Glaucoma: Biological Mechanism and its Clinical Translation

Sandra   C.   Durán-Cristiano
doi:10.2174/1566524022666220508182051
Abstract

Glaucoma is a common cause of visual loss and irreversible blindness, affecting visual and life quality. Various mechanisms are involved in retinal ganglion cell (RGC) apoptosis and functional and structural loss in the visual system. The prevalence of glaucoma has increased in several countries. However, its early diagnosis has contributed to prompt attention. Molecular and cellular biological mechanisms are important for understanding the pathological process of glaucoma and new therapies. Thus, this review discusses the factors involved in glaucoma, from basic science to cellular and molecular events (e.g., mitochondrial dysfunction, endoplasmic reticulum stress, glutamate excitotoxicity, the cholinergic system, and genetic and epigenetic factors), which in recent years have been included in the development of new therapies, management, and diagnosis of this disease.
Keywords: Glaucoma, oxidative stress, apoptosis, excitotoxicity, cholinergic system, disease.
[1]
Artero-Castro A, Rodriguez-Jimenez FJ, Jendelova P, VanderWall KB, Meyer JS, Erceg S. Glaucoma as a neurodegenerative disease caused by intrinsic vulnerability factors. Prog Neurobiol  2020; 193: 101817.
 [PMID: 32360241]

[2]
Shpak AA, Guekht AB, Druzhkova TA, Kozlova KI, Gulyaeva NV. Ciliary neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract. Mol Vis  2017; 23: 799-809.
 [PMID: 29225456]

[3]
Cha YW, Kim ST. Serum and aqueous humor levels of brain-derived neurotrophic factor in patients with primary open-angle glaucoma and normal-tension glaucoma. Int Ophthalmol  2021; 41(11): 3869-75.
 [http://dx.doi.org/10.1007/s10792-021-01959-y] [PMID: 34533687]

[4]
Sampaio TB, Savall AS, Gutierrez MEZ, Pinton S. Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: Implications for pathogenesis and therapy. Neural Regen Res  2017; 12(4): 549-57.
 [http://dx.doi.org/10.4103/1673-5374.205084] [PMID: 28553325]

[5]
Mufson EJ, Counts SE, Ginsberg SD, et al. Nerve growth factor pathobiology during the progression of Alzheimer’s disease. Front Neurosci  2019; 13: 533.
 [http://dx.doi.org/10.3389/fnins.2019.00533] [PMID: 31312116]

[6]
Almasieh M, Zhou Y, Kelly ME, Casanova C, Di Polo A. Structural and functional neuroprotection in glaucoma: Role of galantamine-mediated activation of muscarinic acetylcholine receptors. Cell Death Dis  2010; 1(2): e27.
 [http://dx.doi.org/10.1038/cddis.2009.23] [PMID: 21364635]

[7]
Ahmad SS. Controversies in the vascular theory of glaucomatous optic nerve degeneration. Taiwan J Ophthalmol  2016; 6(4): 182-6.
 [http://dx.doi.org/10.1016/j.tjo.2016.05.009] [PMID: 29018738]

[8]
Rosenthal R, Fromm M. Endothelin antagonism as an active principle for glaucoma therapy. Br J Pharmacol  2011; 162(4): 806-16.
 [http://dx.doi.org/10.1111/j.1476-5381.2010.01103.x] [PMID: 21054341]

[9]
Minton AZ, Phatak NR, Stankowska DL, et al. Endothelin B receptors contribute to retinal ganglion cell loss in a rat model of glaucoma. PLoS One  2012; 7(8): e43199.
 [http://dx.doi.org/10.1371/journal.pone.0043199] [PMID: 22916224]

[10]
Izzotti A, Ceccaroli C, Longobardi MG, et al. Molecular damage in glaucoma: From anterior to posterior eye segment. The MicroRNA Role. MicroRNA  2015; 4(1): 3-17.
 [http://dx.doi.org/10.2174/2211536604666150707124640] [PMID: 26149270]

[11]
McMonnies C. Reactive oxygen species, oxidative stress, glaucoma and hyperbaric oxygen therapy. J Optom  2018; 11(1): 3-9.
 [http://dx.doi.org/10.1016/j.optom.2017.06.002] [PMID: 28760643]

[12]
Nucci C, Tartaglione R, Rombolà L, Morrone LA, Fazzi E, Bagetta G. Neurochemical evidence to implicate elevated glutamate in the mechanisms of high intraocular pressure (IOP)-induced retinal ganglion cell death in rat. Neurotoxicology  2005; 26(5): 935-41.
 [http://dx.doi.org/10.1016/j.neuro.2005.06.002] [PMID: 16126273]

[13]
Fleenor DL, Shepard AR, Hellberg PE, Jacobson N, Pang IH, Clark AF. TGFbeta2-induced changes in human trabecular meshwork: Implications for intraocular pressure. Invest Ophthalmol Vis Sci  2006; 47(1): 226-34.
 [http://dx.doi.org/10.1167/iovs.05-1060] [PMID: 16384967]

[14]
Pasquale LR, Loomis SJ, Kang JH, et al. CDKN2B-AS1 genotype-glaucoma feature correlations in primary open angle glaucoma patients from the United States. Am J Ophthalmol  2013; 155(2): 342-353.e5.
 [http://dx.doi.org/10.1016/j.ajo.2012.07.023] [PMID: 23111177]

[15]
Gauthier AC, Liu J. Epigenetics and signaling pathways in glaucoma. BioMed Res Int  2017; 2017: 5712341.
 [http://dx.doi.org/10.1155/2017/5712341] [PMID: 28210622]

