DOI: https://doi.org/10.29296/24999490-2023-05-08

N.V. Balatskaya, D.V. Fadeev, M.V. Zueva, N.V. Neroeva
FSBI "National Medical Research Center for Eye Diseases named after Helmholtz" Ministry of Health of Russia,
Russian Federation, Moscow, 105062, st. Sadovaya-Chernogryazskaya, 14/19

Introduction. Recently, a new approach to visual response has been discussed, based on the use of optical signals of a heavy structure, manifested by fractal dynamics. However, the molecular mechanisms of action of fractal phototherapy (FF) have not been studied. Purpose of the study: to study the effect of low-intensity fractal optical stimulation on the intraocular production of neurotrophic cytokines in an in vivo experiment. Material and methods. The material for the study was the vitreous body (VH), isolated from the enucleated eyes of 17 healthy Soviet Chinchilla rabbits. 14 animals, depending on the duration of FF courses, were divided into five groups. 3 rabbits (6 eyes) made up the control group. In this work we used an original device for conducting FF in laboratory animals with two emitters. Photostimulation sessions were carried out daily. The duration of each FF session was 20 minutes. The duration of FF courses for different rabbits ranged from 7 to 180 days. Using enzyme immunoassay, the concentrations of 5 mediators were determined in vitreous samples: brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), interleukin(IL)-6, IL-1β and pigment epithelium dependent factor (PEDF). The results were recorded using a Cytation 5 multifunctional photometer. Results. BDNF and PEDF were detected in 100% of ST test samples of the main and control groups of animals. IL-1β and CNTF were absent in all biomaterial samples. In only one case, IL-6 was detected in a small concentration in the material from an experimental eye at late stages of FF. This work was the first to study the dynamics of intraocular production of neurotrophic factors under the influence of fractal photostimulation. Individual analysis demonstrated multidirectional changes in PEDF concentration (relative to normal levels) in the early stages of FF, namely: An increase in the intraocular content of this cytokine was observed in approximately 17% of experimental eyes after the 7th session, while the BDNF value was in the normal range. Conclusion. For the first time, local production of neurotrophic factors in intact eyes was studied. The features of the dynamics of neurotrophic factors depending on the duration of FF were studied. It has been shown that FF has stimulating activity (with an accumulative effect) on local BDNF production. The data obtained seem important for the development of the FF method and its translation into the clinic for visual rehabilitation of patients with neurodegenerative diseases of the retina and indicate the need for further research into the molecular mechanisms that realize the biological effects of FF.
BDNF, CNTF, IL-1β, IL-6, PEDF, fractal phototherapy, visual rehabilitation

