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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2023; 69(6): 33-42


SV Ziablitzev1, DB Zhupan1, OO Dyadyk2

  1. Bogomolets National Medical University, Kyiv, Ukraine
  2. Shupyk National University Healthcare of Ukraine, Kyiv, Ukraine


Diabetic retinopathy is a progressive tissue-specific neurovascular complication of diabetes with a multifactorial pathogenesis, in which microvascular disorders are preceded by damage to nerve elements. The latter begin with the early involvement of glia, including astrocytes and Müller cells. Taking into account the establishment of GABA-ergic deficiency, the use of modulators of the GABA-benzodiazepine receptor complex, for example, Carbacetam, which has shown satisfactory neuroprotective properties, seems promising. Diabetes mellitus was modeled by a single administration of streptozotocin (50 mg/kg; “Sigma-Aldrich”, China) to threemonth-old male Wistar rats. Already after 7 days, according to immunohistochemical detection of glial fibrillary acidic protein (GFAP), reactive gliosis of astrocytes of the inner retina layers was detected, to which Müller cells joined from the 14th day. The content of GFAP in retinal tissues increased significantly. GFAP-positive cells were in close contact with foci of pathological angiogenesis in the inner layers of the retina and also took part in the formation of fibrous proliferates in the outer layers. Detection of caspase-3 showed the activation of apoptosis in astrocytes and radial processes of Müller cells in the inner plexiform layer. Carbacetam in combination with insulin reduced the expression of GFAP and caspase-3 in the retina and prevented the development of reactive gliosis, angiogenesis, and the formation of fibrous proliferates, which makes it a candidate for further studies in the treatment of diabetic retinopathy.

Keywords: carbacetam; immunohistochemistry; immunoblotting; glial fibrillary acidic protein (GFAP); reactive gliosis; caspase-3; streptozotocin