[16]
Zhang DW, Zhang S, Wu J. Expression profile analysis to predict potential biomarkers for glaucoma: BMP1, DMD and GEM. PeerJ  2020; 8: e9462.
 [http://dx.doi.org/10.7717/peerj.9462] [PMID: 32953253]

[17]
Rozek LS, Dolinoy DC, Sartor MA, Omenn GS. Epigenetics: Relevance and implications for public health. Annu Rev Public Health  2014; 35: 105-22.
 [http://dx.doi.org/10.1146/annurev-publhealth-032013-182513] [PMID: 24641556]

[18]
He S, Li X, Chan N, Hinton DR. Review: Epigenetic mechanisms in ocular disease. Mol Vis  2013; 19: 665-74.
 [PMID: 23559860]

[19]
Kimura A, Namekata K, Guo X, Harada C, Harada T. Neuroprotection, growth factors and BDNF-TrkB signalling in retinal degeneration. Int J Mol Sci  2016; 17(9): E1584.
 [http://dx.doi.org/10.3390/ijms17091584] [PMID: 27657046]

[20]
Symmank J, Zimmer G. Regulation of neuronal survival by DNA methyltransferases. Neural Regen Res  2017; 12(11): 1768-75.
 [http://dx.doi.org/10.4103/1673-5374.219027] [PMID: 29239313]

[21]
Pelzel HR, Schlamp CL, Nickells RW. Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis. BMC Neurosci  2010; 11: 62.
 [http://dx.doi.org/10.1186/1471-2202-11-62] [PMID: 20504333]

[22]
Zhou M, Luo J, Zhang H. Role of Sirtuin 1 in the pathogenesis of ocular disease (Review). Int J Mol Med  2018; 42(1): 13-20.
 [http://dx.doi.org/10.3892/ijmm.2018.3623] [PMID: 29693113]

[23]
Kim SH, Park JH, Kim YJ, Park KH. The neuroprotective effect of resveratrol on retinal ganglion cells after optic nerve transection. Mol Vis  2013; 19: 1667-76.
 [PMID: 23901250]

[24]
Shen W, Han Y, Huang B, et al. MicroRNA-483-3p inhibits extracellular matrix production by targeting Smad4 in human trabecular meshwork cells. Invest Ophthalmol Vis Sci  2015; 56(13): 8419-27.
 [http://dx.doi.org/10.1167/iovs.15-18036] [PMID: 26747772]

[25]
Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov  2011; 10(3): 209-19.
 [http://dx.doi.org/10.1038/nrd3366] [PMID: 21358740]

[26]
Mysona BA, Zhao J, Smith S, Bollinger KE. Relationship between Sigma-1 receptor and BDNF in the visual system. Exp Eye Res  2018; 167: 25-30.
 [http://dx.doi.org/10.1016/j.exer.2017.10.012] [PMID: 29031856]

[27]
Chen KW, Chen L. Epigenetic regulation of BDNF gene during development and diseases. Int J Mol Sci  2017; 18(3): 571.
 [http://dx.doi.org/10.3390/ijms18030571] [PMID: 28272318]

[28]
Wu J, Bell OH, Copland DA, et al. Gene therapy for glaucoma by ciliary body aquaporin 1 disruption using CRISPR-Cas9. Mol Ther  2020; 28(3): 820-9.
 [http://dx.doi.org/10.1016/j.ymthe.2019.12.012] [PMID: 31981492]

[29]
Bucolo C, Platania CBM, Drago F, et al. Novel therapeutics in glaucoma management. Curr Neuropharmacol  2018; 16(7): 978-92.
 [http://dx.doi.org/10.2174/1570159X15666170915142727] [PMID: 28925883]

[30]
Lu Y, Brommer B, Tian X, et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature  2020; 588(7836): 124-9.
 [http://dx.doi.org/10.1038/s41586-020-2975-4] [PMID: 33268865]

[31]
Ghaffariyeh A, Honarpisheh N, Shakiba Y, et al. Brain-derived neurotrophic factor in patients with normal-tension glaucoma. Optometry  2009; 80(11): 635-8.
 [http://dx.doi.org/10.1016/j.optm.2008.09.014] [PMID: 19861219]

[32]
Minegishi Y, Nakayama M, Iejima D, Kawase K, Iwata T. Significance of optineurin mutations in glaucoma and other diseases. Prog Retin Eye Res  2016; 55: 149-81.
 [http://dx.doi.org/10.1016/j.preteyeres.2016.08.002] [PMID: 27693724]

[33]
Elliott MH, Ashpole NE, Gu X, et al. Caveolin-1 modulates intraocular pressure: Implications for caveolae mechanoprotection in glaucoma. Sci Rep  2016; 6(1): 37127.
 [http://dx.doi.org/10.1038/srep37127] [PMID: 27841369]

[34]
Sunderland DK, Physiology SA. Physiology, aqueous humor circulation. Treasure Island: FL: StatPearls 2020.

[35]
Vranka JA, Kelley MJ, Acott TS, Keller KE. Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma. Exp Eye Res  2015; 133: 112-25.
 [http://dx.doi.org/10.1016/j.exer.2014.07.014] [PMID: 25819459]

[36]
Aires ID, Ambrósio AF, Santiago AR. Modeling human glaucoma: Lessons from the in vitro models. Ophthalmic Res  2017; 57(2): 77-86.
 [http://dx.doi.org/10.1159/000448480] [PMID: 27618367]

[37]
Inatani M, Tanihara H, Katsuta H, Honjo M, Kido N, Honda Y. Transforming growth factor-beta 2 levels in aqueous humor of glaucomatous eyes. Graefes Arch Clin Exp Ophthalmol  2001; 239(2): 109-13.
 [http://dx.doi.org/10.1007/s004170000241] [PMID: 11372538]

