Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of Reactive Gliosis in the Retina of Rats with Streptozotocin-Induced Diabetes under the Action of Hydrated C60 Fullerene

  • Published:
Neurophysiology Aims and scope

Reactive gliosis induced by metabolic disturbances and development of oxidative stress in the retina at diabetes mellitus is the key pathogenetic factor for the development of diabetic retinopathy. Fullerene C60 and some of its water-soluble derivates are known as rather potent antioxidants displaying neuroprotective capacities during the development of a number of pathologies and harmful influences on the organism. In our study, effects of nanostructures of hydrated C60 fullerene (C60HyFn) on the content and polypeptide composition of glial fibrillary acidic protein (GFAP) in the rat retina under conditions of streptozotocin (STZ)-induced diabetes were evaluated for the first time. Using immunoblotting, strong (more than twofold) up-regulation of GFAP expression in the diabetic rat retina, as compared with the control, was shown (P < 0.01). This was a result of activation of retinal glial cells induced by hyperglycemia. Increased GFAP immunolabeling that was indicative of reactive gliosis in the retina of diabetic rats was also confirmed immunohystochemically. Consumption of C60HyFn solution (60 nM) in drinking water by diabetic rats for 12 weeks caused a significant decrease in the GFAP level in comparison with that in untreated diabetic animals (P < 0.05). In addition, C60HyFn caused statistically significant lowering of the glycated hemoglobin concentration in blood serum of STZ-diabetic rats (P < 0.05). However, it exerted no effects on the insulin and glucose levels in blood of diabetic rats. Our results demonstrated that hydrated C60 fullerene as a potential high-efficacy retinoprotective agent within the initial period of diabetic retinopathy; it significantly suppresses activation of retinal macroglia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. E. Rungger-Brändle, A. A. Dosso, and P. M. Leuenberger, “Glial reactivity, an early feature of diabetic retinopathy,” Invest. Ophthalmol. Vis. Sci., 41, No. 7, 1971-1980 (2000).

    PubMed  Google Scholar 

  2. A. Ebneter and M. S. Zinkernagel, “Novelties in diabetic retinopathy,” Endocr. Dev., 31, 84–96 (2016).

    PubMed  Google Scholar 

  3. R. Klein, B. E. K. Klein, and S. E. Moss, “Epidemiology of proliferative diabetic retinopathy,” Diabetes Care, 15, No. 12, 1875-1891 (1992).

  4. B. Liu, X. Ma, D. Guo, et al., “Neuroprotective effect of alpha-lipoic acid on hydrostatic pressure-induced damage of retinal ganglion cells in vitro,” Neurosci. Lett., 526, No. 1, 24-28 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. V. S. Nedzvetskii, G. A. Ushakova, S. G. Busygina, et al., “Effects of small doses of ionizing radiation on intermediate filaments and Ca2+-activated system of proteolysis in the rat brain,” Radiobiologiya, 31, No. 3, 333-339 (1991).

  6. R. Dringen, P. G. Pawlowski, and J. Hirrlinger, “Peroxide detoxification by brain cells,” J. Neurosci. Res., 79, Nos. 1-2, 157-165 (2005).

  7. M. A. Di Leo, G. Ghirlanda, N. Gentiloni Silveri, et al., “Potential therapeutic effect of antioxidants in experimental diabetic retina: a comparison between chronic taurine and vitamin E plus selenium supplementations,” Free Radic. Res., 37, No. 3, 323-330 (2003).

    Article  PubMed  Google Scholar 

  8. V. Nedzvetsky, G. Andrievsky, T. Chachibaia, and A. Tykhomyrov, “Differences in antioxidant/protective efficacy of hydrated C60 fullerene nanostructures in liver and brain of rats with streptozotocin-induced diabetes,” J. Diabetes Metab., 3, No. 8, 1-9 (2012).

    Article  Google Scholar 

  9. G. Andrievsky, V. I. Bruskov, A. A. Tykhomyrov, and S. V. Gudkov, “Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostuctures in vitro and in vivo,” Free Radical Biol. Med., 47, No. 6, 786-793 (2009).

    Article  CAS  Google Scholar 

  10. J. Ryan, H. R. Bateman, A. Stover, et al., “Fullerene nanomaterials inhibit the allergic response,” J. Immunol., 179, No. 1, 665-672 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. T. Mori, S. Ito, M. Namiki, et al., “Involvement of free radicals followed by the activation of phospholipase A2 in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: Comparison of the therapeutic potential of fullerene, mepacrine, and cooling,” Toxicology, 236, No. 3, 149-157 (2007).

  12. R. Bal, G. Türk, M. Tuzcu, et al., “Protective effects of nanostructures of hydrated C(60) fullerene on reproductive function in streptozotocin-diabetic male rats,” Toxicology, 282, No. 3, 69-81 (2011).

  13. T. Baati, F. Bourasset, N. Gharbi, et al., “The prolongation of the lifespan of rats by repeated oral administration of [60]fullerene,” Biomaterials, 33, No. 19, 4936-4946 (2012).

