{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:13:24Z","timestamp":1791267204625,"version":"4.1.0"},"reference-count":132,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Glaucoma is a neurodegenerative disease that affects primarily the retinal ganglion cells (RGCs). Increased intraocular pressure (IOP) is one of the major risk factors for glaucoma. The mainstay of current glaucoma therapy is limited to lowering IOP; however, controlling IOP in certain patients can be futile in slowing disease progression. The understanding of potential biomolecular processes that occur in glaucomatous degeneration allows for the development of glaucoma treatments that modulate the death of RGCs. Neuroprotection is the modification of RGCs and the microenvironment of neurons to promote neuron survival and function. Numerous studies have revealed effective neuroprotection modalities in animal models of glaucoma; nevertheless, clinical translation remains a major challenge. In this review, we select the most clinically relevant treatment strategies, summarize preclinical and clinical data as well as recent therapeutic advances in IOP-independent neuroprotection research, and discuss the feasibility and hurdles of each therapeutic approach based on possible pathogenic mechanisms. We also summarize the potential therapeutic mechanisms of various agents in neuroprotection related to glutamate excitotoxicity.<\/jats:p>","DOI":"10.3390\/jpm12111884","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T19:17:34Z","timestamp":1668107854000},"page":"1884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Neuroprotection in Glaucoma: Basic Aspects and Clinical Relevance"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8795-6368","authenticated-orcid":false,"given":"Che-Yuan","family":"Kuo","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine Jui-Ling","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ophtha.2013.07.054","article-title":"The United Kingdom Glaucoma Treatment Study: A multicenter, randomized, placebo-controlled clinical trial: Design and methodology","volume":"120","author":"Lascaratos","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1001\/archopht.120.10.1268","article-title":"Reduction of intraocular pressure and glaucoma progression: Results from the Early Manifest Glaucoma Trial","volume":"120","author":"Heijl","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1001\/archopht.120.6.701","article-title":"The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma","volume":"120","author":"Kass","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Collaborative Normal-Tension Glaucoma Study Group (1998). Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am. J. Ophthalmol., 126, 487\u2013497.","DOI":"10.1016\/S0002-9394(98)00223-2"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00401-011-0807-1","article-title":"The optic nerve head is the site of axonal transport disruption, axonal cytoskeleton damage and putative axonal regeneration failure in a rat model of glaucoma","volume":"121","author":"Chidlow","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1001\/archopht.1981.03930010635009","article-title":"Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage","volume":"99","author":"Quigley","year":"1981","journal-title":"Arch. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/j.1442-9071.2011.02563.x","article-title":"Translational neuroprotection research in glaucoma: A review of definitions and principles","volume":"40","author":"Casson","year":"2012","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1001\/archopht.117.11.1540","article-title":"Is neuroprotection a viable therapy for glaucoma?","volume":"117","author":"Weinreb","year":"1999","journal-title":"Arch. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"834","DOI":"10.3389\/fnins.2018.00834","article-title":"The Role of Endogenous Neuroprotective Mechanisms in the Prevention of Retinal Ganglion Cells Degeneration","volume":"12","author":"Amadio","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/0955-0674(95)80022-0","article-title":"Neurotrophic factors and their receptors","volume":"7","author":"Barbacid","year":"1995","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kimura, A., Namekata, K., Guo, X., Harada, C., and Harada, T. (2016). Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091584"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.ophtha.2011.11.003","article-title":"Glaucoma 2.0: Neuroprotection, neuroregeneration, neuroenhancement","volume":"119","author":"Chang","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1080\/08923970802379819","article-title":"The role of neurotrophic factors in the pathology and treatment of multiple sclerosis","volume":"31","year":"2009","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1007\/s11033-021-06968-9","article-title":"Therapeutic potential of neurotrophic factors in Alzheimer\u2019s Disease","volume":"49","author":"Nasrolahi","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.cytogfr.2011.05.001","article-title":"Neurotrophic factors for the treatment of Parkinson\u2019s disease","volume":"22","author":"Sullivan","year":"2011","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.0953-816X.2003.03107.x","article-title":"CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: The possible involvement of STAT3 pathway","volume":"19","author":"Ji","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0306-4522(01)00557-7","article-title":"Neurturin enhances the survival of axotomized retinal ganglion cells in vivo: Combined effects with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor","volume":"110","author":"Koeberle","year":"2002","journal-title":"Neuroscience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13469","DOI":"10.1073\/pnas.0906678106","article-title":"Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma","volume":"106","author":"Lambiase","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Oddone, F., Roberti, G., Micera, A., Busanello, A., Bonini, S., Quaranta, L., Agnifili, L., and Manni, G. (2017). Exploring Serum Levels of Brain Derived Neurotrophic Factor and Nerve Growth Factor Across Glaucoma Stages. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0168565"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1080\/02713680490517872","article-title":"Adeno-associated viruses containing bFGF or BDNF are neuroprotective against excitotoxicity","volume":"29","author":"Schuettauf","year":"2004","journal-title":"Curr. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ajo.2021.11.002","article-title":"Phase 1b Randomized Controlled Study of Short Course Topical Recombinant Human Nerve Growth Factor (rhNGF) for Neuroenhancement in Glaucoma: Safety, Tolerability, and Efficacy Measure Outcomes","volume":"234","author":"Beykin","year":"2022","journal-title":"Am. J. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.exer.2010.05.016","article-title":"Neurotrophic factor delivery as a protective treatment for glaucoma","volume":"93","author":"Johnson","year":"2011","journal-title":"Exp. Eye Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.1007\/s10792-021-01959-y","article-title":"Serum and aqueous humor levels of brain-derived neurotrophic factor in patients with primary open-angle glaucoma and normal-tension glaucoma","volume":"41","author":"Cha","year":"2021","journal-title":"Int. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s00417-018-3923-y","article-title":"The effect of trabeculectomy on serum brain-derived neurotrophic factor levels in primary open-angle glaucoma","volume":"256","author":"Uzel","year":"2018","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0304-3940(01)01830-4","article-title":"Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats","volume":"305","author":"Ko","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_27","first-page":"489","article-title":"Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study","volume":"37","author":"Salvador","year":"1996","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_28","first-page":"382","article-title":"Neuroprotective effects of exogenous brain-derived neurotrophic factor on amyloid-beta 1-40-induced retinal degeneration","volume":"18","author":"Lazaldin","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_29","first-page":"799","article-title":"Ciliary neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract","volume":"23","author":"Shpak","year":"2017","journal-title":"Mol. Vis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ajo.2016.07.013","article-title":"Long-term Follow-up of Patients With Retinitis Pigmentosa Receiving Intraocular Ciliary Neurotrophic Factor Implants","volume":"170","author":"Birch","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1089\/ten.2004.10.1617","article-title":"Sustained secretion of ciliary neurotrophic factor to the vitreous, using the encapsulated cell therapy-based NT-501 intraocular device","volume":"10","author":"Thanos","year":"2004","journal-title":"Tissue Eng."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s13311-015-0415-1","article-title":"Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans","volume":"13","author":"Gordon","year":"2016","journal-title":"Neurotherapeutics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.preteyeres.2018.02.002","article-title":"Neuroprotective strategies for retinal disease","volume":"65","author":"Pardue","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1016\/j.ajpath.2016.07.017","article-title":"Electrical Stimulation as a Means for Improving Vision","volume":"186","author":"Sehic","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.exer.2016.06.010","article-title":"Whole-eye electrical stimulation therapy preserves visual function and structure in P23H-1 rats","volume":"149","author":"Hanif","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.expneurol.2009.06.016","article-title":"Neuroprotective effect of transcorneal electrical stimulation on light-induced photoreceptor degeneration","volume":"219","author":"Ni","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_37","first-page":"1243","article-title":"Inhibitory effect of the leaf extract of Ginkgo biloba L. on oxidative stress-induced platelet aggregation","volume":"46","author":"Akiba","year":"1998","journal-title":"Biochem. Mol. Biol. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1089\/jop.1999.15.233","article-title":"Ginkgo biloba extract increases ocular blood flow velocity","volume":"15","author":"Chung","year":"1999","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/0140-6736(92)93158-J","article-title":"Ginkgo biloba","volume":"340","author":"Kleijnen","year":"1992","journal-title":"Lancet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1089\/089771502753594936","article-title":"Enhanced survival and regeneration of axotomized retinal ganglion cells by a mixture of herbal extracts","volume":"19","author":"Cheung","year":"2002","journal-title":"J. Neurotrauma"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1006\/bbrc.1994.1764","article-title":"The nitric oxide-scavenging properties of Ginkgo biloba extract EGb 761","volume":"201","author":"Marcocci","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1054\/mehy.1999.0025","article-title":"Potential role for Ginkgo biloba extract in the treatment of glaucoma","volume":"54","author":"Ritch","year":"2000","journal-title":"Med. Hypotheses"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1001\/archopht.123.4.458","article-title":"Oxidative DNA damage in the human trabecular meshwork: Clinical correlation in patients with primary open-angle glaucoma","volume":"123","author":"Sacca","year":"2005","journal-title":"Arch. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0161-6420(02)01745-1","article-title":"Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma","volume":"110","author":"Quaranta","year":"2003","journal-title":"Ophthalmology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1097\/IJG.0b013e3182595075","article-title":"Effect of Ginkgo biloba extract on visual field progression in normal tension glaucoma","volume":"22","author":"Lee","year":"2013","journal-title":"J. Glaucoma"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1167\/iovs.13-13168","article-title":"Effect of Ginkgo biloba on visual field and contrast sensitivity in Chinese patients with normal tension glaucoma: A randomized, crossover clinical trial","volume":"55","author":"Guo","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s10792-020-01663-3","article-title":"Ginkgo Biloba affects microvascular morphology: A prospective optical coherence tomography angiography pilot study","volume":"41","author":"Sabaner","year":"2021","journal-title":"Int. Ophthalmol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1167\/tvst.9.13.26","article-title":"Correlation of Visual Field With Peripapillary Vessel Density Through Optical Coherence Tomography Angiography in Normal-Tension Glaucoma","volume":"9","author":"Lin","year":"2020","journal-title":"Trans. Vis. Sci. Technol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s12967-022-03323-9","article-title":"Peripapillary vessel density correlates with visual field mean sensitivity in highly myopic eyes","volume":"20","author":"Zhong","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.exer.2008.02.008","article-title":"Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments","volume":"86","author":"Urcola","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/j.1442-9071.2011.02573.x","article-title":"Prevention of retinal ganglion cell swelling by systemic brimonidine in a rat experimental glaucoma model","volume":"39","author":"Urcola","year":"2011","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_52","first-page":"65","article-title":"Alpha2-adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration","volume":"40","author":"Yoles","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"705405","DOI":"10.3389\/fphar.2021.705405","article-title":"Brimonidine is Neuroprotective in Animal Paradigm of Retinal Ganglion Cell Damage","volume":"12","author":"Conti","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1001\/archopht.120.6.797","article-title":"Up-regulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells","volume":"120","author":"Gao","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ejphar.2015.08.035","article-title":"\u03b12-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model","volume":"765","author":"Jung","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5085","DOI":"10.1167\/iovs.06-1249","article-title":"Distribution