[38]
Seet LF, Finger SN, Chu SWL, Toh LZ, Wong TT. Novel insight into the inflammatory and cellular responses following experimental glaucoma surgery: A roadmap for inhibiting fibrosis. Curr Mol Med  2013; 13(6): 911-28.
 [http://dx.doi.org/10.2174/15665240113139990021] [PMID: 23651348]

[39]
Tian B, Geiger B, Epstein DL, Kaufman PL. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci  2000; 41(3): 619-23.
 [PMID: 10711672]

[40]
Bermudez JY, Montecchi-Palmer M, Mao W, Clark AF. Cross-Linked Actin Networks (CLANs) in glaucoma. Exp Eye Res  2017; 159: 16-22.
 [http://dx.doi.org/10.1016/j.exer.2017.02.010] [PMID: 28238754]

[41]
Murphy KC, Morgan JT, Wood JA, Sadeli A, Murphy CJ, Russell P. The formation of cortical actin arrays in human trabecular meshwork cells in response to cytoskeletal disruption. Exp Cell Res  2014; 328(1): 164-71.
 [http://dx.doi.org/10.1016/j.yexcr.2014.06.014] [PMID: 24992043]

[42]
Wilson GN, Smith MA, Inman DM, Dengler-Crish CM, Crish SD. Early cytoskeletal protein modifications precede overt structural degeneration in the DBA/2J mouse model of glaucoma. Front Neurosci  2016; 10: 494.
 [http://dx.doi.org/10.3389/fnins.2016.00494] [PMID: 27857681]

[43]
Mehran NA, Sinha S, Razeghinejad R. New glaucoma medications: Latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprost. Eye (Lond)  2020; 34(1): 72-88.
 [http://dx.doi.org/10.1038/s41433-019-0671-0] [PMID: 31695162]

[44]
Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res  2013; 8(21): 2003-14.
 [http://dx.doi.org/10.3969/j.issn.1673-5374.2013.21.009] [PMID: 25206509]

[45]
Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol  2009; 7(1): 65-74.
 [http://dx.doi.org/10.2174/157015909787602823] [PMID: 19721819]

[46]
Ray PD, Huang B-W, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal  2012; 24(5): 981-90.
 [http://dx.doi.org/10.1016/j.cellsig.2012.01.008] [PMID: 22286106]

[47]
Cui H, Kong Y, Zhang H. Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct  2012; 2012: 646354.
 [http://dx.doi.org/10.1155/2012/646354] [PMID: 21977319]

[48]
Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging  2018; 13: 757-72.
 [http://dx.doi.org/10.2147/CIA.S158513] [PMID: 29731617]

[49]
Alfadda AA, Sallam RM. Reactive oxygen species in health and disease. J Biomed Biotechnol  2012; 2012: 936486.
 [http://dx.doi.org/10.1155/2012/936486] [PMID: 22927725]

[50]
Görlach A, Dimova EY, Petry A, et al. Reactive oxygen species, nutrition, hypoxia and diseases: Problems solved? Redox Biol  2015; 6: 372-85.
 [http://dx.doi.org/10.1016/j.redox.2015.08.016] [PMID: 26339717]

[51]
Ammar DA, Hamweyah KM, Kahook MY. Antioxidants protect trabecular meshwork cells from hydrogen peroxide-induced cell death. Transl Vis Sci Technol  2012; 1(1): 4.
 [http://dx.doi.org/10.1167/tvst.1.1.4] [PMID: 24049700]

[52]
Kondkar AA, Sultan T, Azad TA, Tabussum L, Osman EA, Al-Obeidan SA. Increased plasma levels of 8-Hydroxy-2′-deoxyguanosine (8-OHdG) in patients with pseudoexfoliation glaucoma. J Ophthalmol  2019; 2019: 8319563.
 [http://dx.doi.org/10.1155/2019/8319563] [PMID: 31341657]

[53]
Kondkar AA, Azad TA, Sultan T, Osman EA, Almobarak FA, Al-Obeidan SA. Elevated plasma level of 8-hydroxy-2′-deoxyguanosine is associated with primary open-angle glaucoma. J Ophthalmol  2020; 2020: 6571413.
 [http://dx.doi.org/10.1155/2020/6571413] [PMID: 32411433]

[54]
Nucci C, Di Pierro D, Varesi C, et al. Increased malondialdehyde concentration and reduced total antioxidant capacity in aqueous humor and blood samples from patients with glaucoma. Mol Vis  2013; 19: 1841-6.
 [PMID: 23946639]

[55]
Sedlak L, Zych M, Wojnar W, Wyględowska-Promieńska D. Effect of topical prostaglandin F2α analogs on selected oxidative stress parameters in the tear film. Medicina (Kaunas)  2019; 55(7): E366.
 [http://dx.doi.org/10.3390/medicina55070366] [PMID: 31336766]

[56]
Tanito M, Kaidzu S, Takai Y, Ohira A. Association between systemic oxidative stress and visual field damage in open-angle glaucoma. Sci Rep  2016; 6(5): 25792.
 [http://dx.doi.org/10.1038/srep25792] [PMID: 27165400]

[57]
Himori N, Inoue Yanagimachi M, Omodaka K, et al. The effect of dietary antioxidant supplementation in patients with glaucoma. Clin Ophthalmol  2021; 15: 2293-300.
 [http://dx.doi.org/10.2147/OPTH.S314288] [PMID: 34113073]

[58]
Bagnis A, Izzotti A, Centofanti M, Saccà SC. Aqueous humor oxidative stress proteomic levels in primary open angle glaucoma. Exp Eye Res  2012; 103: 55-62.
 [http://dx.doi.org/10.1016/j.exer.2012.07.011] [PMID: 22974818]

