Выбор экспериментальной модели и метода моделирования при изучении патогенеза и способов лечения возрастной макулярной дегенерации (обзор)

Введение. Экспериментальное моделирование различных патологических процессов в органе зрения является неотъемлемой частью как фундаментальных, так и прикладных исследований. Для более глубокого понимания патогенеза возрастной макулярной дегенерации (ВМД) и апробации новых методов ее лечения были разработаны различные экспериментальные модели ВМД на животных. Однако на этапе постановки эксперимента перед каждым исследователем стоит сложная задача выбора адекватной животной модели, имеющей наиболее близкую гомологию с анатомией и патологией человека, а также способа ее моделирования

 Цель: проанализировать данные литературы, касающиеся выбора экспериментальной модели ВМД и методов ее моделирования, оценить сильные стороны и ограничения их использования при изучении патогенеза и эффективности современных способов лечения данной офтальмопатологии.

Материалы и методы. Проведен анализ публикаций на ресурсах PubMed, eLibrary, Cyberleninka за период с 2000 года по настоящее время.

Результаты. В обзоре рассмотрены критерии выбора экспериментальных моделей и группы животных, чаще всего используемых в качестве объекта исследования (мыши, крысы, кролики, свиньи и приматы). Среди способов моделирования ВМД проанализированы химически-индуцированные (использование йодата натрия, N-метил-N-нитрозомочевины и хлорида кобальта), а также физически-индуцированные методы (механическое и световое повреждение сетчатки).

Выводы. Использование кроликов в качестве объекта исследования, даже несмотря на отсутствие макулярной области, является хорошо зарекомендовавшей себя моделью ВМД, ввиду того что строение их сетчатки соответствует общей структуре сетчатки млекопитающих в зонах наибольшей остроты зрения. Среди способов моделирования ВМД, светоиндуцированное повреждение сетчатки занимает лидирующее положение, характеризующееся рядом преимуществ, таких так контроль времени и интенсивности воздействия для получения необходимой степени дегенерации. Представленная в данном обзоре информация позволит исследователям подобрать для решения своей задачи наиболее адекватную модель среди экспериментальных животных и способ моделирования ВМД.

1. Jonas J.B., Cheung C.M.G., Panda-Jonas S. Updates on the epidemiology of age-related macular degeneration. Asia Pac J Ophthalmol (Phila). 2017;6(6):493–497. https://doi.org/10.22608/APO.2017251

2. Mitchell P., Liew G., Gopinath B., Wong T.Y. Age-related macular degeneration. Lancet. 2018;392(10153):1147–1159. https://doi.org/10.1016/S0140-6736(18)31550-2

3. Fleckenstein M., Keenan T.D.L., Guymer R.H. et al. Age-related macular degeneration. Nat Rev Dis Primers. 2021;7(1):31. https://doi.org/10.1038/s41572-021-00265-2

4. Thomas C.J., Mirza R.G., Gill M.K. Age-related macular degene ration. Med Clin North Am. 2021;105(3):473–491. https://doi.org/10.1016/j.mcna.2021.01.003

5. Ambati J., Fowler B.J. Mechanisms of age-related macular degeneration. Neuron. 2012;75(1):26–39. https://doi.org/10.1016/j.neuron.2012.06.018

6. Muraoka Y., Iida Y., Ikeda H.O. et al. KUS121, an ATP regulator, mitigates chorioreti nal pathologies in animal models of age-related macular degeneration. Heliyon. 2018;4(5):e00624. https://doi.org/10.1016/j.heliyon.2018.e00624

7. Fletcher E.L., Jobling A.I., Greferath U. et al. Studying age-related macular degeneration using animal models. Optom Vis Sci. 2014;91(8):878–886. https://doi.org/10.1097/OPX.0000000000000322

8. Ibbett P., Goverdhan S.V., Pipi E. et al. A lasered mouse model of reti nal degeneration displays progressive outer reti nal pathology providing insights into early geographic atrophy. Sci Rep. 2019;9(1):7475. https://doi.org/10.1038/s41598-019-43906-z

