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Pharmacology and Therapeutics

The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes

  1. Ruth Ibán-Arias1,
  2. Silvia Lisa1,
  3. Niki Mastrodimou1,
  4. Despina Kokona1,
  5. Emmanuil Koulakis1,
  6. Panagiota Iordanidou1,
  7. Antonis Kouvarakis2,
  8. Myrto Fothiadaki1,
  9. Sofia Papadogkonaki1,
  10. Aggeliki Sotiriou1,
  11. Haralambos E. Katerinopoulos3,
  12. Achille Gravanis1,4,
  13. Ioannis Charalampopoulos1 and
  14. Kyriaki Thermos1⇑
  1. 1Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete, Greece
  2. 2Laboratory of Environmental Chemical Processes, Department of Chemistry, University of Crete, Heraklion, Crete, Greece
  3. 3Organic Chemistry, Department of Chemistry, University of Crete, Heraklion, Crete, Greece
  4. 4Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology-Hellas, University of Crete, Crete, Greece
  1. Corresponding author: Kyriaki Thermos, thermos{at}uoc.gr.
Diabetes 2018 Feb; 67(2): 321-333. https://doi.org/10.2337/db17-0391
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Abstract

BNN27, a C17-spiroepoxy derivative of DHEA, was shown to have antiapoptotic properties via mechanisms involving the nerve growth factor receptors (tropomyosin-related kinase A [TrkA]/neurotrophin receptor p75 [p75NTR]). In this study, we examined the effects of BNN27 on neural/glial cell function, apoptosis, and inflammation in the experimental rat streptozotocin (STZ) model of diabetic retinopathy (DR). The ability of BNN27 to activate the TrkA receptor and regulate p75NTR expression was investigated. BNN27 (2,10, and 50 mg/kg i.p. for 7 days) administration 4 weeks post–STZ injection (paradigm A) reversed the diabetes-induced glial activation and loss of function of amacrine cells (brain nitric oxide synthetase/tyrosine hydroxylase expression) and ganglion cell axons via a TrkA receptor (TrkAR)-dependent mechanism. BNN27 activated/phosphorylated the TrkAY490 residue in the absence but not the presence of TrkAR inhibitor and abolished the diabetes-induced increase in p75NTR expression. However, it had no effect on retinal cell death (TUNEL+ cells). A similar result was observed when BNN27 (10 mg/kg i.p.) was administered at the onset of diabetes, every other day for 4 weeks (paradigm B). However, BNN27 decreased the activation of caspase-3 in both paradigms. Finally, BNN27 reduced the proinflammatory (TNFα and IL-1β) and increased the anti-inflammatory (IL-10 and IL-4) cytokine levels. These findings suggest that BNN27 has the pharmacological profile of a therapeutic for DR, since it targets both the neurodegenerative and inflammatory components of the disease.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0391/-/DC1.

  • S.L. is currently affiliated with the Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León, University of Salamanca, and Institute of Biomedical Research, Salamanca, Spain. D.K. is currently affiliated with the Department of Ophthalmology, Inselspital, Bern, Switzerland.

  • Received March 29, 2017.
  • Accepted November 18, 2017.
  • © 2017 by the American Diabetes Association.
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The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes
Ruth Ibán-Arias, Silvia Lisa, Niki Mastrodimou, Despina Kokona, Emmanuil Koulakis, Panagiota Iordanidou, Antonis Kouvarakis, Myrto Fothiadaki, Sofia Papadogkonaki, Aggeliki Sotiriou, Haralambos E. Katerinopoulos, Achille Gravanis, Ioannis Charalampopoulos, Kyriaki Thermos
Diabetes Feb 2018, 67 (2) 321-333; DOI: 10.2337/db17-0391

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The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes
Ruth Ibán-Arias, Silvia Lisa, Niki Mastrodimou, Despina Kokona, Emmanuil Koulakis, Panagiota Iordanidou, Antonis Kouvarakis, Myrto Fothiadaki, Sofia Papadogkonaki, Aggeliki Sotiriou, Haralambos E. Katerinopoulos, Achille Gravanis, Ioannis Charalampopoulos, Kyriaki Thermos
Diabetes Feb 2018, 67 (2) 321-333; DOI: 10.2337/db17-0391
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