[59]
Kaeslin MA, Killer HE, Fuhrer CA, Zeleny N, Huber AR, Neutzner A. Changes to the aqueous humor proteome during glaucoma. PLoS One  2016; 11(10): e0165314.
 [http://dx.doi.org/10.1371/journal.pone.0165314] [PMID: 27788204]

[60]
Ježek J, Cooper KF, Strich R. Reactive oxygen species and mitochondrial dynamics: The yin and yang of mitochondrial dysfunction and cancer progression. Antioxidants  2018; 7(1): E13.
 [http://dx.doi.org/10.3390/antiox7010013] [PMID: 29337889]

[61]
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev  2014; 94(3): 909-50.
 [http://dx.doi.org/10.1152/physrev.00026.2013] [PMID: 24987008]

[62]
Nadalutti CA, Stefanick DF, Zhao ML, et al. Mitochondrial dysfunction and DNA damage accompany enhanced levels of formaldehyde in cultured primary human fibroblasts. Sci Rep  2020; 10(1): 5575.
 [http://dx.doi.org/10.1038/s41598-020-61477-2] [PMID: 32221313]

[63]
Sharma P, Sampath H. Mitochondrial DNA integrity: Role in health and disease. Cells  2019; 8(2): E100.
 [http://dx.doi.org/10.3390/cells8020100] [PMID: 30700008]

[64]
Cieślik M, Czapski GA, Wójtowicz S, et al. Alterations of transcription of genes coding anti-oxidative and mitochondria-related proteins in amyloid β toxicity: Relevance to alzheimer’s disease. Mol Neurobiol  2020; 57(3): 1374-88.
 [http://dx.doi.org/10.1007/s12035-019-01819-y] [PMID: 31734880]

[65]
Abu-Amero KK, Morales J, Bosley TM. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci  2006; 47(6): 2533-41.
 [http://dx.doi.org/10.1167/iovs.05-1639] [PMID: 16723467]

[66]
Chrysostomou V, Rezania F, Trounce IA, Crowston JG. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol  2013; 13(1): 12-5.
 [http://dx.doi.org/10.1016/j.coph.2012.09.008] [PMID: 23069478]

[67]
Izzotti A, Saccà SC, Longobardi M, Cartiglia C. Mitochondrial damage in the trabecular meshwork of patients with glaucoma. Arch Ophthalmol  2010; 128(6): 724-30.
 [http://dx.doi.org/10.1001/archophthalmol.2010.87] [PMID: 20547950]

[68]
Izzotti A, Longobardi M, Cartiglia C, Saccà SC. Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. PLoS One  2011; 6(1): e14567.
 [http://dx.doi.org/10.1371/journal.pone.0014567] [PMID: 21283745]

[69]
Kamel K, Farrell M, O’Brien C. Mitochondrial dysfunction in ocular disease: Focus on glaucoma. Mitochondrion  2017; 35: 44-53.
 [http://dx.doi.org/10.1016/j.mito.2017.05.004] [PMID: 28499981]

[70]
Barron MJ, Griffiths P, Turnbull DM, Bates D, Nichols P. The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head. Br J Ophthalmol  2004; 88(2): 286-90.
 [http://dx.doi.org/10.1136/bjo.2003.027664] [PMID: 14736793]

[71]
Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet  2009; 43: 95-118.
 [http://dx.doi.org/10.1146/annurev-genet-102108-134850] [PMID: 19659442]

[72]
Li N, Zhan X. Mitochondrial dysfunction pathway networks and mitochondrial dynamics in the pathogenesis of pituitary adenomas. Front Endocrinol (Lausanne)  2019; 10: 690.
 [http://dx.doi.org/10.3389/fendo.2019.00690] [PMID: 31649621]

[73]
Xiong S, Mu T, Wang G, Jiang X. Mitochondria-mediated apoptosis in mammals. Protein Cell  2014; 5(10): 737-49.
 [http://dx.doi.org/10.1007/s13238-014-0089-1] [PMID: 25073422]

[74]
Suri F, Yazdani S, Elahi E. LTBP2 knockdown and oxidative stress affect glaucoma features including TGFβ pathways, ECM genes expression and apoptosis in trabecular meshwork cells. Gene  2018; 673: 70-81.
 [http://dx.doi.org/10.1016/j.gene.2018.06.038] [PMID: 29908281]

[75]
Wang Y, Li F, Wang S. MicroRNA-93 is overexpressed and induces apoptosis in glaucoma trabecular meshwork cells. Mol Med Rep  2016; 14(6): 5746-50.
 [http://dx.doi.org/10.3892/mmr.2016.5938] [PMID: 27878244]

[76]
Yan X, Wu S, Liu Q, Li Y, Zhu W, Zhang J. Accumulation of Asn450Tyr mutant myocilin in ER promotes apoptosis of human trabecular meshwork cells. Mol Vis  2020; 26: 563-73.
 [PMID: 32818018]

[77]
Perdicchi A, Iester M, Iacovello D, et al. Evaluation of agreement between HRT III and iVue OCT in glaucoma and ocular hypertension patients. J Ophthalmol  2015; 2015: 691031.
 [http://dx.doi.org/10.1155/2015/691031] [PMID: 26788363]

[78]
Cordeiro MF, Normando EM, Cardoso MJ, et al. Real-time imaging of single neuronal cell apoptosis in patients with glaucoma. Brain  2017; 140(6): 1757-67.
 [http://dx.doi.org/10.1093/brain/awx088] [PMID: 28449038]

[79]
Izzotti A, Longobardi M, Cartiglia C, Saccà SC. Proteome alterations in primary open angle glaucoma aqueous humor. J Proteome Res  2010; 9(9): 4831-8.
 [http://dx.doi.org/10.1021/pr1005372] [PMID: 20666514]

