Current Opportunities and Future Prospects of Neuroprotective Therapy in Glaucoma. Literature Review. Part 2

This literature review is devoted to one of the most challenging problems of ophthalmology — neuroprotective and neuroregenerative treatment of glaucoma and consists of two parts. The second part of the review deals with the role of glia, inflammation and autoimmunization in the pathogenesis of neuroretinal degeneration in glaucoma optic neuropathy (GON), new treatment strategies based on modern achievements of gene and immunotherapy. Special attention is paid to promising therapeutic approaches based on artificial intelligence application, usage of peptide bioregulators, immunomodulators and mixed-action drugs. Alternative methods of axonal regeneration, including gene therapy and stem cell therapy, are discussed.

1. Yang J, Yang P, Tezel G, Patil RV, Hernandez MR, Wax MB. Induction of HLA‑DR expression in human lamina cribrosa astrocytes by cytokines and simulated ischemia. Invest Ophthalmol Vis Sci. 2001;42:365–371.

2. Gupta N, Ang L, de Tilly LN. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophthalmol. 2006;90(6):674–678. doi: 10.1136/bjo.2005.086769.

3. Guo L, Salt TE, Maass A. Assessment of neuroprotective effects of glutamate modulation on glaucoma‑ related retinal ganglion cell apoptosis in vivo. Investigative Ophthalmology and Visual Science. 2006;47(2):626–633. doi: 10.1167/iovs.05‑0754.

4. Wax MB, Tezel G, Yang J, Peng G, Patil RV, Agarwal N, Sappington RM, Calkins DJ. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T‑cell‑derived fas‑ligand. J Neurosci. 2008;28(46):12085–12096. doi: 10.1523/JNEUROSCI.3200‑08.2008.

5. Ekici E, Moghimi S. Advances in understanding glaucoma pathogenesis: A multifaceted molecular approach for clinician scientists. Mol Aspects Med. 2023;94:101223. doi: 10.1016/j.mam.2023.101223.

6. Reichelt J, Joachim SC, Pfeiffer N, Grus FH. Analysis of autoantibodies against human retinal antigens in sera of patients with glaucoma and ocular hypertension. Curr Eye Res. 2008;33(3):253–261. doi: 10.1080/02713680701871157.

7. Kurysheva NI, Erichev VP, Vinetskaya MI. On the permeability of the blood‑aqueous humor barrier in primary open‑angle glaucoma. Annals of Ophthalmology. 1998;1:10–13.

8. Tezel G, Li LY, Patil RV, Wax MB. TNF‑alpha and TNF‑alpha receptor‑1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 2001 Jul;42(8):1787–1794.

9. Ben Simon GJ, Bakalash S, Aloni E, Rosner M. A rat model for acute rise in intraocular pressure: immune modulation as a therapeutic strategy. Am J Ophthalmol. 2006;141(6):1105–1111. doi: 10.1016/j.ajo.2006.01.073.

10. Rudzinski M, Wong TP, Saragovi HU. Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension. J Neurobiol. 2004;58(3):341–354. doi: 10.1002/neu.10293.

11. Nishijima E, Honda S, Kitamura Y, Namekata K, Kimura A, Guo X, Azuchi Y, Harada C, Murakami A, Matsuda A, Nakano T, Parada LF, Harada T. Vision protection and robust axon regeneration in glaucoma models by membrane‑associated Trk receptors. Mol Ther. 2023;31(3):810–824. doi: 10.1016/j.ymthe.2022.11.018.

12. Lambiase A, Aloe L, Centofanti M, Parisi V, Báo SN, Mantelli F, Colafrancesco V, Manni GL, Bucci MG, Bonini S, Levi‑Montalcini R. Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma. Proc Natl Acad Sci USA. 2009;106(32):13469–13474. doi: 10.1073/pnas.0906678106.

13. Colafrancesco V, Parisi V, Sposato V, Rossi S, Russo MA, Coassin M, Lambiase A, Aloe L. Ocular application of nerve growth factor protects degenerating retinal ganglion cells in a rat model of glaucoma. J Glaucoma. 2011;20(2):100–108. doi: 10.1097/IJG.0b013e3181d787e5.

14. Kobayashi‑Otsugu M, Kishimoto Y, Azuma M, Fukiage C. FK962 protects retinal ganglion cell under hypoxia/reoxygenation: Possible involvement of glial cell linederived neurotrophic factor signaling pathway. Exp Eye Res. 2024;248:110099. doi: 10.1016/j.exer.2024.110099.