Список литературы: 
  1. Нероев В.В., Нероева Н.В., Зуева М.В., Катаргина Л.А., Цапенко И.В., Илюхин П.А., Лосанова О.А., Кармокова А.Г., Рогов С.В. Электроретинографические признаки ремоделирования сетчатки после индукции атрофии ретинального пигментного эпителия в эксперименте. Вестник офтальмологии. 2021; 137 (4): 24–30. DOI: 10.17116/oftalma202113704124
  2. [Neroev V.V., Neroeva N.V., Zueva M.V., Katargina L.A., Tsapenko I.V., Ilyukhin P.A., Losanova O.A., Karmokova A.G., Rogov S.V. Electroretinographic signs of remodeling retina after induction of atrophy of the retinal pigment epithelium in the experiment. The Russian Annals of Ophthalmology. Vestnik Oftalmologii. 2021; 137 (4): 24–30 (in Russian)] DOI: 10.17116/oftalma202113704124
  3. Cuenca N., Fernández-Sánchez L., Campello L., Maneu V., De la Villa P., Lax P., Pinilla I. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res. 2014; 43: 17–75. DOI: 10.1016/j.preteyeres.2014.07.001.
  4. Serruyaa M.D., Kahana M.J. Techniques and devices to restore cognition. Behav Brain Res. 2008; 192 (2): 149. DOI: 10.1016/j.bbr.2008.04.007
  5. Sabel B.A., Flammer J., Merabet L.B. Residual vision activation and the brain-eye-vascular triad: dysregulation, plasticity and restoration in low vision and blindness – a review. Restor Neurol Neurosci. 2018; 36: 767–91. DOI: 10.3233/RNN-180880.
  6. Gidday J.M. Adaptive plasticity in the retina: Protection against acute injury and neurodegenerative disease by conditioning stimuli. Cond Med. 2018; 1 (2): 85–97.
  7. Zueva M.V. Fractality of sensations and the brain health: the theory linking neurodegenerative disorder with distortion of spatial and temporal scale-invariance and fractal complexity of the visible world. Front Aging Neurosci. 2015; 7: 135. DOI: 10.3389/fnagi.2015.00135
  8. Зуева М.В., Каранкевич А.И., стимулятор сложноструктурированными оптическими сигналами и способ его использования, номер патента: RU 2 680 185 C1, Бюл. № 5 от 18.02.2019.
  9. [Zueva M.V., Karankevich A.I., Stimulator with complex-structured optical signals and method for operation thereof, patent number: RU 2 680 185 C1, Bull. № 5, 18.02.2019 (in Russian)]
  10. Goldberger A.L., Amaral L.A.N., Hausdorff J.M., Ivanov P.Ch., Peng C.-K., Stanley H.E. Fractal dynamics in physiology: Alterations with disease and aging. Proc. Nat. Acad. Sci. 2002; 99 (1): 2466–72. DOI: 10.1073/pnas.012579499.
  11. Зуева М.В., Ковалевская М.А., Донкарева О.В., Каранкевич А.И., Цапенко И.В., Таранов А.А., Антонян В.Б. Фрактальная фототерапия в нейропротекции глаукомы. Офтальмология. 2019; 16 (3): 317–28. DOI: 10.18008/1816-5095-2019-3-317-328
  12. [Zueva M.V., Kovalevskaya M.A., Donkareva O.V., Karankevich A.I., Tsapenko I.V., Taranov A.A., Antonyan V.B. Fractal phototherapy in the neuroprotection of glaucoma. Ophthalmology. 2019; 16 (3): 317–28 (in Russian)]
  13. Zueva M., Spiridonov I., Semenova N., Tsapenko I., Maglakelidze N., Stadelman J. The LED fractal stimulator and first evidence of its application in electroretinography. Doc. Ophthalmologica. 2017; 135 (1): 35–6.
  14. Huang E.J., Reichardt L.F, Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001; 24: 677–736. DOI: 10.1146/annurev.neuro.24.1.677.
  15. Vecino E., Heller J.P., Veiga-Crespo P., Martin K.R., Fawcett J.W. Influence of extracellular matrix components on the expression of integrins and regeneration of adult retinal ganglion cells. PLoS One. 2015; 10 (5): e0125250. DOI: 10.1371/journal.pone.0125250.
  16. Muste J.C, Russell M.W., Singh R.P. Photobiomodulation Therapy for Age-Related Macular Degeneration and Diabetic Retinopathy: A Review, 2021; 15: 3709–20.
  17. Mishra I.R. Knerr M., Stewart1 A.A., Payette W.I., Richter M.M., Ashley Light N.T. at night disrupts diel patterns of cytokine gene expression and endocrine profiles in zebra finch (Taeniopygia guttata), Sci Rep. 2019; 9 (1): 15833. DOI: 10.1038/s41598-019-51791-9
  18. Alcalá-Barraza S.R., Lee M.S., Hanson L.R., McDonald A.A., Frey W.H. 2nd, McLoon L.K. Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS. J. Drug Target. 2010; 18 (3): 179–90. DOI: 10.3109/10611860903318134.
  19. Porciatti V., Ventura L.M. Retinal Ganglion Cell Functional Plasticity and Optic Neuropathy: A Comprehensive Model. J. Neuroophthalmol. 2012; 32 (4): 354–8. DOI: 10.1097/WNO.0b013e3182745600
  20. ARVO Statement for the Use of Animals in Ophthalmic and Visual Research, http://www.arvo.org/about_arvo/policies/statement_for_the_use_of_animals_in_ophthalmic_and_visual_research/, Accessed 2016
  21. Ma Y.T., Hsieh T., Forbes M.E., Johnson J.E., Frost D.O. BDNF injected into the superior colliculus reduces developmental retinal ganglion cell death. J. Neurosci. 1998; 18: 2097–107. DOI: 10.1523/JNEUROSCI.18-06-02097.1998
  22. Binley K.E., Ng W.S., Barde Y.A., Song B., Morgan J.E. Brain-derived neurotrophic factor prevents dendritic retraction of adult mouse retinal ganglion cells. Eur. J. Neurosci. 2016; 44 (3): 2028–39. DOI: 10.1111/ejn.13295
  23. Harada C., Azuchi Y., Noro T., Guo X., Kimura A., Namekata K., Harada T. TrkB signaling in retinal glia stimulates neuroprotection after optic nerve injury. Am. J. Pathol. 2015; 185 (12): 3238–47. DOI: 10.1016/j.ajpath.2015.08.005
  24. Mui A.M., Yang V., Aung M.H., Fu J., Adekunle A.N., Prall B.C., Sidhu C.S., Park H., Boatright J.H., Iuvone P.M., Pardue M.T., Daily visual stimulation in the critical period enhances multiple aspects of vision through BDNF-mediated pathways in the mouse retina. PLoS ONE 2018; 13 (2): e0192435. DOI: 10.1371/journal.pone.0192435
  25. Barnstable C.J., Tombran-Tink J. Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential. Prog Retin Eye Res. 2004; 23: 561–77.
  26. Tombran-Tink J., Chader G.G., Johnson L.V. PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity". Experimental Eye Research. 53 (3): 411–4. DOI: 10.1016/0014-4835(91)90248-D
  27. He J., Neumann D., Kakazu A., Pham T.L, Musarrat F., Cortina M.S., Bazan H.E.P. PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection. Exp Eye Res. 2017; 161: 153–62. DOI: 10.1016/j.exer.2017.06.015