[80]
Qiu X, Johnson JR, Wilson BS, Gammon ST, Piwnica-Worms D, Barnett EM. Single-cell resolution imaging of retinal ganglion cell apoptosis in vivo using a cell-penetrating caspase-activatable peptide probe. PLoS One  2014; 9(2): e88855.
 [http://dx.doi.org/10.1371/journal.pone.0088855] [PMID: 24586415]

[81]
Yap TE, Davis BM, Guo L, Normando EM, Cordeiro MF. Annexins in glaucoma. Int J Mol Sci  2018; 19(4): E1218.
 [http://dx.doi.org/10.3390/ijms19041218] [PMID: 29673196]

[82]
Yap TE, Donna P, Almonte MT, Cordeiro MF. Real-time imaging of retinal ganglion cell apoptosis. Cells  2018; 7(6): E60.
 [http://dx.doi.org/10.3390/cells7060060] [PMID: 29914056]

[83]
Thomas CN, Berry M, Logan A, Blanch RJ, Ahmed Z. Caspases in retinal ganglion cell death and axon regeneration. Cell Death Discov  2017; 3(1): 17032.
 [http://dx.doi.org/10.1038/cddiscovery.2017.32] [PMID: 29675270]

[84]
Choudhury S, Liu Y, Clark AF, Pang IH. Caspase-7: A critical mediator of optic nerve injury-induced retinal ganglion cell death. Mol Neurodegener  2015; 10: 40.
 [http://dx.doi.org/10.1186/s13024-015-0039-2] [PMID: 26306916]

[85]
Schuettauf F, Stein T, Choragiewicz TJ, et al. Caspase inhibitors protect against NMDA-mediated retinal ganglion cell death. Clin Exp Ophthalmol  2011; 39(6): 545-54.
 [http://dx.doi.org/10.1111/j.1442-9071.2010.02486.x] [PMID: 21176044]

[86]
Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. J Pathol  2010; 221(1): 3-12.
 [http://dx.doi.org/10.1002/path.2697] [PMID: 20225336]

[87]
Mariño G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: The interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol  2014; 15(2): 81-94.
 [http://dx.doi.org/10.1038/nrm3735] [PMID: 24401948]

[88]
Gatica D, Chiong M, Lavandero S, Klionsky DJ. Molecular mechanisms of autophagy in the cardiovascular system. Circ Res  2015; 116(3): 456-67.
 [http://dx.doi.org/10.1161/CIRCRESAHA.114.303788] [PMID: 25634969]

[89]
Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med  2013; 19(8): 983-97.
 [http://dx.doi.org/10.1038/nm.3232] [PMID: 23921753]

[90]
Lin W, Xu G. Autophagy: A Role in the apoptosis, survival, inflammation, and development of the retina. Ophthalmic Res  2019; 61(2): 65-72.
 [http://dx.doi.org/10.1159/000487486] [PMID: 29694961]

[91]
Adornetto A, Parisi V, Morrone LA, et al. The role of autophagy in glaucomatous optic neuropathy. Front Cell Dev Biol  2020; 8: 121.
 [http://dx.doi.org/10.3389/fcell.2020.00121] [PMID: 32211404]

[92]
Feng L, Liao X, Zhang Y, Wang F. Protective effects on age-related macular degeneration by activated autophagy induced by amyloid-β in retinal pigment epithelial cells. Discov Med  2019; 27(148): 153-60.
 [PMID: 31095924]

[93]
Moreno M-L, Mérida S, Bosch-Morell F, Miranda M, Villar VM. Autophagy dysfunction and oxidative stress, two related mechanisms implicated in retinitis pigmentosa. Front Physiol  2018; 9: 1008.
 [http://dx.doi.org/10.3389/fphys.2018.01008] [PMID: 30093867]

[94]
Pan M, Yin Y, Wang X, et al. Mice deficient in UXT exhibit retinitis pigmentosa-like features via aberrant autophagy activation. Autophagy  2020; 1-16.
 [http://dx.doi.org/10.1080/15548627.2020.1796015] [PMID: 32744119]

[95]
Wang Y, Huang C, Zhang H, Wu R. Autophagy in glaucoma: Crosstalk with apoptosis and its implications. Brain Res Bull  2015; 117: 1-9.
 [http://dx.doi.org/10.1016/j.brainresbull.2015.06.001] [PMID: 26073842]

[96]
Park HL, Kim JH, Park CK. Different contributions of autophagy to retinal ganglion cell death in the diabetic and glaucomatous retinas. Sci Rep  2018; 8(1): 13321.
 [http://dx.doi.org/10.1038/s41598-018-30165-7] [PMID: 30190527]

[97]
Gump JM, Thorburn A. Autophagy and apoptosis: What is the connection? Trends Cell Biol  2011; 21(7): 387-92.
 [http://dx.doi.org/10.1016/j.tcb.2011.03.007] [PMID: 21561772]

[98]
Rodgers K, Wang D, Ben Y, Qu J, Grosskreutz CL. Autophagy in experimental glaucoma. Invest Ophthalmol Vis Sci  2010; 51(13): 2117.