15. AAO 2024: Phase II study on the safety of intravitreal NT‑501 encapsulated cell therapy implantation for glaucoma treatment. https://www.clinicaltrialsarena.com/analyst‑comment/aao‑2024‑phase‑ii‑study‑cntf/?cf‑view

16. Sharma R, Grover A. Myocilin‑associated Glaucoma: A Historical Perspective and Recent Research Progress. Mol Vis. 2021;27:480–493.

17. Scheetz TE, Faga B, Ortega L, Roos BR, Gordon MO, Kass MA, Wang K, Fingert JH. Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study. Ophthalmology. 2016 Dec;123(12):2527–2536. doi: 10.1016/j.ophtha.2016.08.036.

18. Trikha S, Saffari E, Nongpiur M, Baskaran M, Ho H, Li Z, Tan PY, Allen J, Khor CC, Perera SA, Cheng CY, Aung T, Vithana E. A Genetic Variant in TGFBR3‑CDC7 Is Associated with Visual Field Progression in Primary Open‑Angle Glaucoma Patients from Singapore. Ophthalmology. 2015;122(12):2416–2422. doi: 10.1016/j.ophtha.2015.08.016.

19. Zhou L, Zhan W, Wei X. Clinical pharmacology and pharmacogenetics of prostaglandin analogues in glaucoma. Front Pharmacol. 2022 Oct 12;13:1015338. doi: 10.3389/fphar.2022.1015338.

20. Anton N, Geamănu A, Iancu R, Pîrvulescu RA, Popa‑Cherecheanu A, Barac RI, Bandol G, Bogdănici CM. A Mini‑Review on Gene Therapy in Glaucoma and Future Directions. Int J Mol Sci. 2024;25(20):11019. doi: 10.3390/ijms252011019.

21. Fischer D, Petkova V, Thanos S, Benowitz LI. Switching mature retinal ganglion cells to a robust growth state in vivo: gene expression and synergy with RhoA inactivation. J Neurosci. 2004;24(40):8726–8740. doi: 10.1523/JNEUROSCI.2774‑04.2004.

22. Wu J, Bell OH, Copland DA, Young A, Pooley JR, Maswood R, Evans RS, Khaw PT, Ali RR, Dick AD, Chu CJ. Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 Disruption Using CRISPR‑Cas9. Mol Ther. 2020 Mar 4;28(3):820–829. doi: 10.1016/j.ymthe.2019.12.012.

23. Donahue RJ, Fehrman RL, Gustafson JR, Nickells RW. BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma. Cell Death Dis. 2021;12(8):781. doi: 10.1038/s41419‑021‑04068‑x.

24. Wang LH, Huang CH, Lin IC. Advances in Neuroprotection in Glaucoma: Pharmacological Strategies and Emerging Technologies. Pharmaceuticals (Basel). 2024 Sep 25;17(10):1261. doi: 10.3390/ph17101261.

25. Tian Y, Zhang T, Li J. Advances in development of exosomes for ophthalmic therapeutics. Adv Drug Deliv Rev. 2023;199:114899. doi: 10.1016/j.addr.2023.114899.

26. Mead B, Ahmed Z, Tomarev S. Mesenchymal Stem Cell‑Derived Small Extracellular Vesicles Promote Neuroprotection in a Genetic DBA/2J Mouse Model of Glaucoma. Invest Ophthalmol Vis Sci. 2018;59(13):5473–5480. doi: 10.1167/iovs.18‑25310.

27. Xia Q, Zhang D. Apoptosis in glaucoma: A new direction for the treatment of glaucoma (Review). Mol Med Rep. 2024;29(5):82. doi: 10.3892/mmr.2024.13207.

28. Pawar M, Busov B, Chandrasekhar A, Yao J, Zacks DN, Besirli CG. FAS apoptotic inhibitory molecule 2 is a stress‑induced intrinsic neuroprotective factor in the retina. Cell Death Differ. 2017;24(10):1799–1810. doi: 10.1038/cdd.2017.109.

29. Liang S. Role of T cell‑induced autoimmune response in the pathogenesis of glaucoma. Int Ophthalmol. 2024;44(1):241. doi: 10.1007/s10792‑024‑03224‑4.

30. Kamat SS, Gregory MS, Pasquale LR. The Role of the Immune System in Glaucoma: Bridging the Divide Between Immune Mechanisms in Experimental Glaucoma and the Human Disease. Semin Ophthalmol. 2016;31(1‑2):147–154. doi: 10.3109/08820538.2015.1114858.