of amyloid precursor protein and amyloid-beta immunoreactivity in DBA\/2J glaucomatous mouse retinas","volume":"48","author":"Goldblum","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e2514","DOI":"10.1038\/cddis.2016.397","article-title":"Non-amyloidogenic effects of \u03b12 adrenergic agonists: Implications for brimonidine-mediated neuroprotection","volume":"7","author":"Nizari","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.ajo.2010.09.026","article-title":"A randomized trial of brimonidine versus timolol in preserving visual function: Results from the Low-Pressure Glaucoma Treatment Study","volume":"151","author":"Krupin","year":"2011","journal-title":"Am. J. Ophthalmol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajo.2011.07.009","article-title":"A randomized trial of brimonidine versus timolol in preserving visual function: Results from the Low-pressure Glaucoma Treatment Study","volume":"152","author":"Garudadri","year":"2011","journal-title":"Am. J. Ophthalmol."},{"key":"ref_60","first-page":"CD006539","article-title":"Neuroprotection for treatment of glaucoma in adults","volume":"1","author":"Sena","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1136\/bjo.87.12.1463","article-title":"Contrast sensitivity improves after brimonidine therapy in primary open angle glaucoma: A case for neuroprotection","volume":"87","author":"Evans","year":"2003","journal-title":"Br. J. Ophthalmol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1089\/jop.2005.21.475","article-title":"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","volume":"21","author":"Tsai","year":"2005","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2010.12.036","article-title":"Neurodegeneration in glaucoma: Progression and calcium-dependent intracellular mechanisms","volume":"176","author":"Crish","year":"2011","journal-title":"Neuroscience"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0361-9230(03)00070-4","article-title":"Effectiveness of levobetaxolol and timolol at blunting retinal ischaemia is related to their calcium and sodium blocking activities: Relevance to glaucoma","volume":"62","author":"Osborne","year":"2004","journal-title":"Brain Res. Bull."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.brainres.2005.11.072","article-title":"Neuroprotective effect of calcium channel blocker against retinal ganglion cell damage under hypoxia","volume":"1071","author":"Yamada","year":"2006","journal-title":"Brain Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0006-8993(02)03951-3","article-title":"Protective effect of nilvadipine against glutamate neurotoxicity in purified retinal ganglion cells","volume":"961","author":"Otori","year":"2003","journal-title":"Brain Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1016\/j.ophtha.2008.05.015","article-title":"A placebo-controlled 3-year study of a calcium blocker on visual field and ocular circulation in glaucoma with low-normal pressure","volume":"115","author":"Koseki","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/00061198-199904000-00006","article-title":"Effects of oral brovincamine on visual field damage in patients with normal-tension glaucoma with low-normal intraocular pressure","volume":"8","author":"Koseki","year":"1999","journal-title":"J. Glaucoma"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0161-6420(96)30703-3","article-title":"Prevention of visual field defect progression with brovincamine in eyes with normal-tension glaucoma","volume":"103","author":"Sawada","year":"1996","journal-title":"Ophthalmology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"749","DOI":"10.2147\/DDDT.S352876","article-title":"Efficacy of Nimodipine Combined with Latanoprost in Treating Open-Angle Glaucoma and Its Influence on Ocular Hemodynamics and Visual Field Defects","volume":"16","author":"Duan","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1080\/02713683.2021.1944645","article-title":"Effect of Nimodipine on Macular and Peripapillary Capillary Vessel Density in Patients with Normal-tension Glaucoma Using Optical Coherence Tomography Angiography","volume":"46","author":"Hu","year":"2021","journal-title":"Curr. Eye Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.preteyeres.2010.09.002","article-title":"Use of calcium channel blockers for glaucoma","volume":"30","author":"Araie","year":"2011","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1080\/00015385.2018.1549004","article-title":"Relationship between primary open angle glaucoma and blood pressure","volume":"75","author":"Yilmaz","year":"2020","journal-title":"Acta Cardiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1167\/iovs.03-0566","article-title":"Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: Functional measures","volume":"45","author":"Hare","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"S284","DOI":"10.1016\/S0039-6257(01)00200-4","article-title":"Efficacy