  1. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S, Boyko EJ, Magliano DJ. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabet Res Clin Pract. 2022 Jan;183:109119. CrossRef PubMed
  2. Wong TY, Sabanayagam C. Strategies to tackle the global burden of diabetic retinopathy: from epidemiology to artificial intelligence. Ophthalmologica. 2020;243(1):9-20. CrossRef PubMed
  3. Wang W, Lo ACY. Diabetic Retinopathy: Pathophysiology and treatments. Int J Mol Sci. 2018 Jun 20;19(6):1816. CrossRef PubMed PubMedCentral
  4. Sinclair SH, Schwartz SS. Diabetic retinopathy-an underdiagnosed and undertreated inflammatory, neurovascular complication of diabetes. Front Endocrinol (Lausanne). 2019 Dec 13;10:843. CrossRef PubMed PubMedCentral
  5. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005 Jun;54(6):1615-25. CrossRef PubMed
  6. Simó R, Stitt AW, Gardner TW. Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia. 2018 Sep;61(9):1902-12. CrossRef PubMed PubMedCentral
  7. Grigsby JG, Cardona SM, Pouw CE, Muniz A, Mendiola AS, Tsin AT, Allen DM, Cardona AE. The role of microglia in diabetic retinopathy. J Ophthalmol. 2014;2014:705783. CrossRef PubMed PubMedCentral
  8. Sundstrom JM, Hernández C, Weber SR, Zhao Y, Dunklebarger M, Tiberti N, Laremore T, Simó-Servat O, GarciaRamirez M, Barber AJ, Gardner TW, Simó R. Proteomic analysis of early diabetic retinopathy reveals mediators of neurodegenerative brain diseases. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2264-74. CrossRef PubMed PubMedCentral
  9. Xu J, Chen LJ, Yu J, Wang HJ, Zhang F, Liu Q, Wu J. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell Physiol Biochem. 2018;48(2):705-17. CrossRef PubMed
  10. Rübsam A, Parikh S, Fort PE. Role of inflammation in diabetic retinopathy. Int J Mol Sci. 2018 Mar 22;19(4):942. CrossRef PubMed PubMedCentral
  11. Eggers ED. Visual dysfunction in diabetes. Annu Rev Vis Sci. 2023 May 10. CrossRef PubMed
  12. Al-Kuraishy HM, Al-Gareeb AI, Saad HM, Batiha GE. Benzodiazepines in Alzheimer's disease: beneficial or detrimental effects. Inflammopharmacology. 2023 Feb;31(1):221-30. CrossRef PubMed
  13. Wan H, Warburton EC, Zhu XO, Koder TJ, Park Y, Aggleton JP, Cho K, Bashir ZI, Brown MW. Benzodiazepine impairment of perirhinal cortical plasticity and recognition memory. Eur J Neurosci. 2004 Oct;20(8):2214-24. CrossRef PubMed
  14. Ziablitsev SV, Starodubska OO, Bogza SL. Influence of carbacetam on neurologic destruction processes under the experimental traumatic brain injury. J Educat Health Sport Form Health Sci. 2017;7(2):601-11.
  15. Kmet OG, Ziablitsev SV, Filipets ND, Kmet TI, Slobodian XV. Carbacetam effect on behavioral reactions in experimental Alzheimer's disease. Arch Balkan Med Union. 2019 Mar; 54(1):124-9. CrossRef
  16. Kmet OG, Ziablitsev SV, Filipets ND. Peculiarities of the antioxidant protection and nitrogen oxide systems of the brain in rats with experimental type 2 diabetes mellitus after carbacetam administration. Int J Endocrinol. 2019;15(5):376-80.
  17. Lelyte I, Ahmed Z, Kaja S, Kalesnykas G. Structure-function relationships in the rodent streptozotocin-induced model for diabetic retinopathy: A systematic review. J Ocul Pharmacol Ther. 2022 May;38(4):271-86. CrossRef PubMed PubMedCentral
  18. Proia AD, Caldwell MC. Intraretinal neovascularization in diabetic retinopathy. Arch Ophthalmol. 2010 Jan;128(1):142-4. CrossRef PubMed
  19. Wu D, Kanda A, Liu Y, Noda K, Murata M, Ishida S. Involvement of Müller glial autoinduction of TGF-β in diabetic fibrovascular proliferation via glial-mesenchymal transition. Invest Ophthalmol Vis Sci. 2020 Dec 1;61(14):29. CrossRef PubMed PubMedCentral
  20. Cheung AK, Fung MK, Lo AC, Lam TT, So KF, Chung SS, Chung SK. Aldose reductase deficiency prevents diabetes-induced blood-retinal barrier breakdown, apoptosis, and glial reactivation in the retina of db/db mice. Diabetes. 2005 Nov;54(11):3119-25. CrossRef PubMed
  21. Fresta CG, Fidilio A, Caruso G, Caraci F, Giblin FJ, Leggio GM, Salomone S, Drago F, Bucolo C. A New human blood-retinal barrier model based on endothelial cells, pericytes, and astrocytes. Int J Mol Sci. 2020 Feb 27;21(5):1636. CrossRef PubMed PubMedCentral
  22. Vujosevic S, Micera A, Bini S, Berton M, Esposito G, Midena E. Aqueous humor biomarkers of Müller cell activation in diabetic eyes. Invest Ophthalmol Vis Sci. 2015 Jun;56(6):3913-8. CrossRef PubMed
  23. Fletcher EL, Phipps JA, Ward MM, Puthussery T, Wilkinson-Berka JL. Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr Pharm Des. 2007;13(26):2699-712. CrossRef PubMed
  24. Lynch SK, Abràmoff MD. Diabetic retinopathy is a neurodegenerative disorder. Vis Res. 2017 Oct;139:101-7. CrossRef PubMed PubMedCentral
  25. Meshi A, Chen KC, You QS, Dans K, Lin T, Bartsch DU, Cheng L, Amador-Patarroyo MJ, Muftuoglu IK, Gomez ML, Nudleman E, Freeman WR. Anatomical and functional testing in diabetic patients without retinopathy: Results of optical coherence tomography angiography and visual acuity under varying contrast and luminance conditions. Retina. 2019 Oct;39(10):2022-31. CrossRef PubMed PubMedCentral
  26. Pitale PM, Gorbatyuk MS. Diabetic retinopathy: From animal models to cellular signaling. Int J Mol Sci. 2022 Jan 27;23(3):1487. CrossRef PubMed PubMedCentral
  27. Eggers ED, Carreon TA. The effects of early diabetes on inner retinal neurons. Vis Neurosci. 2020 Sep 16;37:E006. CrossRef PubMed PubMedCentral
  28. Castilho Á, Ambrósio AF, Hartveit E, Veruki ML. Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus. J Neurosci. 2015 Apr 1;35(13):5422-33. CrossRef PubMed PubMedCentral
  29. Lee YJ, Kim M, Lee JY, Jung SH, Jeon HY, Lee SA, Kang S, Han ET, Park WS, Hong SH, Kim YM, Ha KS. The benzodiazepine anesthetic midazolam prevents hyperglycemia-induced microvascular leakage in the retinas of diabetic mice. FASEB J. 2018 May 21:fj201800014RR. CrossRef PubMed
  30. Fang W, Huang X, Wu K, Zong Y, Yu J, Xu H, Shi J, Wei J, Zhou X, Jiang C. Activation of the GABA-alpha receptor by berberine rescues retinal ganglion cells to attenuate experimental diabetic retinopathy. Front Mol Neurosci. 2022 Aug 9;15:930599. CrossRef PubMed PubMedCentral
  31. Ali SA, Zaitone SA, Dessouki AA, Ali AA. Pregabalin affords retinal neuroprotection in diabetic rats: Suppression of retinal glutamate, microglia cell expression and apoptotic cell death. Exp Eye Res. 2019 Jul;184:78-90. CrossRef PubMed
  32. Al-Kuraishy HM, Al-Gareeb AI, Saad HM, Batiha GE. Benzodiazepines in Alzheimer's disease: beneficial or detrimental effects. Inflammopharmacology. 2023 Feb;31(1):221-30. CrossRef PubMed

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