31. Suzuki M, Meguro A, Ota M, Nomura E, Kato T. Genotyping HLA‑DRB1 and HLA‑DQB1 alleles in Japanese patients with normal tension glaucoma. Mol Vis. 2010;16:1874–1879.

32. Soleimani M, Tavalaee M, Aboutorabi R, Adib M, Bahramian H. Evaluation of Fas positive sperm and complement mediated lysis in subfertile individuals. J Assist Reprod Genet. 2010;27(8):477–482. doi: 10.1007/s10815‑010‑9425‑4.

33. Von Thun Und Hohenstein‑Blaul N, Kunst S, Pfeiffer N, Grus FH. Biomarkers for glaucoma: from the lab to the clinic. Eye (Lond). 2017;31(2):225–231. doi: 10.1038/eye.2016.300.

34. Joachim SC, Pfeiffer N, Grus FH. Autoantibodies in patients with glaucoma: a comparison of IgG serum antibodies against retinal, optic nerve, and optic nerve head antigens. Graefes Arch Clin Exp Ophthalmol. 2005;243(8):817–823. doi: 10.1007/s00417‑004‑1094‑5.

35. Maruyama I, Ikeda Y, Nakazawa M, Ohguro H. Clinical roles of serum autoantibody against neuron‑specific enolase in glaucoma patients. Tohoku J Exp Med. 2002 Jul;197(3):125–132. doi: 10.1620/tjem.197.125.

36. Wang LH, Huang CH, Lin IC. Advances in Neuroprotection in Glaucoma: Pharmacological Strategies and Emerging Technologies. Pharmaceuticals (Basel). 2024 Sep 25;17(10):1261. doi: 10.3390/ph17101261.

37. Maciulaitiene R, Kalesnykas G, Pauza DH. A combination of topical and systemic administration of brimonidine is neuroprotective in the murine optic nerve crush model. PLoS One. 2024;19(8):e0308671. doi: 10.1371/journal.pone.0308671.

38. Kurysheva NI. Selective α2 agonists in the treatment of glaucoma: neuroprotective properties and impact on ocular blood flow (in Russian only). Russian Annals of Ophthalmology. 2019;135(3):113–120 (In Russ.). doi: 10.17116/oftalma2019135031113.

39. Simpkins JW, Wen Y, Perez E. Role of nonfeminizing estrogens in brain protection from cerebral ischemia: an animal model of Alzheimer’s disease neuropathology. Ann N Y Acad Sci. 2005;1052:233–242. doi: 10.1196/annals.1347.019.

40. Razmara A, Duckles SP, Krause DN. Estrogen suppresses brain mitochondrial oxidative stress in female and male rats. Brain Res. 2007;1176:71–81. doi: 10.1016/j.brainres.2007.08.036.

41. Kumar DM, Perez E, Cai ZY. Role of nonfeminizing estrogen analogues in neuroprotection of rat retinal ganglion cells against glutamate‑induced cyto‑toxicity. Free Radical Biology and Medicine. 2005;38:1152–1163. doi: 10.1016/j.freeradbiomed.2004.12.007.

42. Nakazawa T, Takahashi H, Shimura M. Estrogen has a neuroprotective effect on axotomized RGCs through ERK signal transduction pathway. Brain Res. 2006;1093(1):141–149. doi: 10.1016/j.brainres.2006.03.084.

43. Zhou X, Li F, Ge J. Retinal ganglion cell protection by 17‑beta‑estradiol in a mouse model of inherited glaucoma. Dev Neurobiol. 2007;67(5):603–616. doi: 10.1002/dneu.20373.

44. Geyer O, Silver DM, Mathalon N. Gender and age effects on pulsatile ocular blood flow. Ophthalmic Res. 2003;35(5):247–250. doi: 10.1159/000072144.

45. Maximov IB. Retinalamin in complex treatment of involutional central dystrophies. Moscow: MEDpress‑Inform, 2006. 136 p. (In Russ.).

46. Alekseev VN, Churilina NYu, Pavlova EA. Morphometric substantiation of neuroprotective action of peptides in primary open‑angle glaucoma. Uspekhi sovremennogo naukosnaniya. 2008;2:89–99 (In Russ.).

47. Stavitskaya TV, Egorov EA. Comparison of neuroprotective properties of retinalamin and emoxipin. Clinical Ophthalmology. 2004;3:108–110 (In Russ.).