and safety of memantine, an NMDA-type open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey","volume":"45","author":"Hare","year":"2001","journal-title":"Surv. Ophthalmol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1097\/00061198-200212000-00003","article-title":"Neuroprotective effect of memantine in different retinal injury models in rats","volume":"11","author":"WoldeMussie","year":"2002","journal-title":"J. Glaucoma"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1001\/archopht.124.2.217","article-title":"Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma","volume":"124","author":"Gupta","year":"2006","journal-title":"Arch. Ophthalmol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1016\/j.ophtha.2018.06.017","article-title":"Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies","volume":"125","author":"Weinreb","year":"2018","journal-title":"Ophthalmology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e199","DOI":"10.1111\/aos.13914","article-title":"Optical coherence tomography angiography analysis of macular flow density in glaucoma","volume":"97","author":"Kromer","year":"2019","journal-title":"Acta Ophthalmol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/IJG.0b013e31815768c4","article-title":"Detection of early glaucoma with optical coherence tomography (StratusOCT)","volume":"17","author":"Nikkhou","year":"2008","journal-title":"J. Glaucoma"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.1161\/hs1001.096010","article-title":"Effects of citicoline on phospholipid and glutathione levels in transient cerebral ischemia","volume":"32","author":"Adibhatla","year":"2001","journal-title":"Stroke"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3389\/fnagi.2016.00073","article-title":"Citicoline: A Food Beneficial for Patients Suffering from or Threated with Glaucoma","volume":"8","author":"Grieb","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1385\/JMN:20:1:53","article-title":"CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons","volume":"20","author":"Mir","year":"2003","journal-title":"J. Mol. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"567","DOI":"10.4103\/0301-4738.121075","article-title":"Human intraretinal myelination: Axon diameters and axon\/myelin thickness ratios","volume":"61","author":"FitzGibbon","year":"2013","journal-title":"Indian J. Ophthalmol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.exer.2006.05.021","article-title":"Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat","volume":"83","author":"Schuettauf","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/S0161-6420(99)90269-5","article-title":"Cytidine-5\u2032-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma","volume":"106","author":"Parisi","year":"1999","journal-title":"Ophthalmology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1007\/s00417-015-3044-9","article-title":"Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma","volume":"253","author":"Parisi","year":"2015","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"549","DOI":"10.4103\/0301-4738.133484","article-title":"A preliminary study of the neuroprotective role of citicoline eye drops in glaucomatous optic neuropathy","volume":"62","author":"Roberti","year":"2014","journal-title":"Indian J. Ophthalmol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000350496","article-title":"Citicoline oral solution in glaucoma: Is there a role in slowing disease progression?","volume":"229","author":"Ottobelli","year":"2013","journal-title":"Ophthalmologica"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1097\/IJG.0000000000001565","article-title":"Can Treatment With Citicoline Eyedrops Reduce Progression in Glaucoma? The Results of a Randomized Placebo-controlled Clinical Trial","volume":"29","author":"Rossetti","year":"2020","journal-title":"J. Glaucoma"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Edwards, G., Lee, Y., Kim, M., Bhanvadia, S., Kim, K.Y., and Ju, W.K. (2020). Effect of Ubiquinol on Glaucomatous Neurodegeneration and Oxidative Stress: Studies for Retinal Ganglion Cell Survival and\/or Visual Function. Antioxidants, 9.","DOI":"10.3390\/antiox9100952"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0074-7742(07)82022-8","article-title":"Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat","volume":"Volume 82","author":"Nucci","year":"2007","journal-title":"International Review of Neurobiology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.brainres.2008.06.026","article-title":"Coenzyme Q10 protects retinal cells against oxidative stress in vitro and in vivo","volume":"1226","author":"Nakajima","year":"2008","journal-title":"Brain Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1167\/iovs.13-12564","article-title":"Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma","volume":"55","author":"Lee","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1177\/1120672119833271","article-title":"Neuroprotective