[99]
Park HYL, Kim JH, Park CK. Activation of autophagy induces retinal ganglion cell death in a chronic hypertensive glaucoma model. Cell Death Dis  2012; 3(4): e290.
 [http://dx.doi.org/10.1038/cddis.2012.26] [PMID: 22476098]

[100]
Bell K, Rosignol I, Sierra-Filardi E, et al. Age related retinal Ganglion cell susceptibility in context of autophagy deficiency. Cell Death Discov  2020; 6(1): 21.
 [http://dx.doi.org/10.1038/s41420-020-0257-4] [PMID: 32337073]

[101]
Ma T, Trinh MA, Wexler AJ, et al. Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci  2013; 16(9): 1299-305.
 [http://dx.doi.org/10.1038/nn.3486] [PMID: 23933749]

[102]
Matus S, Lopez E, Valenzuela V, Nassif M, Hetz C. Functional contribution of the transcription factor ATF4 to the pathogenesis of amyotrophic lateral sclerosis. PLoS One  2013; 8(7): e66672.
 [http://dx.doi.org/10.1371/journal.pone.0066672] [PMID: 23874395]

[103]
Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci  2002; 22(24): 10690-8.
 [http://dx.doi.org/10.1523/JNEUROSCI.22-24-10690.2002] [PMID: 12486162]

[104]
Segev Y, Barrera I, Ounallah-Saad H, et al. PKR inhibition rescues memory deficit and atf4 overexpression in apoe ε4 human replacement mice. J Neurosci  2015; 35(38): 12986-93.
 [http://dx.doi.org/10.1523/JNEUROSCI.5241-14.2015] [PMID: 26400930]

[105]
Rivera-Krstulović C, Duran-Aniotz C. La respuesta a proteínas mal plegadas como blanco terapéutico en la enfermedad de Alzheimer. Rev Med Chil  2020; 148(2): 216-23.
 [http://dx.doi.org/10.4067/s0034-98872020000200216] [PMID: 32730499]

[106]
Ozcan L, Tabas I. Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med  2012; 63: 317-28.
 [http://dx.doi.org/10.1146/annurev-med-043010-144749] [PMID: 22248326]

[107]
Anholt RRH, Carbone MA. A molecular mechanism for glaucoma: Endoplasmic reticulum stress and the unfolded protein response. Trends Mol Med  2013; 19(10): 586-93.
 [http://dx.doi.org/10.1016/j.molmed.2013.06.005] [PMID: 23876925]

[108]
Kasetti RB, Phan TN, Millar JC, Zode GS. Expression of mutant myocilin induces abnormal intracellular accumulation of selected extracellular matrix proteins in the trabecular meshwork. Invest Ophthalmol Vis Sci  2016; 57(14): 6058-69.
 [http://dx.doi.org/10.1167/iovs.16-19610] [PMID: 27820874]

[109]
Peters JC, Bhattacharya S, Clark AF, Zode GS. Increased endoplasmic reticulum stress in human glaucomatous trabecular meshwork cells and tissues. Invest Ophthalmol Vis Sci  2015; 56(6): 3860-8.
 [http://dx.doi.org/10.1167/iovs.14-16220] [PMID: 26066753]

[110]
Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin  2009; 30(4): 379-87.
 [http://dx.doi.org/10.1038/aps.2009.24] [PMID: 19343058]

[111]
Kang JI, Huppé-Gourgues F, Vaucher E. Boosting visual cortex function and plasticity with acetylcholine to enhance visual perception. Front Syst Neurosci  2014; 8: 172.
 [http://dx.doi.org/10.3389/fnsys.2014.00172] [PMID: 25278848]

[112]
Nava-Mesa MO, Jiménez-Díaz L, Yajeya J, Navarro-Lopez JD. GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease. Front Cell Neurosci  2014; 8(June): 167.
 [http://dx.doi.org/10.3389/fncel.2014.00167] [PMID: 24987334]

[113]
Ishikawa M. Abnormalities in glutamate metabolism and excitotoxicity in the retinal diseases. Scientifica (Cairo)  2013; 2013: 528940.
 [http://dx.doi.org/10.1155/2013/528940] [PMID: 24386591]

[114]
Brandstätter JH, Koulen P, Wässle H. Diversity of glutamate receptors in the mammalian retina. Vision Res  1998; 38(10): 1385-97.
 [http://dx.doi.org/10.1016/S0042-6989(97)00176-4] [PMID: 9667006]

[115]
Bringmann A, Pannicke T, Biedermann B, et al. Role of retinal glial cells in neurotransmitter uptake and metabolism. Neurochem Int  2009; 54(3-4): 143-60.
 [http://dx.doi.org/10.1016/j.neuint.2008.10.014] [PMID: 19114072]

[116]
Jahani-Asl A, Pilon-Larose K, Xu W, et al. The mitochondrial inner membrane GTPase, Optic atrophy 1 (Opa1), restores mitochondrial morphology and promotes neuronal survival following excitotoxicity. J Biol Chem  2011; 286(6): 4772-82.
 [http://dx.doi.org/10.1074/jbc.M110.167155] [PMID: 21041314]

[117]
Lee D, Kim KY, Noh YH, et al. Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury. PLoS One  2012; 7(10): e47098.
 [http://dx.doi.org/10.1371/journal.pone.0047098] [PMID: 23056591]

[118]
Christensen I, Lu B, Yang N, Huang K, Wang P, Tian N. The susceptibility of retinal ganglion cells to glutamatergic excitotoxicity is type-specific. Front Neurosci  2019; 13: 219.
 [http://dx.doi.org/10.3389/fnins.2019.00219] [PMID: 30930737]

[119]
Ju WK, Kim KY. Measuring glutamate receptor activation-induced apoptotic cell death in ischemic rat retina using the TUNEL assay. Methods Mol Biol  2011; 740: 149-56.
 [http://dx.doi.org/10.1007/978-1-61779-108-6_16] [PMID: 21468976]

[120]
Li Q, Puro DG. Diabetes-induced dysfunction of the glutamate transporter in retinal Müller cells. Invest Ophthalmol Vis Sci  2002; 43(9): 3109-16.
 [PMID: 12202536]