48. Avetisov SE, Yerichev VP, Fedorov AA, Yaremenko TV, Murakhovskaya YuK. Evaluation of therapeutic sensitivity of retinal ganglion cells in culture to target peptide bioregulator. Annals of Ophthalmology. 2019;1:82–87 (In Russ.). doi: 10.17116/oftalma201913501182.

49. Verlov NA, Dorotenko AR, Gulina LS, Kalatanova AV, Trashkov AP, Burdakov VS. Study of ligand‑receptor interaction and biodistribution at different modes of administration of a drug containing polypeptides of cattle retina. Annals of Ophthalmology. 2021;137(5):88–95 (In Russ.). doi: 10.17116/oftalma20211370518.

50. Neroev VV, Yerichev VP, Lovpache D. Peptides in neuroprotective therapy of patients with primary open‑angle glaucoma with normalized tone. Retinalamin in complex treatment of involutional central dystrophies. Moscow: MEDpress‑Inform, 2006. 136 p.

51. Astakhov YuS, Butin EV, Morozova NV, Sokolov VO, Florentseva SS. Experience of Retinalamin application in the treatment of glaucoma neurooptikopathy and agerelated macular degeneration. Ophthalmologicheskie vedomosti. 2013;5(2):45–49.

52. Alekseev VN, Kozlova NV. Application of retinalamine in patients with primary open‑angle glaucoma. GLAUCOMA. 2013;1:49–52.

53. Strakhov VV, Egorov EA, Yerichev VP, Yartsev AV, Petrov SYu, Dorofeev DA. Effect of long‑term retinoprotective therapy on glaucoma progression according to structural and functional studies. Annals of Ophthalmology. 2020;136(5):58–66 (In Russ.).

54. Strakhov VV, Egorov EA, Erichev VP. The influence of long‑term retinal protective therapy on glaucoma progression according to structural and functional tests. Vestnik Oftalmoljgii. 2020;136(5):58–66 (In Russ.). doi: 10.17116/oftalma202013605158.

55. Erichev VP, Shamshinova AM, Lovpache JN, Egorova IV, Kolomoitseva EM. Comparative assessment of the neuroprotective effect of peptide bioregulators in patients with different stages of primary open‑angle glaucoma. Glaucoma. 2005;1: 18–24.

56. Dorofeev DA, Kirilik EV, Klimova AV. Vliyanie retinoprotektornoi terapii na pokazateli opticheskoi kogerentnoi tomografii s funktsiei angiografii (pilotnoe issledovanie) [Effect of retinal protective therapy on optical coherence tomography angiography (pilot study)]. Vestn Oftalmol. 2021;137(1):60‑67. Russian. doi: 10.17116/oftalma202113701160

57. Polunin GS, Nurieva SM, Bayandin DL Evaluation of therapeutic effect of new Russian drug semax in optic nerve disease. Annals of Ophthalmology. 2000;116(1):15–18 (In Russ.).

58. Kurysheva NI, Shpak AA, Ioyleva EE. “Semaks” in treatment of glaucomatous optic neuropathy in patients with normalized ophthalmotonus. Annals of Ophthalmology. 2001;4:5–8 (In Russ.).

59. Latib F, Zafendi MAI, Mohd Lazaldin MA. The use of vitamin E in ocular health: Bridging omics approaches with Tocopherol and Tocotrienol in the management of glaucoma. Food Chem (Oxf). 2024;9:100224. doi: 10.1016/j.fochms.2024.100224.

60. Korneeva AV, Kuroyedov AV, Gazizova IR, Brezhnev AYu, Lovpache DN, Loskoutov IA. Influence of nicotinamide on glaucoma patients. National Journal Glaucoma. 2020;19(3):75–81 (In Russ.). doi: 10.25700/NJG.2020.03.08.

61. Li S, Jakobs TC. Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage. Life Sci Alliance. 2023;6(8):e202301976. doi: 10.26508/lsa.202301976.

62. Ramdas WD, Wolfs RC, Kiefte‑de Jong JC. Nutrient intake and risk of open‑angle glaucoma: the Rotterdam Study. Eur J Epidemiol. 2012;27(5):385–393. doi: 10.1007/s10654‑012‑9672‑z.

63. Pan SY, Chen YY, Hsu MY, Sheen YJ, Weng CH. Associations of different types of statins with the risk of open‑angle glaucoma: a systematic review and network meta‑analysis. Graefes Arch Clin Exp Ophthalmol. 2024 Aug 30. doi: 10.1007/s00417‑024‑06620‑9.