9. Rastoin O., Pagès G., Dufies M. Experimental models in neovascular age related macular degeneration. Int J Mol Sci. 2020;21(13):4627. https://doi.org/10.3390/ijms21134627

10. Picaud S., Dalkara D., Marazova K. et al. The primate model for understanding and restoring vision. Proc Natl Acad Sci USA. 2019;116(52):26280–26287. https://doi.org/10.1073/pnas.1902292116

11. Gouras P., Ivert L., Landauer N. et al. Drusenoid maculopathy in rhesus monkeys (Macaca mulatta): effects of age and gender. Graefes Arch Clin Exp Ophthalmol. 2008;246(10):1395-1402. https://doi.org/10.1007/s00417-008-0910-8

12. Kiilgaard J.F., Andersen M.V., Wiencke A.K. et al. A new animal model of choroidal neovascularization. Acta Ophthalmol Scand. 2005;83(6):697–704. https://doi.org/10.1111/j.1600-0420.2005.00566.x

13. Al-Zamil W.M., Yassin S.A. Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017;12:1313–1330. https://doi.org/10.2147/CIA.S143508

14. Pennington K.L., DeAngelis M.M. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond). 2016;3:34. https://doi.org/10.1186/s40662-016-0063-5

15. Pennesi M.E., Neuringer M., Courtney R.J. Animal models of age related macular degeneration. Mol Aspects Med. 2012;33(4):487– 509. https://doi.org/10.1016/j.mam.2012.06.003

16. Zeiss C.J. Animals as models of age-related macular degeneration: an imperfect measure of the truth. Vet Pathol. 2010;47(3):396–413. https://doi.org/10.1177/0300985809359598

17. Kozhevnikova O.S., Korbolina E.E., Ershov N.I., Kolosova N.G. Rat reti nal transcriptome: effects of aging and AMD-like retinopathy. Cell Cycle. 2013;12(11):1745–1761. https://doi.org/10.4161/cc.24825

18. Stefanova N.A., Zhdankina A.A., Fursova A.Zh., Kolosova N.G. [Potential of melatonin for prevention of age-related macular degeneration: experimental study]. Adv Gerontol. 2013;26(1):122–129.

19. Rho J., Percelay P., Pilkinton S. et al. An overview of age-related macular degeneration: clinical, pre-clinical animal models and bidirectional translation. Purevjav E., Pierre J.F., Lu L., eds. Preclinical Animal Modeling in Medicine. London: IntechOpen, 2022. 304 p. https://doi.org/10.5772/intechopen.92923

20. Bryda E.C. The Mighty Mouse: the impact of rodents on advances in biomedical research. Mo Med. 2013;110(3):207–211.

21. Lossi L., D’Angelo L., De Girolamo P., Merighi A. Anatomical features for an adequate choice of experimental animal model in biomedicine: II. Small laboratory rodents, rabbit, and pig. Ann Anat. 2016;204:11–28. https://doi.org/10.1016/j.aanat.2015.10.002

22. Abokyi S., To C.H., Lam T.T., Tse D.Y. Central role of oxidative stress in age-related macular degeneration: evidence from a review of the molecular mechanisms and animal models. Oxid Med Cell Longev. 2020;2020:7901270. https://doi.org/10.1155/2020/7901270

23. Байгильдин С.С., Мусина Л.А., Хисматуллина З.Р. Генетические и индуцированные модели животных с дегенерацией сетчатки. Биомедицина. 2021;17(1):70–81. https://doi.org/10.33647/2074-5982-17-1-70-81

24. Jones B.W., Marc R.E. Reti nal remodeling during reti nal degeneration. Exp Eye Res. 2005;81(2):123–137. https://doi.org/10.1016/j.exer.2005.03.006

25. Geng Y., Greenberg K.P., Wolfe R. et al. In vivo imaging of microscopic structures in the rat reti na. Invest Ophthalmol Vis Sci. 2009;50(12):5872–5879. https://doi.org/10.1167/iovs.09-3675