effects of topical coenzyme Q10\u2009+\u2009vitamin E in mechanic optic nerve injury model","volume":"30","year":"2020","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1097\/IJG.0b013e318279b836","article-title":"Effects of coenzyme Q10 in conjunction with vitamin E on retinal-evoked and cortical-evoked responses in patients with open-angle glaucoma","volume":"23","author":"Parisi","year":"2014","journal-title":"J. Glaucoma"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1177\/1120672118779486","article-title":"Evaluation of oxidative stress in pseudo-exfoliative glaucoma patients treated with and without topical coenzyme Q10 and vitamin E","volume":"29","author":"Ozates","year":"2019","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1007\/s12325-019-01023-3","article-title":"Evaluating the Effects of an Ophthalmic Solution of Coenzyme Q10 and Vitamin E in Open-Angle Glaucoma Patients: A Study Protocol","volume":"36","author":"Quaranta","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.aac4854","article-title":"NAD\u207a in aging, metabolism, and neurodegeneration","volume":"350","author":"Verdin","year":"2015","journal-title":"Science"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.aal0092","article-title":"Vitamin B(3) modulates mitochondrial vulnerability and prevents glaucoma in aged mice","volume":"355","author":"Williams","year":"2017","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1167\/iovs.19-27099","article-title":"Nicotinamide Deficiency in Primary Open-Angle Glaucoma","volume":"60","author":"Guehlouz","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/ceo.13818","article-title":"Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial","volume":"48","author":"Hui","year":"2020","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1001\/jamaophthalmol.2021.4576","article-title":"Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial","volume":"140","author":"John","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/aos.14769","article-title":"Cholesterol and glaucoma: A systematic review and meta-analysis","volume":"100","author":"Michelitsch","year":"2022","journal-title":"Acta Ophthalmol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Kim, M.L., Sung, K.R., Kwon, J., Choi, G.W., and Shin, J.A. (2021). Neuroprotective Effect of Statins in a Rat Model of Chronic Ocular Hypertension. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212500"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1442-9071.2007.01529.x","article-title":"Effect of statin drugs and aspirin on progression in open-angle glaucoma suspects using confocal scanning laser ophthalmoscopy","volume":"35","author":"Punjabi","year":"2007","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Kang, J.M., Jammal, A.A., and Medeiros, F.A. (2022). Association between statin use and rates of structural and functional loss in glaucoma. Br. J. Ophthalmol.","DOI":"10.1136\/bjophthalmol-2021-320734"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"101364","DOI":"10.1016\/j.eclinm.2022.101364","article-title":"Associations of statin use with the onset and progression of open-angle glaucoma: A systematic review and meta-analysis","volume":"46","author":"Yuan","year":"2022","journal-title":"eClinicalMedicine"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1001\/jama.2016.15450","article-title":"Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement","volume":"316","author":"Grossman","year":"2016","journal-title":"JAMA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1161\/STROKEAHA.107.488791","article-title":"Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease","volume":"39","author":"Vergouwen","year":"2008","journal-title":"Stroke"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3129\/i10-077","article-title":"Current approaches and future prospects for stem cell rescue and regeneration of the retina and optic nerve","volume":"45","author":"Vijay","year":"2010","journal-title":"Can. J. Ophthalmol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"8397521","DOI":"10.1155\/2019\/8397521","article-title":"Therapeutic Strategies for Attenuation of Retinal Ganglion Cell Injury in Optic Neuropathies: Concepts in Translational Research and Therapeutic Implications","volume":"2019","author":"Fu","year":"2019","journal-title":"Biomed Res. Int."