1. The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes.
- Author
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Ibán-Arias R, Lisa S, Mastrodimou N, Kokona D, Koulakis E, Iordanidou P, Kouvarakis A, Fothiadaki M, Papadogkonaki S, Sotiriou A, Katerinopoulos HE, Gravanis A, Charalampopoulos I, and Thermos K
- Subjects
- Amacrine Cells immunology, Amacrine Cells metabolism, Amacrine Cells pathology, Animals, Anti-Inflammatory Agents administration & dosage, Axons drug effects, Axons immunology, Axons metabolism, Axons pathology, Dehydroepiandrosterone administration & dosage, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental physiopathology, Diabetic Retinopathy immunology, Diabetic Retinopathy metabolism, Diabetic Retinopathy pathology, Dose-Response Relationship, Drug, Eye Proteins agonists, Eye Proteins metabolism, Female, Ganglia, Sensory drug effects, Ganglia, Sensory immunology, Ganglia, Sensory metabolism, Ganglia, Sensory pathology, Male, Nerve Tissue Proteins agonists, Nerve Tissue Proteins metabolism, Neuroglia drug effects, Neuroglia immunology, Neuroglia metabolism, Neuroglia pathology, Neuroprotective Agents administration & dosage, Phosphorylation drug effects, Protein Processing, Post-Translational drug effects, Rats, Sprague-Dawley, Receptor, Nerve Growth Factor agonists, Receptor, Nerve Growth Factor metabolism, Receptor, trkA metabolism, Retina immunology, Retina pathology, Retina physiopathology, Streptozocin, Amacrine Cells drug effects, Anti-Inflammatory Agents therapeutic use, Dehydroepiandrosterone therapeutic use, Diabetic Retinopathy prevention & control, Neuroprotective Agents therapeutic use, Receptor, trkA agonists, Retina drug effects
- 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 [p75
NTR ]). 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., (© 2017 by the American Diabetes Association.)- Published
- 2018
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