico ad an golo aperto: Ruolo della citicolina in soluzione orale. Ottica Fisiopatologica 2011;16:171–177.
- ↑ 75.0 75.1 Ottobelli L, Manni GL, Centofanti M, et al. Citicoline oral solution in glaucoma: Is there a role in slowing disease progression? Ophthalmologica 2013;229:219–226.
- ↑ 76.0 76.1 Lanza M, Gironi Carnevale UA, Mele L, et al. Morphological and functional evaluation of oral citicoline therapy in chronic open-angle glaucoma patients: A pilot study with a 2-year follow-up. Front. Pharmacol. 2019;10:1117.
- ↑ 77.0 77.1 Parisi V, Coppola G, Centofanti M, et al. Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog. Brain Res. 2008;173:541–554.
- ↑ Parisi V, Centofanti M, Ziccardi L, et al. Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma. Graefes Arch. Clin. Exp. Ophthalmol. 2015;253:1327–1340.
- ↑ Roberti G, Tanga L, Parisi V, et al. A preliminary study of the neuroprotective role of citicoline eye drops in glaucomatous optic neuropathy. Indian J. Ophthalmol. 2014;62:549–553.
- ↑ Parisi V, Oddone F, Roberti G, et al. Enhancement of retinal function and of neural conduction along the visual pathway induced by treatment with citicoline eye drops in liposomal formulation in open angle glaucoma: A pilot electrofunctional study. Adv. Ther. 2019;36:987–996.
- ↑ 81.0 81.1 Grieb P, Junemann A, Rekas M, et al. A food beneficial for patients su_ering from or threated with glaucoma. Front. Aging Neurosci. 2016;8:73.
- ↑ Grieb P, Rejdak R. Pharmacodynamics of citicoline relevant to the treatment of glaucoma. J. Neurosci. Res. 2002;67:143–148.
- ↑ Gandolfi S, Marchini G, Caporossi A, et al. Cytidine 5'-Diphosphocholine (Citicoline): Evidence for a Neuroprotective Role in Glaucoma. Nutrients. 2020;12(3)
- ↑ Otori Y, Kusaka S, Kawasaki A, et al. Protective effect of nilvadipine against glutamate neurotoxicity in purified retinal ganglion cells. Brain Res 2003;961:213‑219.
- ↑ Mayama C. Calcium channels and their blockers in intraocular pressure and glaucoma. Eur J Pharmacol 2014;739:96‑105.
- ↑ Sawada A, Kitazawa Y, Yamamoto T, et al. Prevention of visual field defect progression with brovincamine in eyes with normal‑tension glaucoma. Ophthalmology 1996;103:283‑288.
- ↑ Koseki N, Araie M, Yamagami J, et al. Effects of oral brovincamine on visual field damage in patients with normal‑tension glaucoma with low‑normal intraocular pressure. J Glaucoma 1999;8:117‑123.
- ↑ Koseki N, Araie M, Tomidokoro A, et al. A placebo‑controlled 3‑year study of a calcium blocker on visual field and ocular circulation in glaucoma with low‑normal pressure. Ophthalmology 2008;115:2049‑2057.
- ↑ Takayama J, Tomidokoro A, Ishii K, et al. Time course of the change in optic nerve head circulation after an acute increase in intraocular pressure. Invest Ophthalmol Vis Sci 2003;44:3977‑3985.
- ↑ Iwase A, Tomidokoro A, Leung C, et al. Clinical relevance of ocular blood flow (OBF) measurements including effects of general medications or specific glaucoma treatment. In: Ocular Blood Flow in Glaucoma. Kugler Publications: Amsterdam; 2009. p. 59.
- ↑ Zhou L, Li Y, Yue BY. Oxidative stress affects cytoskeletal structure and cell‑matrix interactions in cells from an ocular tissue: The trabecular meshwork. J Cell Physiol 1999;180:182‑189.
- ↑ Parisi V, Centofanti M, Gandolfi S, et al. Effects of coenzyme Q10 in conjunction with vitamin E on retinal‑evoked and cortical‑evoked responses in patients with open‑angle glaucoma. J Glaucoma 2014;23:391‑404.
- ↑ Whitmore AV, Libby RT, John SWM. Glaucoma: thinking in new ways—a role for autonomous axonal self-destruction and other compartmentalized processes? Prog Retin Eye Res 2005; 24: 639–62.
- ↑ Araie M, Mayama C. Use of calcium channel blockers for glaucoma. Prog Retin Eye Res 2011;30:54–71.
- ↑ Kaushik S, Pandav SS, Ram J. Neuroprotection in glaucoma. J Postgrad Med 2003;49: 90–5.
- ↑ Pasquale LR. Vascular and autonomic dysregulation in primary open-angle glaucoma. Curr Opin Ophthalmol 2016; 27: 94–101.
- ↑ Resch H, Garhofer G, Fuchsjäger-Mayrl G, et al. Endothelial dysfunction in glaucoma. Acta Ophthalmol 2009; 87: 4–12.
- ↑ Mokudai T, Ayoub IA, Sakakibara Y, et al. Delayed treatment with nicotinamide (vitamin B(3)) improves neurological outcome and reduces infarct volume after transient focal cerebral ischemia in Wistar rats. Stroke 2000; 31: 679–85.
- ↑ Williams PA, Harder JM, Foxworth NE, et al. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 2017; 355: 756–60.
- ↑ Williams PA, Harder JM, Foxworth NE, et al. Nicotinamide and WLDS act together to prevent neurodegeneration in glaucoma. Front Neurosci 2017; 11:1–10.
- ↑ Kouassi Nzoughet J, Chao de la Barca JM, Guehlouz K, et al. Nicotinamide deficiency in primary open-angle glaucomanicotinamide deficiency in glaucoma. Invest Ophthalmol Vis Sci. 2019;60(7):2509–14.
- ↑ Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618–26.