Теоретическое обоснование нейропротекторной терапии при глаукоме как инволюционно зависимой патологии

Несмотря на эффективную гипотензивную терапию, глаукомная оптическая нейропатия нередко прогрессирует. Возможный патогенетический механизм этой прогрессии — нейродегенерация, объединяющая многие инволюционные заболевания, такие как болезнь Альцгеймера, болезнь Паркинсона и другие. Несмотря на разную этиологию и клиническую картину, всех их объединяет несколько общих признаков, характерных для инволюционных заболеваний: увеличение заболеваемости с возрастом, практически бессимптомное начало и прогрессирующее ухудшение функций, генетическая предрасположенность. Гибель нейронов при всех нейродегенеративных заболеваниях (в том числе и глаукоме) осуществляется по механизму апоптоза, в основе которого лежат следующие патологические процессы: депривация нейротрофических факторов, повышение концентрации возбуждающих аминокислот, окислительный стресс и нейровоспаление. В данном обзоре представлены современные данные об аксональной и транссинаптической нейродегенерации, об оксидативном стрессе и глутаматной эксайтоксичности при глаукоме как ведущих звеньях в распространении патологического процесса и основных мишенях для нейропротекторной терапии.

1. Quigley H.A., Broman A.T. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006; 90(3):262-267. doi: 10.1136/bjo.2005.081224.

2. Peters D., Bengtsson B., Heijl A. Lifetime risk of blindness in open angle glaucoma. Am J Ophthalmol. 2013; 156:724–730. doi: 10.1111/aos.12203.

3. Malihi M., Moura Filho E.R., Hodge D.O., Sit A.J. Long-term trends in glaucoma-related blindness in Olmsted County, Minnesota. Ophthal mology. 2014; 121:134–141. doi: 10.1016/j.ophtha.2013.09.003.

4. Broman A.T., Quigley H.A., West S.K., Katz J. et al. Estimating the rate of progressive visual field damage in those with open-angle glauco ma, from cross-sectional data. Invest Ophthalmol Vis Sci. 2008; 49(1): 66–76. doi: 10.1167/iovs.07-0866.

5. Musch D.C., Gillespie B.W., Lichter P.R., Niziol L.M. et al. Visual field progression in the Collaborative Initial Glaucoma Treatment Study the impact of treatment and other baseline factors. Ophthalmology. 2009; 116(2):200-207. doi: 10.1016/j.ophtha.2008.08.051.

6. Kingwell K. Alzheimer disease: Alzheimer disease biomarkers in healthy individuals can predict cognitive decline several years later. Nat Rev Neurol. 2013; 9(6):300. doi: 10.1038/nrneurol.2013.81.

7. Shapira A.H.V., Olanow C.W. Neuroprotection in Parkinson’s disease: mysteries, myths, and misconceptions. JAMA. 2004; 291(3):358–364. doi: 10.1001/jama.291.3.358.

8. Khan A.O. Genetics of primary open angle glaucoma. Curr Opin Oph thalmol. 2011; 22(5):347–355. doi: 10.1097/icu.0b013e32834922d2.

9. Weber A.J., Chen H., Hubbard W.C., Kaufman P.L. Experimental glau coma and cell size, density, and number in the primate lateral genicu late nucleus. Invest Ophthalmol Vis Sci. 2000; 41(6):1370–1379.

10. Yücel Y.H., Zhang Q., Weinreb R.N., Kaufman P.L. et al. Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res. 2003; 22(4):465–481. doi: 10.1016/s1350-9462 (03)00026-0.

11. Chaturvedi N., Hedley-Whyte E.T., Dreyer E.B. Lateral geniculate nucleus in glaucoma. Am J Ophthalmol. 1993; 116(2):182–188. doi: 10.1016/s0002-9394 (14) 71283-8.

12. Gupta N. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Oph thalmol. 2006; 90(6):674-678. doi: 10.1136/bjo.2005.086769.

13. Алексеев В.Н., Газизова И.Р., Никитин Д.Н., Тубаджи Е., Ринджибал А.М., Фарзад З. Первичная открытоугольная глаукома и дегенеративные изменения в центральных отделах зрительного анализатора. Офтальмологические ведомости. 2012; 5(3):23-28.

14. Еричев В.П., Туманов В.П., Панюшкина Л.А., Федоров А.А. Сравнительный анализ морфологических изменений в зрительных центрах при первичной глаукоме и болезни Альцгемера. Национальный журнал глаукома. 2014; 13(3):5-13.