26. Albright C.D., Zeisel S.H., Salganik R.I. Choline deficiency induces apoptosis and decreases the number of eosinophilic preneoplastic foci in the liver of OXYS rats. Pathobiology. 1998;66(2):71–76. https://doi.org/10.1159/000027999

27. Kozhevnikova O.S., Korbolina E.E., Stefanova N.A. et al. Association of AMD-like retinopathy development with an Alzheimer’s disease metabolic pathway in OXYS rats. Biogerontology. 2013;14(6):753–762. https://doi.org/10.1007/s10522-013-9439-2

28. Суетов А.А., Алекперов С.И., Одинокая М.А., Костина А.А. Мультифокальная электроретинография в исследовании очаговых и диффузных изменений сетчатки кролика. Вестник офтальмологии. 2020;136(4):47–56.

29. Muraoka Y., Ikeda H.O., Nakano N. et al. Real-time imaging of rabbit retina with retinal degeneration by using spectral-domain optical coherence tomography. PLoS One. 2012;7(4):e36135. https://doi.org/10.1371/journal.pone.0036135

30. Animal models in eye research. Edited by Tsonis P.A. San Diego, CA, USA: Academic Press, 2008. 232 p.

31. Peiffer R.L. Jr, Pohm-Thorsen L., Corcoran K. Models in ophthalmology and vision research. The Biology of the Laboratory Rabbit. 1994;409–433. https://doi.org/10.1016/B978-0-12-469235-0.50025-7

32. Zahn G., Vossmeyer D., Stragies R. et al. Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch Ophthalmol. 2009 Oct;127(10):1329–1335. https://doi.org/10.1001/archophthalmol.2009.265

33. Julien S., Kreppel F., Beck S. et al. A reproducible and quantifi-able model of choroidal neovascularization induced by VEGF A165 after subreti nal adenoviral gene transfer in the rabbit. Mol Vis. 2008;14:1358–1372.

34. Qiu G., Stewart J.M., Sadda S. et al. A new model of experimental subreti nal neovascularization in the rabbit. Exp Eye Res. 2006;83(1):141–152. https://doi.org/10.1016/j.exer.2005.11.014

35. Wong C.G., Rich K.A., Liaw L.H. et al. Intravitreal VEGF and bFGF produce florid reti nal neovascularization and hemorrhage in the rabbit. Curr Eye Res. 2001;22(2):140–147. https://doi.org/10.1076/ceyr.22.2.140.5528

36. Lima L.H., Farah M.E., Gum G. et al. Sustained and targeted episcleral delivery of celecoxib in a rabbit model of retinal and choroidal neovascularization. Int J Reti na Vitreous. 2018;4:31. https://doi.org/10.1186/s40942-018-0131-1

37. Nirmal J., Barathi V.A., Dickescheid A. et al. Potential of subconjunctival aflibercept in treating choroidal neovascularization. Exp Eye Res. 2020;199:108187. https://doi.org/10.1016/j.exer.2020.108187

38. Bertschinger D.R., Beknazar E., Simonutti M. et al. A review of in vivo animal studies in reti nal prosthesis research. Graefes Arch Clin Exp Ophthalmol. 2008;246(11):1505–1517. https://doi.org/10.1007/s00417-008-0891-7

39. Sanchez I., Martin R., Ussa F., Fernandez-Bueno I. The parameters of the porcine eyeball. Graefes Arch Clin Exp Ophthalmol. 2011;249(4):475–482. https://doi.org/10.1007/s00417-011-1617-9

40. Kleinwort K.J.H., Amann B., Hauck S.M. et al. Retinopathy with central oedema in an INS C94Y transgenic pig model of long-term diabetes. Diabetologia. 2017;60(8):1541–1549. https://doi.org/10.1007/s00125-017-4290-7

41. Scott P.A., de Castro J.P., DeMarco P.J. et al. Progression of Pro23His retinopathy in a miniature swine model of retinitis pigmentosa. Transl Vis Sci Technol. 2017;6(2):4. https://doi.org/10.1167/tvst.6.2.4