[121]
Lieth E, Barber AJ, Xu B, et al. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Diabetes  1998; 47(5): 815-20.
 [http://dx.doi.org/10.2337/diabetes.47.5.815] [PMID: 9588455]

[122]
Smith SB. Diabetic retinopathy and the NMDA Receptor. Drug News Perspect  2002; 15(4): 226-32.
 [http://dx.doi.org/10.1358/dnp.2002.15.4.840055] [PMID: 12677206]

[123]
Gao L, Zheng QJ, Ai LQY, et al. Exploration of the glutamate-mediated retinal excitotoxic damage: A rat model of retinal neurodegeneration. Int J Ophthalmol  2018; 11(11): 1746-54.
 [http://dx.doi.org/10.18240/ijo.2018.11.03] [PMID: 30450303]

[124]
Ju WK, Lindsey JD, Angert M, Patel A, Weinreb RN. Glutamate receptor activation triggers OPA1 release and induces apoptotic cell death in ischemic rat retina. Mol Vis  2008; 14: 2629-38.
 [PMID: 19122832]

[125]
Lee D, Shim MS, Kim KY, et al. Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma. Invest Ophthalmol Vis Sci  2014; 55(2): 993-1005.
 [http://dx.doi.org/10.1167/iovs.13-12564] [PMID: 24458150]

[126]
Strang CE, Long Y, Gavrikov KE, Amthor FR, Keyser KT. Nicotinic and muscarinic acetylcholine receptors shape ganglion cell response properties. J Neurophysiol  2015; 113(1): 203-17.
 [http://dx.doi.org/10.1152/jn.00405.2014] [PMID: 25298382]

[127]
Duncan G, Collison DJ. Role of the non-neuronal cholinergic system in the eye: A review. Life Sci  2003; 72(18-19): 2013-9.
 [http://dx.doi.org/10.1016/S0024-3205(03)00064-X] [PMID: 12628451]

[128]
Elgueta C, Vielma AH, Palacios AG, Schmachtenberg O. Acetylcholine induces GABA release onto rod bipolar cells through heteromeric nicotinic receptors expressed in A17 amacrine cells. Front Cell Neurosci  2015; 9: 6.
 [http://dx.doi.org/10.3389/fncel.2015.00006] [PMID: 25709566]

[129]
Hampel H, Mesulam M-M, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain  2018; 141(7): 1917-33.
 [http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]

[130]
Nyakas C, Granic I, Halmy LG, Banerjee P, Luiten PGM. The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behav Brain Res  2011; 221(2): 594-603.
 [http://dx.doi.org/10.1016/j.bbr.2010.05.033] [PMID: 20553766]

[131]
Volpato D, Holzgrabe U. Designing hybrids targeting the cholinergic system by modulating the muscarinic and nicotinic receptors: A concept to treat Alzheimer’s disease. Molecules  2018; 23(12): E3230.
 [http://dx.doi.org/10.3390/molecules23123230] [PMID: 30544533]

[132]
Chamoun M, Sergeeva EG, Henrich-Noack P, et al. Cholinergic potentiation of restoration of visual function after optic nerve damage in rats. Neural Plast  2017; 2017: 6928489.
 [http://dx.doi.org/10.1155/2017/6928489] [PMID: 28928986]

[133]
Gratton C, Yousef S, Aarts E, Wallace DL, D’Esposito M, Silver MA. Cholinergic, but not dopaminergic or noradrenergic, enhancement sharpens visual spatial perception in humans. J Neurosci  2017; 37(16): 4405-15.
 [http://dx.doi.org/10.1523/JNEUROSCI.2405-16.2017] [PMID: 28336568]

[134]
Störmer VS, Passow S, Biesenack J, Li SC. Dopaminergic and cholinergic modulations of visual-spatial attention and working memory: Insights from molecular genetic research and implications for adult cognitive development. Dev Psychol  2012; 48(3): 875-89.
 [http://dx.doi.org/10.1037/a0026198] [PMID: 22103306]

[135]
Yáñez M, Viña D. Dual inhibitors of monoamine oxidase and cholinesterase for the treatment of Alzheimer disease. Curr Top Med Chem  2013; 13(14): 1692-706.
 [http://dx.doi.org/10.2174/15680266113139990120] [PMID: 23889051]

[136]
Guo L, Tian J, Du H. Mitochondrial dysfunction and synaptic transmission failure in Alzheimer’s disease. J Alzheimers Dis  2017; 57(4): 1071-86.
 [http://dx.doi.org/10.3233/JAD-160702] [PMID: 27662318]

[137]
Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: Cholinergic signaling shapes nervous system function and behavior. Neuron  2012; 76(1): 116-29.
 [http://dx.doi.org/10.1016/j.neuron.2012.08.036] [PMID: 23040810]

[138]
Ueki Y, Shchepetkina V, Lefcort F. Retina-specific loss of Ikbkap/Elp1 causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration in a mouse model of familial dysautonomia. Dis Model Mech  2018; 11(7): dmm033746.
 [http://dx.doi.org/10.1242/dmm.033746] [PMID: 29929962]

[139]
Grieb P. Neuroprotective properties of citicoline: Facts, doubts and unresolved issues. CNS Drugs  2014; 28(3): 185-93.
 [http://dx.doi.org/10.1007/s40263-014-0144-8] [PMID: 24504829]

[140]
Qian K, Gu Y, Zhao Y, Li Z, Sun M. Citicoline protects brain against closed head injury in rats through suppressing oxidative stress and calpain over-activation. Neurochem Res  2014; 39(7): 1206-18.
 [http://dx.doi.org/10.1007/s11064-014-1299-x] [PMID: 24691765]