15. Chan K.C., So K.F., Wu E.X. Proton magnetic spectroscopy revealed choline reduction in the visual cortex in an experimental model of chronic glaucoma. Exp Eye Res. 2009; 88(1):65-70. doi: 10.1016/j.exer.2008.10.002.

16. Boucard C.C., Hernowo A.T., Maguire R.P., Jansonius N.M. et al. Cornelissen. Changes in cortical grey matter density associated with long standing retinal visual field defects. Brain. 2009; 132(7):1898–1906. doi: 10.1093/brain/awp119.

17. Gupta N., Greenberg G., Noël de Tilly L., Gray B. et al. Atrophy of the lateral geniculate nucleus in human glaucoma detected by mag netic resonance imaging. Br J Ophthalmol. 2009; 93(1):56–60. doi: 10.1136/bjo.2008.138172.

18. Kashiwagi K., Okubo T., Tsukahara S. Association of magnetic resonance imaging of anterior optic pathway with glaucomatous visual field damage and optic disc cupping. J Glaucoma. 2004; 13(3):189-95. doi: 10.1097/00061198-200406000-00003.

19. Lagreze W.A., Gaggl M., Weigel M., Schulte-Mönting J. et al. Retro bulbar optic nerve diameter measured by high-speed magnetic resonance imaging as a biomarker for axonal loss in glaucomatous optic atrophy. Invest Ophthalmol Vis Sci. 2009; 50(9):4223-4228. doi: 10.1167/iovs.08-2683.

20. Dai H., Mu K.T., Qi J.P., Wang C.Y. et al. Assessment of lateral geniculate nucleus atrophy with 3T MR imaging and correlation with clinical stage of glaucoma. Am J Neuroradiol. 2011; 32(7):1347–1353. doi: 10.3174/ajnr.a2486.

21. Hui E.S., Fu Q.L., So K.F., Wu E.X. Diffusion tensor MR study of optic nerve degeneration in glaucoma. Conf Proc IEEE Eng Med Biol Soc. 2007; 4312-4315. doi: 10.1109/iembs.2007.4353290.

22. Garaci F.G., Bolacchi F., Cerulli A., Melis M. et al. Optic nerve and optic radiation neurodegeneration in patients with glaucoma: in vivo analysis with 3-T Diffusion-Tensor MR Imaging. Radiology. 2009; 252(2):496-501. doi: 10.1148/radiol.2522081240.

23. Engelhorn T., Michelson G., Waerntges S., Otto M. et al. Changes of radial diffusivity and fractional anisotropy in the optic nerve and optic radiation of glaucoma patients. Sci World Journal. 2012; 849632. doi: 10.1100/2012/849632.

24. Nucci C., Mancino R., Martucci A., Bolacchi F. et al. 3-T Diffusion ten sor imaging of the optic nerve in subjects with glaucoma: correlation with GDx-VCC, HRT-III and Stratus optical coherence tomography findings. Br J Ophthalmol. 2012; 96(7):976–980. doi: 10.1136/bjophthalmol-2011-301280 .

25. El-Rafei A., Engelhorn T., Warntges S., Dorfler A. et al. A framework for voxel-based morphometric analysis of the optic radiation using diffusion tensor imaging in glaucoma. Magn Reson Imaging. 2011; 29(8):1076–1087. doi: 10.1016/j.mri.2011.02.034.

26. Michelson G., Engelhorn T., Warntges S., El Rafei A. et al. DTI parameters of axonal integrity and demyelination of the optic radiation correlate with glaucoma indices. Graefes Arch Clin Exp Ophthalmol. 2012; 251(1):243-253. doi: 10.1007/s00417-011-1887-2.

27. Wang M.Y., Wu K., Xu J.M., Dai J. et al. Quantitative 3-T diffusion ten sor imaging in detecting optic nerve degeneration in patients with glaucoma: association with retinal nerve fiber layer thickness and clinical severity. Neuroradiology. 2013; 55(4):493-498. doi: 10.1007/s00234-013-1133-1.

28. Еричев В.П., Панюшкина Л.А., Новиков И.А. Диффузионно-тензорная магнитно-резонансная томография в диагностике нейродегенеративных изменений зрительного пути при глаукоме. Вестник офтальмологии. 2015; 131(2):59-63. doi: 10.17116/oftalma2015131259-63.

29. Venderova K., Park D.S. Programmed cell death in Parkinson’s disease. Cold Spring Harbor Perspectives in Medicine. 2012; 2(8):a009365. doi: 10.1101/cshperspect.a009365.