64. Tsai YE, Chen YH, Sun CA, Chung CH, Chien WC, Chien KH. Relationship between Using Fibrate and Open‑Angle Glaucoma in Hyperlipidemic Patients: A Population‑Based Cohort Study. Int J Environ Res Public Health. 2022;19(4):2415. doi: 10.3390/ijerph19042415.

65. Wan MJ, Daniel S, Kassam F. Survey of complementary and alternative medicine use in glaucoma patients. J Glaucoma. 2012;21(2):79–82. doi: 10.1097/IJG.0b013e3182027c0c.

66. Golmohammadi M, Meibodi SA, Al‑Hawary SI. Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review. Animal Model Exp Med. 2024;7(3):195–207. doi: 10.1002/ame2.12438

67. Adeghate J, Rahmatnejad K, Waisbourd M, Katz LJ. Intraocular pressure‑independent management of normal tension glaucoma. Surv Ophthalmol. 2019;64(1):101– 110. doi: 10.1016/j.survophthal.2018.08.005.

68. Kim MJ, Martin CA, Kim J. Computational methods in glaucoma research: Current status and future outlook. Mol Aspects Med. 2023;94:101222. doi: 10.1016/j.mam.2023.101222.

69. Cetinel S, Montemagno C. Nanotechnology Applications for Glaucoma. Asia Pac J Ophthalmol (Phila). 2016;5(1):70–78. doi: 10.1097/APO.0000000000000171.

70. Weinreb RN, Liebmann JM, Cioffi GA, Goldberg I, Brandt JD, Johnson CA, Zangwill LM, Schneider S, Badger H, Bejanian M. Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo‑Controlled, Phase 3 Studies. Ophthalmology. 2018;125(12):1874–1885. doi: 10.1016/j.ophtha.2018.06.017.

71. Chen A, Montesano G, Lu R, Lee CS, Crabb DP, Lee AY. Visual Field Endpoints for Neuroprotective Trials: A Case for AI‑Driven Patient Enrichment. Am J Ophthalmol. 2022;243:118–124. doi: 10.1016/j.ajo.2022.07.013.

72. Normando EM, Yap TE, Maddison J, Miodragovic S, Bonetti P. A CNN‑aided method to predict glaucoma progression using DARC (Detection of Apoptosing Retinal Cells). Expert Rev Mol Diagn. 2020;20(7):737–748. doi: 10.1080/14737159.2020.1758067.

73. Davis BM, Tian K, Pahlitzsch M, Brenton J, Ravindran N. Topical Coenzyme Q10 demonstrates mitochondrial‑mediated neuroprotection in a rodent model of ocular hypertension. Mitochondrion. 2017;36:114–123. doi: 10.1016/j.mito.2017.05.010.

74. Lazzaro EC, Mallick A, Singh M, Reich I, Elmann S The effect of positional changes on intraocular pressure during sleep in patients with and without glaucoma. J Glaucoma. 2014;23(5):282–287. doi: 10.1097/01.ijg.0000435848.90957.fe.

75. Zhu MM, Lai JSM, Choy BNK. Physical exercise and glaucoma: a review on the roles of physical exercise on intraocular pressure control, ocular blood flow regulation, neuroprotection and glaucoma‑related mental health. Acta ophthalmologica, 2018;96(6):e676–e691. doi: 10.1111/aos.13661.

76. Lee JY, Kim JM, Lee KY, Kim B, Lee MY, Park KH. Relationships between Obe‑ sity, Nutrient Supply and Primary Open Angle Glaucoma in Koreans. Nutrients. 2020;12(3):878. doi: 10.3390/nu12030878.

77. Jung Y, Han K, Park HYL, Lee SH, Park CK. Metabolic Health, Obesity, and the Risk of Developing Open-Angle Glaucoma: Metabolically Healthy Obese Patients versus Metabolically Unhealthy but Normal Weight Patients. Diabetes Metab J. 2020;44(3):414–425. doi: 10.4093/dmj.2019.0048.

78. Dada T, Mondal S, Midha N, Mahalingam K, Sihota R. Effect of Mindfulness-Based StressReductiononIntraocularPressure inPatientsWithOcularHypertension: ARand‑ omizedControlTrial. Am J Ophthalmol. 2022;239:66–73. doi: 10.1016/j.ajo.2022.01.017.