[141]
Zazueta C, Buelna-Chontal M, Macías-López A, et al. Cytidine-5′-diphosphocholine protects the liver from ischemia/reperfusion injury preserving mitochondrial function and reducing oxidative stress. Liver Transpl  2018; 24(8): 1070-83.
 [http://dx.doi.org/10.1002/lt.25179] [PMID: 29679463]

[142]
Hernández-Esquivel L, Pavón N, Buelna-Chontal M, González-Pacheco H, Belmont J, Chávez E. Cardioprotective properties of citicoline against hyperthyroidism-induced reperfusion damage in rat hearts. Biochem Cell Biol  2015; 93(3): 185-91.
 [http://dx.doi.org/10.1139/bcb-2014-0116] [PMID: 25589288]

[143]
Nashine S, Kenney MC. Role of Citicoline in an in vitro AMD model. Aging (Albany NY)  2020; 12(10): 9031-40.
 [http://dx.doi.org/10.18632/aging.103164] [PMID: 32470946]

[144]
Gareri P, Castagna A, Cotroneo AM, et al. The citicholinage study: Citicoline plus cholinesterase inhibitors in aged patients affected with Alzheimer’s disease study. J Alzheimers Dis  2017; 56(2): 557-65.
 [http://dx.doi.org/10.3233/JAD-160808] [PMID: 28035929]

[145]
Kitamura Y, Bikbova G, Baba T, Yamamoto S, Oshitari T. In vivo effects of single or combined topical neuroprotective and regenerative agents on degeneration of retinal ganglion cells in rat optic nerve crush model. Sci Rep  2019; 9(1): 101.
 [http://dx.doi.org/10.1038/s41598-018-36473-2] [PMID: 30643179]

[146]
Matteucci A, Varano M, Gaddini L, et al. Neuroprotective effects of citicoline in in vitro models of retinal neurodegeneration. Int J Mol Sci  2014; 15(4): 6286-97.
 [http://dx.doi.org/10.3390/ijms15046286] [PMID: 24736780]

[147]
Chițu I, Voinea LM, Istrate S, Vrapciu A, Ciuluvică RC, Tudosescu R. The neuroprotective role of citicoline treatment in glaucoma - 6 months results of a prospective therapeutic trial. Rom J Ophthalmol  2019; 63(3): 222-30.
 [http://dx.doi.org/10.22336/rjo.2019.34] [PMID: 31687623]

[148]
Iulia C, Ruxandra T, Costin LB, Liliana-Mary V. Citicoline - a neuroprotector with proven effects on glaucomatous disease. Rom J Ophthalmol  2017; 61(3): 152-8.
 [http://dx.doi.org/10.22336/rjo.2017.29] [PMID: 29450391]

[149]
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(4): 987-96.
 [http://dx.doi.org/10.1007/s12325-019-0897-z] [PMID: 30790180]

[150]
Roberti G, Tanga L, Parisi V, Sampalmieri M, Centofanti M, Manni G. A preliminary study of the neuroprotective role of citicoline eye drops in glaucomatous optic neuropathy. Indian J Ophthalmol  2014; 62(5): 549-53.
 [http://dx.doi.org/10.4103/0301-4738.133484] [PMID: 24881599]

[151]
Herrero JL, Gieselmann MA, Thiele A. Muscarinic and nicotinic contribution to contrast sensitivity of macaque area V1 neurons. Front Neural Circuits  2017; 11: 106.
 [http://dx.doi.org/10.3389/fncir.2017.00106] [PMID: 29311843]

[152]
Nyström P, Gredebäck G, Bölte S, Falck-Ytter T. Hypersensitive pupillary light reflex in infants at risk for autism. Mol Autism  2015; 6(1): 10.
 [http://dx.doi.org/10.1186/s13229-015-0011-6] [PMID: 25750705]

[153]
Szatko KP, Korympidou MM, Ran Y, et al. Neural circuits in the mouse retina support color vision in the upper visual field. Nat Commun  2020; 11(1): 3481.
 [http://dx.doi.org/10.1038/s41467-020-17113-8] [PMID: 32661226]

[154]
Gracitelli CPB, Duque-Chica GL, Moura AL, et al. A positive association between intrinsically photosensitive retinal ganglion cells and retinal nerve fiber layer thinning in glaucoma. Invest Ophthalmol Vis Sci  2014; 55(12): 7997-8005.
 [http://dx.doi.org/10.1167/iovs.14-15146] [PMID: 25406281]

[155]
McKendrick AM, Sampson GP, Walland MJ, Badcock DR. Contrast sensitivity changes due to glaucoma and normal aging: Low-spatial-frequency losses in both magnocellular and parvocellular pathways. Invest Ophthalmol Vis Sci  2007; 48(5): 2115-22.
 [http://dx.doi.org/10.1167/iovs.06-1208] [PMID: 17460269]

[156]
Park JW, Kang BH, Kwon JW, Cho KJ. Analysis of various factors affecting pupil size in patients with glaucoma. BMC Ophthalmol  2017; 17(1): 168.
 [http://dx.doi.org/10.1186/s12886-017-0564-6] [PMID: 28915799]
Rights & Permissions Print Cite
Article Metrics
59
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1566524022666220508182051	Print ISSN 1566-5240
Publisher Name Bentham Science Publisher	Online ISSN 1875-5666
Current Molecular Medicine

Glaucoma: Biological Mechanism and its Clinical Translation

Abstract

Molecular and Cellular Mechanisms in Vertigo / Vestibular Disorders

Current Molecular Medicine

Glaucoma: Biological Mechanism and its Clinical Translation

Abstract

Call for Papers in Thematic Issues

Molecular and Cellular Mechanisms in Vertigo / Vestibular Disorders

Related Journals

Related Books

Related Articles