30. Hickey M., Chesselet M.F. Apoptosis in Huntington’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(2):255-265. doi: 10.1016/S0278-5846(03)00021-6.

31. Quigley H.A. Neuronal death in glaucoma. Prog Retin Eye Res. 1999; 18(1):39-57. doi: 10.1016/s1350-9462(98)00014-7.

32. Quigley H.A., McKinnon S.J., Zack D.J., Pease M.E. et al. Retro grade axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci. 2000; 41(11): 3460-3466.

33. Pease M.E., McKinnon S.J., Quigley H.A., Kerrigan-Baumrind L.A. et al. Obstructed axonal transport of BDNF and its receptor TrkB in experi mental glaucoma. Invest Ophthalmol Vis Sci. 2000; 41(3):764-774.

34. Spalding K.L., Rush R.A., Harvey A.R. Target-derived and locally derived neurotrophins support retinal ganglion cell survival in the neonatal rat retina. J Neurobiol. 2004; 60(3):319–327. doi: 10.1002/neu.20028.

35. Arango-González B., Cellerino A., Kohler K. Exogenous brain-derived neurotrophic factor (BDNF) reverts phenotypic changes in the retinas of transgenic mice lacking the BDNF gene. Invest Ophthalmol Vis Sci. 2009; 50(3):1416–1422. doi: 10.1167/iovs.08-2244.

36. Mey J., Thanos S. Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res. 1993; 602(2):304–317. doi: 10.1016/0006-8993(93)90695-j.

37. Meyer-Franke A., Kaplan M.R., Pfrieger F.W., Barres B.A. Characte rization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron. 1995; 15(4):805–819. doi: 10.1016/0896-6273(95)90172-8.

38. Weibel D., Kreutzberg G.W., Schwab M.E. Brain-derived neurotrophic factor (BDNF) prevents lesion-induced axonal die-back in young rat optic nerve. Brain Res. 1995; 679(2):249–254. doi: 10.1016/0006-8993(95)00238-l.

39. Omodaka K., Kurimoto T., Nakamura O., Sato K. et al. Artemin aug ments survival and axon regeneration in axotomized retinal gan glion cells. J Neurosci Res. 2014; 92(12) :1637–1646. doi: 10.1002/jnr.23449.

40. Perígolo-Vicente R., Ritt K., Gonçalves-de-Albuquerque C.F., Castro Faria-Neto H.C. et al. IL-6, A1 and A2aR: A crosstalk that modulates BDNF and induces neuroprotection. Biochem Biophys Res Commun. 2014; 449(4):477–482. doi: 10.1016/j.bbrc.2014.05.036.

41. Unoki K., LaVail M.M. Protection of the rat retina from ischemic inju ry by brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor. Invest Ophthalmol Vis Sci. 1994; 35:907–915.

42. Bartesaghi S., Marinovich M., Corsini E., Galli C.L. Erythropoietin: A novel neuroprotective cytokine. Neurotoxicology. 2005; 26(5): 923–928. doi: 10.1016/j.neuro.2005.01.016.

43. Fang J.H., Wang X.H., Xu Z.R., Jiang F.G. Neuroprotective effects of bis (7)-tacrine against glutamate-induced retinal ganglion cells dam age. BMC Neurosci. 2010; 11(1):31. doi: 10.1186/1471-2202-11-31.

44. Miguel-Hidalgo J.J., Alvarez X.A., Cacabelos R., Quack G. Neuropro tection by memantine against neurodegeneration induced by beta amyloid (1-40) Brain Res. 2002; 958(1):210–221. doi: 10.1016/s0006-8993(02)03731-9.

45. Brooks D.E., Garcia G.A., Dreyer E.B., Zurakowski D. et al. Vitreous body glutamate concentration in dogs with glaucoma. Am J Vet Res. 1997; 58(8):864-867.

46. Carter-Dawson L., Crawford M.L., Harwerth R.S., Smith E.L. et al. Vit real glutamate concentration in monkeys with experimental glauco ma. Invest Ophthalmol Vis Sci. 2002; 43:2633–2637.

47. Dreyer E.B., Zurakowski D., Schumer R.A., Podos S.M. et al. Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol. 1996; 114(3):299-305. doi: 10.1001/archopht.1996.01100130295012.