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Edo, A., Sugita, S., Futatsugi, Y., Sho, J., Onishi, A., Kiuchi, Y., and Takahashi, M. (2020). Capacity of Retinal Ganglion Cells Derived from Human Induced Pluripotent Stem Cells to Suppress T-Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217831"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4299","DOI":"10.1016\/j.cell.2021.06.031","article-title":"Preservation of vision after CaMKII-mediated protection of retinal ganglion cells","volume":"184","author":"Guo","year":"2021","journal-title":"Cell"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"7869130","DOI":"10.1155\/2019\/7869130","article-title":"Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of Glaucoma","volume":"2019","author":"Harrell","year":"2019","journal-title":"Stem Cells Int"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.jcyt.2014.12.005","article-title":"Neuroprotective effects of intravitreally transplanted adipose tissue and bone marrow-derived mesenchymal stem cells in an experimental ocular hypertension model","volume":"17","author":"Emre","year":"2015","journal-title":"Cytotherapy"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"4506","DOI":"10.1167\/iovs.11-7346","article-title":"Transplantation of BDNF-secreting mesenchymal stem cells provides neuroprotection in chronically hypertensive rat eyes","volume":"52","author":"Harper","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1167\/iovs.09-4509","article-title":"Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma","volume":"51","author":"Johnson","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1167\/iovs.17-22855","article-title":"Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma","volume":"59","author":"Mead","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"8852517","DOI":"10.1155\/2021\/8852517","article-title":"Human Umbilical Cord-Mesenchymal Stem Cells Survive and Migrate within the Vitreous Cavity and Ameliorate Retinal Damage in a Novel Rat Model of Chronic Glaucoma","volume":"2021","author":"Wang","year":"2021","journal-title":"Stem Cells Int."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s13287-015-0168-0","article-title":"Intraocular pressure reduction and neuroprotection conferred by bone marrow-derived mesenchymal stem cells in an animal model of glaucoma","volume":"6","author":"Roubeix","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10633-021-09817-z","article-title":"Retinal function after intravitreal injection of autologous bone marrow-derived mesenchymal stromal cells in advanced glaucoma","volume":"143","author":"Vilela","year":"2021","journal-title":"Doc. Ophthalmol."},{"key":"ref_123","first-page":"699","article-title":"Microenvironmental considerations in the application of human mesenchymal stem cells in regenerative therapies","volume":"2","author":"Greco","year":"2008","journal-title":"Biol. Targets Ther."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"662838","DOI":"10.3389\/fneur.2021.662838","article-title":"Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison","volume":"12","author":"Newman","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"21587","DOI":"10.1038\/srep21587","article-title":"Efficacy and Safety of rAAV2-ND4 Treatment for Leber\u2019s Hereditary Optic Neuropathy","volume":"6","author":"Wan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"11199","DOI":"10.1073\/pnas.1706193114","article-title":"CRISPR-Cas9-based treatment of myocilin-associated glaucoma","volume":"114","author":"Jain","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/s41419-018-1041-8","article-title":"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","volume":"9","author":"Osborne","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1167\/iovs.08-3013","article-title":"Effect of CNTF on retinal ganglion cell survival in experimental glaucoma","volume":"50","author":"Pease","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/s41419-021-04068-x","article-title":"BCLX(L) gene therapy moderates neuropathology in the DBA\/2J mouse model of inherited glaucoma","volume":"12","author":"Donahue","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.ymthe.2022.01.035","article-title":"NMNAT2 is downregulated in glaucomatous RGCs, and RGC-specific gene therapy rescues neurodegeneration and visual function","volume":"30","author":"Fang","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1167\/iovs.63.2.5","article-title":"Neuroprotective Gene Therapy by Overexpression of the Transcription Factor MAX in Rat Models of Glaucomatous Neurodegeneration","volume":"63","author":"Marra","year":"2022","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41434-021-00281-7","article-title":"XIAP gene therapy effects on retinal ganglion cell structure and function in a mouse model of glaucoma","volume":"29","author":"Visuvanathan","year":"2022","journal-title":"Gene Ther."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/11\/1884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:13:42Z","timestamp":1760145222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/11\/1884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":132,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["jpm12111884"],"URL":"https:\/\/doi.org\/10.3390\/jpm12111884","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]}}}