  14. M. M. Bradford, “A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding,” Anal. Biochem., 72, 248-254 (1976).

    Article  CAS  PubMed  Google Scholar 

  15. U. K. Laemmli, “Cleavage of structural proteins during the assembly of the head of bacteriophage T4,” Nature, 227, No. 5259, 680-685 (1970).

  16. K. Canene-Adams, “Preparation of formalin-fixed paraffin-embedded tissue for immunohistochemistry,” Methods Enzymol., 533, 225-233 (2013).

  17. G. V. Andrievsky, V. K. Klochkov, E. L. Karyakina, and N. O. Mchedlov-Petrossyan, “Studies of aqueous colloidal solutions of fullerene C60 by electron microscopy,” Chem. Phys. Lett., 300, Nos. 3-4, 392-396 (1999).

  18. A. Tura, F. Schuettauf, P. P. Monnier, et al., “Efficacy of Rho-kinase inhibition in promoting cell survival and reducing reactive gliosis in the rodent retina,” Invest. Ophthalmol. Vis. Sci., 50, No. 1, 452-461 (2009).

    Article  PubMed  Google Scholar 

  19. M. Sugaya-Fukasawa, T. Watanabe, M. Tamura, et al., “Glial fibrillary acidic protein is one of the key factors underlying neuron-like elongation in PC12 cells,” Exp. Ther. Med., 2, No. 1, 85-87 (2011).

    CAS  PubMed  Google Scholar 

  20. A. M. Joussen, S. Doehmen, M. L. Le, et al., “TNF-α mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations,” Mol. Vis., 15, 1418-1428 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. L. P. Aiello, A. Clermont, V. Arora, et al., “Inhibition of PKC by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients,” Invest. Ophthalmol. Vis. Sci., 47, No. 1, 86-92 (2006).

    Article  PubMed  Google Scholar 

  22. V. Haurigot, P. Villacampa, A. Ribera, et al., “Increased intraocular insulin-like growth factor-I triggers bloodretinal barrier breakdown,” J. Biol. Chem., 284, No. 34, 22961-22969 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. A. Hennis, S. Y. Wu, B. Nemesure, et al., “Hypertension, diabetes, and longitudinal changes in intraocular pressure ,” Ophthalmology, 110, No. 5, 908-914 (2003).

  24. H. Zong, M. Ward, and A. W. Stitt, “AGEs, RAGE, and diabetic retinopathy,” Curr. Diabetes Rep., 11, No. 4, 244-252 (2011).

    Article  Google Scholar 

  25. B. E. K. Klein, M. D. Knudtson, M. Y. Tsai, and R. Klein, “The relation of markers of inflammation and endothelial dysfunction to the prevalence and progression of diabetic retinopathy: Wisconsin epidemiologic study of diabetic retinopathy,” Arch. Ophthalmol., 127, No. 9, 1175-1182 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. E. Lieth, A. J. Barber, B. Xu, et al., “Glial reactivity and impaired flutamate metabolism in short-term experimental diabetic retinopathy,” Diabetes, 47, No. 5, 815-820 (1998).

  27. J. L. Wilkinson-Berka, “Angiotensin and diabetic retinopathy,” Int. J. Biochem. Cell Biol., 38, Nos. 5-6, 752-765 (2006).

  28. W.-K. Ju, K-Y. Kim, Y. H. Noh, et al, “Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes,” Glia, 63, No. 5, 736-753 (2015).

  29. P. Mamczur, B. Borsuk, J. Paszko, et al., “Astrocyteneuron crosstalk regulates the expression and subcellular localization of carbohydrate metabolism enzymes,” Glia, 63, No. 2, 328-340 (2015).

  30. B. S. Ganesh and S. K. Chintala, “Inhibition of reactive gliosis attenuates excitotoxicity-mediated death of retinal ganglion cells,” PLoS One, 6, No. 3, e18305 (2011).

  31. K. R. Hegde, S. Kovtun, and S. D. Varma, “Inhibition of glycolysis in the retina by oxidative stress: prevention by pyruvate,” Mol. Cell Biochem., 343, Nos. 1-2, 101-105 (2010).

  32. L. Pellerin and P. J. Magistretti, “Sweet sixteen for ANLS,” J. Cerebr. Blood Flow Metab., 32, No. 7, 1152-1166 (2012).

    Article  CAS  Google Scholar 

  33. M. V. Sofroniew, “Molecular dissection of reactive astrogliosis and glial scar formation,” Trends Neurosci., 32, No. 12, 638-647 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Q. J. Wang, “PKD at the crossroads of DAG and PKC signaling,” Trends Pharmacol. Sci., 27, No. 6, 317-323 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. D. Koya and G. L. King, “Protein kinase C activation and the development of diabetic complications,” Diabetes, 47, No. 6, 859-866 (1998).

  36. L. P. Aiello, S. E. Bursell, A. Clermont, et al., “Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform-selective inhibitor,” Diabetes, 46, No. 9, 1473-1480 (1997).

  37. Q. Li and D. G. Puro, “Diabetes-induced dysfunction of the glutamate transporter in retinal Muller cells,” Invest. Ophthalmol. Vis. Sci., 43, No. 9, 3109-3116 (2002).