48. Hare W.A., WoldeMussie E., Lai R.K., Ton H. et al. Efficacy and safety of memantine treatment for reduction of changes associated with experi mental glaucoma in monkey, I: Functional measures. Invest Ophthalmol Vis Sci. 2004; 45(8):2625–2639. doi: 10.1167/iovs.03-0566.

49. Danesh-Meyer H.V., Levin L.A. Neuroprotection: extrapolating from neurologic diseases to the eye. Am J Ophthalmol. 2009; 148(2):186–191. doi: 10.1016/j.ajo.2009.03.029.

50. Vorwerk C.K., Lipton S.A., Zurakowski D., Hyman B.T. et al. Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Invest Ophthalmol Vis Sci. 1996; 37:1618–1624.

51. Wang H., Carlier P.R., Ho W.L., Wu D.C. et al. Effects of bis(7)-tacrine, a novel anti-Alzheimer’s agent, on rat brain AChE. Neuroreport. 1999; 10(4):789–793. doi: 10.1097/00001756-199903170-00023.

52. Blanpied T.A., Boeckman F.A., Aizenman E., Johnson J.W. Trapping chan nel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol. 1997; 77(1):309–323. doi: 10.1152/jn.1997.77.1.309.

53. El-Remessy A.B., Khalil I.E., Matragoon S., Abou-Mohamed G. et al. Neuroprotective effect of (-) Delta9-tetrahydrocannabinol and canna bidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involve ment of peroxynitrite. Am J Pathol. 2003; 163(5):1997–2008. doi: 10.1016/s0002-9440(10)63558-4.

54. Wang H.G., Pathan N., Ethell I.M., Krajewski S. et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of Bad. Science. 1999; 284(5412):339–343. doi: 10.1126/science.284.5412.339.

55. Huang W., Fileta J.B., Dobberfuhl A., Filippopolous T. et al. Calcineu rin cleavage is triggered by elevated intraocular pressure, and calci neurin inhibition blocks retinal ganglion cell death in experimental glaucoma. Proc Natl Acad Sci USA. 2005; 102(34):12242–12247. doi: 10.1073/pnas.0505138102.

56. Crish S.D., Calkins D.J. Neurodegeneration in glaucoma: Progression and calcium-dependent intracellular mechanisms. Neuroscience. 2011; 176:1–11. doi: 10.1016/j.neuroscience.2010.12.036.

57. Yamada H., Chen Y.N., Aihara M., Araie M. Neuroprotective effect of calcium channel blocker against retinal ganglion cell damage under hypoxia. Brain Res. 2006; 1071(1):75–80. doi.org/10.1016/j.brainres.2005.11.072.

58. Osborne N.N., Wood J.P.M., Chidlow G., Casson R. et al. Effectiveness of levobetaxolol and timolol at blunting retinal ischemia is related to their calcium and sodium blocking activities: relevance to glaucoma. Brain Res. Bull. 2004; 62(6):525-528. doi: 10.1016/s0361-9230(03)00070-4.

59. Sawada A., Kitazawa Y., Yamamoto T., Okabe I. et al. Prevention of visual field defect progression with brovincamine in eyes with nor mal-tension glaucoma. Ophthalmology. 1996; 103(2):283–288. doi: 10.1016/s0161-6420(96)30703-3.

60. Koseki N., Araie M., Yamagami J., Shirato S. et al. Effects of oral brovincamine on visual field damage in patients with normal-tension glaucoma with low-normal intraocular pressure. J Glaucoma. 1999; 8(2):117–123. doi: 10.1097/00061198-199904000-00006.

61. Koseki N., Araie M., Tomidokoro A., Nagahara M. et al. A placebo controlled 3-year study of a calcium blocker on visual field and ocu lar circulation in glaucoma with low-normal pressure. Ophthalmology. 2008; 115(11):2049–2057.

62. Takayama J., Tomidokoro A., Ishii K., Tamaki Y. et al. Time course of the change in optic nerve head circulation after an acute increase in intraocular pressure. Invest Ophthalmol Vis Sci. 2003; 44(9):3977–3985. doi: 10.1167/iovs.03-0024.

63. Tezel G. Oxidative stress in glaucomatous neurodegeneration: mecha nisms and consequences. Prog Retin Eye Res. 2006; 25(5):490–513. doi: 10.1016/j.preteyeres.2006.07.003.

64. Lin M.T., Beal M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006; 443(7113):787–795. doi: 10.1038/nature05292.

65. Mizuno Y., Ikebe S.I., Hattori N., Nakagawa-Hattori Y.0. et al. Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim Biophys Acta. 1995; 1271:265–274. doi: 10.1016/0925-4439(95)00038-6.