42. Zeng B., Zhang H., Peng Y. et al. Spontaneous fundus lesions in elderly monkeys: an ideal model for age-related macular degeneration and high myopia clinical research. Life Sci. 2021;282:119811. https://doi.org/10.1016/j.lfs.2021.119811

43. Dominik Fischer M., Zobor D., Keliris G.A. et al. Detailed functional and structural characterization of a macular lesion in a rhesus macaque. Doc Ophthalmol. 2012;125(3):179–194. https://doi.org/10.1007/s10633-012-9340-3

44. Yiu G., Tieu E., Munevar C. et al. In vivo multimodal imaging of drusenoid lesions in rhesus macaques. Sci Rep. 2017;7(1):15013. https://doi.org/10.1038/s41598-017-14715-z

45. Милюшина Л.А., Кузнецова А.В., Александрова М.А. Экспериментальные модели дегенеративно-дистрофических заболеваний сетчатки человека: индуцированные модели. Вестник Офтальмологии. 2013;129(3):94–97.

46. Koh A.E., Alsaeedi H.A., Rashid M.B.A. et al. Reti nal degeneration rat model: A study on the structural and functional changes in the reti na following injection of sodium iodate. J Photochem Photobiol B. 2019;196:111514. https://doi.org/10.1016/j.jphotobiol.2019.111514

47. Zhou R., Li Y., Qian H. et al. Sodium iodate-induced reti na and choroid damage model in rabbits to test efficacy of RPE auto-transplants. Investigative Ophthalmology & Visual Science September 2016;57:2253.

48. Balmer J., Zulliger R., Roberti S., Enzmann V. Reti nal cell death caused by sodium iodate involves multiple caspase-dependent and caspase-independent cell-death pathways. Int J Mol Sci. 2015;16(7):15086–15103. https://doi.org/10.3390/ijms160715086

49. Hariri S., Moayed A.A., Choh V., Bizheva K. In vivo assessment of thickness and reflectivity in a rat outer reti nal degeneration model with ultrahigh resolution optical coherence tomography. Invest Ophthalmol Vis Sci. 2012;53(4):1982–1989. https://doi.org/10.1167/iovs.11-8395

50. Kiuchi K., Yoshizawa K., Shikata N. et al. Morphologic characteristics of reti nal degeneration induced by sodium iodate in mice. Curr Eye Res. 2002;25(6):373–379. https://doi.org/10.1076/ceyr.25.6.373.14227

51. Hariri S., Tam M.C., Lee D. et al. Noninvasive imaging of the early effect of sodium iodate toxicity in a rat model of outer reti na degeneration with spectral domain optical coherence tomography. J Biomed Opt. 2013;18(2):26017. https://doi.org/10.1117/1.JBO.18.2.026017

52. Obata R., Yanagi Y., Tamaki Y. et al. Reti nal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits. Eye (Lond). 2005;19(4):464–468. https://doi.org/10.1038/sj.eye.6701531

53. Cha S., Choi K.E., Ahn J. et al. Electrical response of reti nal ganglion cells in an N-methyl-N-nitrosourea-induced retinal degeneration porcine model. Sci Rep. 2021;11(1):24135. https://doi.org/10.1038/s41598-021-03439-w

54. Sugano E., Tabata K., Takezawa T. et al. N-methyl-N-nitrosourea-induced photoreceptor degeneration is inhibited by nicotinamide via the blockade of upstream events before the phosphorylation of signalling proteins. Biomed Res Int. 2019;2019:3238719. https://doi.org/10.1155/2019/3238719

55. Tsuruma K., Yamauchi M., Inokuchi Y. et al. Role of oxidative stress in reti nal photoreceptor cell death in N-methyl-N-nitrosourea-treated mice. J Pharmacol Sci. 2012;118:351–362.