    PubMed  Google Scholar 

  38. G. Baydas, V. S. Nedzvetskii, S. V. Kirichenko, and P. A. Nerush, “Astrogliosis in the hippocampus and cortex and cognitive deficits in rats with streptozotocin-induced diabetes: effects of melatonin,” Neurophysiology, 40, No. 2, 91-97 (2008).

  39. M. Ulas, C. Orhan, M. Tuzcu, et al., “Anti-diabetic potential of chromium histidinate in diabetic retinopathy rats,” BMC Complement. Alternat. Med., 15:16, 1-8 (2015).

  40. A. A. Tykhomyrov, V. S. Nedzvetsky, V. K. Klochkov, and G. V. Andrievsky, “Nanostructures of hydrated C60 fullerene (C60HyFn) protect rat brain against alcohol impact and attenuate behavioral impairments of alcoholized animals,” Toxicology, 246, Nos. 2-3, 158-165 (2008).

  41. S. Ye, T. Zhou, K. Cheng, et al., “Carboxylic acid fullerene (C60) derivatives attenuated neuroinflammatory responses by modulating mitochondrial dynamics,” Nanoscale Res. Lett., 10, No. 1, 953 (2015).

  42. F. Fluri, D. Grünstein, E. Cam, et al., “Fullerenols and glucosamine fullerenes reduce infarct volume and cerebral inflammation after ischemic stroke in normotensive and hypertensive rats,” Exp. Neurol., 265, 142-151 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. D. Giust, T. Da Ros, M. Martín, and J. L. Albasanz, “[60]Fullerene derivative modulates adenosine and metabotropic glutamate receptors gene expression: a possible protective effect against hypoxia,” J. Nanobiotechnol., 12, 27 (2014).

    Article  Google Scholar 

  44. L. L. Dugan, L. Tian L, K. L. Quick, et al., “Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates,” Ann. Neurol., 76, No. 3, 393-402 (2014).

  45. E. G. Makarova, R. Y. Gordon, and I. Y. Podolski, “Fullerene C60 prevents neurotoxicity induced by intrahippocampal microinjection of amyloid-beta peptide,”J. Nanosci. Nanotechnol., 12, No. 1, 119-126 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. A. G. Bobylev, N. V. Pen’kov, P. A. Troshin, and S. V. Gudkov, “Effect of dilution on aggregation of nanoparticles of polycarboxylic derivative of fullerene C60,” Biofizika, 60, No. 1, 38-43 (2015).

  47. Y. Cheng, J. Qu, Y. Chen, et al., “Anterior segment neovascularization in diabetic retinopathy: a masquerade,” PLos One., 10, No. 6, e0123627 (2015).

  48. I. Suárez, G. Bodega, M. Rubio, et al., “Astroglial induction of in vivo angiogenesis,” J. Neural. Transplant. Plast., 5, No. 1, 1-10 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  49. N. J. Coorey, W. Shen, S. H. Chung, et al., “The role of glia in retinal vascular disease,” Clin. Exp. Optom., 95, No. 3, 266-281 (2012).

    Article  PubMed  Google Scholar 

  50. D. A. Antonetti, R. Klein, and T. W. Gardner, “Diabetic retinopathy,” New Engl. J. Med., 366, No. 13, 1227-1239 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. B. A. Barres, “The mystery and magic of glia: a perspective on their roles in health and disease,” Neuron, 60, No. 3, 430-440 (2008).

  52. S. M. Tan, D. Deliyanti, W. A. Figgett, et al., “Ebselen by modulating oxidative stress improves hypoxiainduced macroglial Müller cell and vascular injury in the retina,” Exp. Eye Res., 136, 1-8 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. R. Pazdro and J. R. Burgess, “The role of vitamin E and oxidative stress in diabetes complications,” Mech. Ageing Dev., 131, No. 4, 276-286 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. T. Jiang, Q. Chang, Z. Zhao, et al., “Melatonin-mediated cytoprotection against hyperglycemic injury in Müller cells,” PLoS One, 7, No. 12, e50661 (2012).

  55. S. Yamagishi, S. Maeda, T. Matsui, et al., “Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes,” Biochim. Biophys. Acta, 1820, No. 5, 663-671 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oles’ Gonchar Dnipropetrovs’k National University, Dnipropetrovs’k, Ukraine

    V. S. Nedzvetskii & I. V. Pryshchepa

  2. Palladin Institute of Biochemistry of the NAS of Ukraine, Kyiv, Ukraine

    A. A. Tykhomyrov

  3. Bingol University, Bingol, Turkey

    G. Baydas

Authors
  1. V. S. Nedzvetskii
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. V. Pryshchepa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. A. Tykhomyrov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Baydas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to V. S. Nedzvetskii, I. V. Pryshchepa or G. Baydas.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nedzvetskii, V.S., Pryshchepa, I.V., Tykhomyrov, A.A. et al. Inhibition of Reactive Gliosis in the Retina of Rats with Streptozotocin-Induced Diabetes under the Action of Hydrated C60 Fullerene. Neurophysiology 48, 130–140 (2016). https://doi.org/10.1007/s11062-016-9579-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11062-016-9579-5

Keywords

Search

Navigation