66. Goyal A., Srivastava A., Sihota R., Kaur J. Evaluation of oxidative stress markers in aqueous humor of primary open angle glaucoma and primary angle closure glaucoma patients. Curr Eye Res. 2014; 39(8):823–829. doi: 10.3109/02713683.2011.556299.

67. Qu J., Kaufman Y., Washington I. Coenzyme Q10 in the human reti na. Invest Ophthalmol Vis Sci. 2009; 50(4):1814–1818. doi: 10.1167/iovs.08-2656.

68. Zhang X., Tohari A.M., Marcheggiani F., Zhou X. et al. Therapeutic potential of co-enzyme Q10 in retinal diseases. Curr Med Chem. 2017; 24(39):4329-4339. doi: 10.2174/0929867324666170801100516.

69. Nakajima Y., Inokuchi Y., Nishi M., Shimazawa M. et al. Coenzyme Q10 protects retinal cells against oxidative stress in vitro and in vivo. Brain Res. 2008; 1226:226-233. doi: 10.1016/j.brainres.2008.06.026

70. Nucci C., Tartaglione R., Cerulli A., Mancino R. et al. Retinal damage caused by high intraocular pressure-induced transient ischemia is pre vented by coenzyme Q10 in rat. Int Rev Neurobiol. 2007; 82:397–406. doi: 10.1016/s0074-7742(07)82022-8.

71. Russo R., Cavaliere F., Rombolà L., Gliozzi M. et al. Rational basis for the development of coenzyme Q10 as a neurotherapeutic agent for retinal protection. Prog Brain Res. 2008; 173:575–582. doi: 10.1016/s0079-6123(08)01139-4.

72. Guo L., Cordeiro M.F. Assessment of neuroprotection in the retina with DARC. Prog Brain Res. 2008; 173:437–450. doi: 10.1016/s0079-6123(08)01130-8.

73. Parisi V., Centofanti M., Gandolfi S., Marangoni D. et al. Effects of coenzyme Q10 in conjunction with vitamin E on retinal evoked and cortical-evoked responses in patients with open angle glaucoma. J Glaucoma. 2014; 23(6):391-404. doi: 10.1097/IJG.0b013e318279b836.

74. Saver J.L. Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair. Rev Neurol Dis. 2008; 5(4):167–177.

75. Secades J.J. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol. 2016; 23;63(S03):S1-S73.

76. Alvarez-Sabín J., Román G.C. The role of citicoline in neuroprotection and neurorepair in ischemic stroke. Brain Sci. 2013; 3(4):1395–1414. doi: 10.3390/brainsci3031395.

77. Fioravanti M., Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005; 18:CD000269. doi: 10.1002/14651858.cd000269.pub2.

78. Agnoli A., Ruggieri S., Denaro A., Bruno G. New strategies in the management of Parkinson’s disease: a biological approach using a phospholipid precursor (CDP-choline). Neuropsychobiology. 1982; 8(6):289–296. doi: 10.1159/000117914.

79. Oshitari T., Fujimoto N., Adachi-Usami E. Citicoline has a protective effect on damaged retinal ganglion cells in mouse culture retina. Neuroreport. 2002; 13(6):2109–2111. doi: 10.1097/00001756-200211150-00023.

80. Schuettauf F., Rejdak R., Thaler S., Bolz S. et al. Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. Exp Eye Res. 2006; 83(5):1128–1134. doi: 10.1016/j.exer.2006.05.021.

81. Pecori-Giraldi J., Virno M., Covelli G., Grechi G. et al. Therapeutic value of citicoline in the treatment of glaucoma (computerized and automated perimetric investigation). Int Ophthalmol. 1989; 13(1-2): 109–112. doi: 10.1007/bf02028649.

82. Virno M., Pecori-Giraldi J., Liguori A., de Gregorio F. The protective effect of citicoline on the progression of the perimetric defects in glaucomatous patients (perimetric study with a 10-year follow up). Acta Ophthalmol Scand. 2000; 78(S232):56–57. doi: 10.1111/j.1600-0420.2000.tb01107.x.

83. Ottobelli L., Manni G.L., Centofanti M., Iester M. et al. Citicoline oral solution in glaucoma: is there a role in slowing disease progression? Ophthalmologica. 2013; 29(4):219–226. doi: 10.1159/000350496.