56. Rösch S., Werner C., Müller F., Walter P. Photoreceptor degene ration by intravitreal injection of N-methyl-N-nitrosourea (MNU) in rabbits: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2017;255:317–331.

57. Yoshizawa K., Yang J., Senzaki H. et al. Caspase-3 inhibitor rescues N -methyl- N -nitrosourea-induced reti nal degeneration in Sprague-Dawley rats. Exp Eye Res. 2000;71:629–635.

58. Niwa M., Aoki H., Hirata A. et al. Reti nal cell degeneration in animal models. Int J Mol Sci. 2016;17(1):110. https://doi.org/10.3390/ijms17010110

59. Fung F.K., Law B.Y., Lo A.C. Lutein attenuates both apoptosis and autophagy upon cobalt (II) chloride-induced hypoxia in rat műller cells. PLoS One. 2016;11(12):e0167828. https://doi.org/10.1371/journal.pone.0167828

60. Yaung J., Kannan R., Wawrousek E.F. et al. Exacerbation of reti nal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia. Exp Eye Res. 2008;86(2):355–365. https://doi.org/10.1016/j.exer.2007.11.007

61. Ahn S.M., Ahn J., Cha S. et al. The effects of intravitreal sodium iodate injection on reti nal degeneration following vitrectomy in rabbits. Sci Rep. 2019 30;9(1):15696. https://doi.org/10.1038/s41598-019-52172-y

62. Бикбов М.М., Файзрахманов Р.Р., Ярмухаметова А.Л. Возрастная макулярная дегенерация. М.: Апрель, 2013. 196 с.

63. Fisher S.K., Lewis G.P., Linberg K.A., Verardo M.R. Cellular remodeling in mammalian reti na: results from studies of experimental reti nal detachment. Prog Retin Eye Res 2005;24(3):395–431.

64. Rózanowska M., Sarna T. Light-induced damage to the reti na: role of rhodopsin chromophore revisited. Photochem Photo-biol. 2005;81(6):1305–1330. https://doi.org/10.1562/2004-11-13-IR-371

65. Zhao Z.C., Zhou Y., Tan G., Li J. Research progress about the effect and prevention of blue light on eyes. Int J Ophthalmol. 2018;11(12):1999–2003. https://doi.org/10.18240/ijo.2018.12.20

66. Wu J., Seregard S., Algvere P.V. Photochemical damage of the reti na. Surv Ophthalmol. 2006;51(5):461–481. https://doi.org/10.1016/j.survophthal.2006.06.009

67. Rezaie T., McKercher S.R., Kosaka K. et al. Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced reti nal degeneration. Invest Ophthalmol Vis Sci. 2012;53(12):7847–7854. https://doi.org/10.1167/iovs.12-10793

68. Song D., Song J., Wang C. et al. Berberine protects against light-induced photoreceptor degeneration in the mouse retina. Exp Eye Res. 2016;145:1–9. https://doi.org/10.1016/j.exer.2015.10.005

69. Wang Y., Zhao L., Lu F. et al. Retinoprotective effects of bilberry anthocyanins via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms in a visible light-induced retinal degeneration model in pigmented rabbits. Molecules. 2015;20(12):22395–22410. https://doi.org/10.3390/molecules201219785

70. Xiao Z., Xing Y., Zhao X. The experimental study on the model of argon laser-induced choroidal neovascularization in rabbits. Medical Journal of Wuhan University. 2005;26(3):343– 346.

71. Zhao S.H., He S.Z. [Study on the experimental model of krypton laser-induced choroidal neovascularization in the rats]. Zhonghua Yan Ke Za Zhi. 2003;39(5):298–302. (In Chinese.)

72. Cui J., Liu Y., Zhang J., Yan H. An experimental study on choroidal neovascularization induced by Krypton laser in rat model. Photomed Laser Surg. 2014;32(1):30–36. https://doi.org/10.1089/pho.2013.3588

73. Abdallah W.F., Zhang Y., Koss M.J. A novel model of choroidal neovascularization in rabbits. Investigative Ophthalmology & Visual Science 2014;55:4950.