84. Parisi V., Centofanti M., Ziccardi L., Tanga L. et al. Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma. Graefes Arch Clin Exp Ophthalmol. 2015; 253(8):1327–1340. doi: 10.1007/s00417-015-3044-9.

85. Parisi V. Electrophysiological assessment of glaucomatous visual dysfunction during treatment with cytidine-51-diphosphocholine (citicoline): a study of 8 years of follow-up. Doc Ophthalmol. 2005; 110(1):91–102. doi: 10.1007/s10633-005-7348-7.

86. Parisi V., Manni G., Colacino G., Bucci M.G. Cytidine-51-diphospho choline (citicoline) improves retinal and cortical responses in patients with glaucoma. Ophthalmology. 1999; 106(6):1126–1134. doi: 10.1016/s0161-6420(99)90269-5.

87. Bylund D.B., Chacko D.M. Characterization of alpha2 adrenergic receptor subtypes in human ocular tissue homogenates. Invest Oph thalmol Vis Sci. 1999; 40:2299–2306.

88. Wheeler L.A., Gil D.W., WoldeMussie E. Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma. Surv Ophthalmol. 2001; 45(Suppl 3):S290–S294. doi: 10.1016/s0039-6257(01)00206-5.

89. Prokosch V., Panagis L., Volk G.F., Dermon C. et al. Alpha2-adrenergic receptors and their core involvement in the process of axonal growth in retinal explants. Invest Ophthalmol Vis Sci. 2010; 51:6688–6699. doi: 10.1167/iovs.09-4835.

90. Lambert W.S., Ruiz L., Crish S.D., Wheeler L.A. et al. Brimonidine pre vents axonal and somatic degeneration of retinal ganglion cell neu rons. Mol Neurodegener. 2011; 6(1):4. doi: 10.1186/1750-1326-6-4.

91. Aung T., Oen F.T., Wong H.T., Chan Y.H. et al. Randomised con trolled trial comparing the effect of brimonidine and timolol on visual field loss after acute primary angle closure. Br J Ophthalmol. 2004; 88(1):88–94. doi: 10.1136/bjo.88.1.88.

92. Krupin T., Liebmann J.M., Greenfield D.S., Ritch R. et al. Low-Pres sure Glaucoma Study Group. A randomized trial of brimonidine versus timolol in preserving visual function: Results from the Low-Pressure Glaucoma Treatment Study. Am J Ophthalmol. 2011; 151(4):671–681. doi: 10.1016/j.ajo.2010.09.026.

93. Liu B., Neufeld A.H. Expression of nitric oxide synthase-2 (NOS-2) in reactive astrocytes of the human glaucomatous optic nerve head. Glia. 2000; 30(2):178–186. doi: 10.1002/(sici)1098-1136(200004)30:2<178::aid-glia7>3.0.co;2-c.

94. Neufeld A.H., Hernandez M.R., Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol. 1997; 115(4):497–503. doi: 10.1001/archopht.1997.01100150499009.

95. Nucci C., Morrone L., Rombolà L., Nisticò R. et al. Multifaceted roles of nitric oxide in the lateral geniculate nucleus: From visual signal trans duction to neuronal apoptosis. Toxicol Lett. 2003; 139(2-3):163–173. doi: 10.1016/s0378-4274(02)00430-7.

96. Hu Z., Du S. Pressure influence on mRNA and protein expression of inducible nitric oxide synthase in purified retinal ganglion cells of rats. Zhonghua Yan Ke Za Zhi. 2002; 38:495–498.

97. Marsicano G., Moosmann B., Hermann H., Lutz B. et al. Neuroprotec tive properties of cannabinoids against oxidative stress: Role of the cannabinoid receptor CB1. J Neurochem. 2002; 80(3):448–456. doi: 10.1046/j.0022-3042.2001.00716.x.

98. Libby R.T., Howell G.R., Pang I.H., Savinova O.V. et al. Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retino pathy in the DBA/2J glaucoma model. BMC Neurosci. 2007; 8(1):108. doi: 10.1186/1471-2202-8-108.

99. Kasmala L.T., Ransom N.L., Conner J.R., McKinnon S.J. Oral administration of SC-51, a nitric oxide synthase inhibitor, does not protect optic nerve axons in a hypertensive rat model of glaucoma. Invest Ophthalmol Vis Sci. 2004; 45:904.

100. Nucci C., Martucci A., Giannini C., Morrone L.A. Neuroprotective agents in the management of glaucoma. Eye. 2018; 32(5):938-945. doi: 10.1038/s41433-018-0050-2.