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Identifier 000417363
Title Investigation of new therapeutic targets for the treatment of diabetic retinopathy : Neurosteroids/Microneurotrophins
Alternative Title Μελέτη νέων θεραπευτικών στόχων για την αντιμετώπιση της διαβητικής αμφιβληστροειδοπάθειος
Author Iban Arias, Ruth
Thesis advisor Θερμού, Κυριακή
Reviewer Γραβάνης, Αχιλλέας
Τσιλιμπάρης, Μιλτιάδης
Καραγωγέως, Δόμνα
Λιαπάκης, Γιώργος
Χαραλαμπόπουλος, Ιωάννης
Νικολετοπούλου, Βασιλική
Abstract Diabetic Retinopathy (DR) is a major ocular complication of diabetes that leads to suboptimal visual acuity and blindness. This disease has been characterized by three pathogenic processes that underlie the mechanisms leading to retinal cell death, namely, inflammation, neurodegeneration and microangiopathy. Standard therapies for DR rely on laser surgery and intravitreal injections of corticosteroids or anti-angiogenic factors like antivascular endothelial growth factor (VEGF) agents, which inhibit and/or reverse the vascular damage. These therapies are effective but have various side effects. New pharmacological approaches are essential in order to treat the inflammatory and neurodegenerative components of the disease. In the present study, we investigated the putative use of the neurosteroidal microneurotrophin BNN27, a 17-spiro DHEA analogue, as a potential therapeutic agent for the treatment of DR. BNN27 has been described as a microneurotrophin given that it is a small-sized molecule and acts as a Nerve Growth Factor (NGF) mimetic that binds specifically to its receptors, TrkA and p75 neurotrophin receptors. Furthermore, it is highly lipophilic, thus able to penetrate the blood brain barrier and it is not metabolized to estrogens or androgens. Employing the STZ-rat model of DR, BNN27 was administered at three doses, 2, 10 and 50mg/kg, either intraperitoneally or by eye-drops, 4 weeks post-STZ-injection for 7 days. We demonstrated the ability of BNN27 to exert its neuroprotective properties to the diabetic retina despite sustained high glucose levels in diabetic rats. BNN27 restored the STZ-induced attenuation of bNOS- and TH-immunoreactivity (IR; retinal amacrine cell markers) and NFL-IR (ganglion cell axon marker) when administered both intraperitoneally and as eye drops. This was further substantiated by the BNN27- dependent activation/phosphorylation of the NGF TrkA receptor. Moreover, a specific TrkA receptor antagonist reversed BNN27's actions. These data strongly suggest that BNN27 mediates its pharmacological pro-survival actions in the diabetic rat retina by activating specifically the NGF TrkA receptor. BNN27 also attenuated the expression of p75NTR death receptor in the diabetic retina when administered intraperitoneally. However, it did not reverse the diabetes-induced increase in TUNEL+ retinal cells but it did attenuate the diabetes-induced activation of cleaved caspase-3. BNN27 also reduced the diabetes-induced up-regulation of the GFAP protein, expressed in Müller macroglial cells and the number of Iba-1-expressing microglia. Finally, BNN27 restored retinal homeostasis after the diabetes induced imbalance between the two isoforms of NGF, mature NGF and immature proNGF, in the diabetic rat retina. In conclusion, the microneurotrophin BNN27 exerts neuroprotective actions to the diabetic rat retina when administered either intraperitoneally or by eye drops. BNN27 was shown to specifically target retinal neurons and glial cells, acting as a pro-survival and antiinflammatory agent, respectively. It displays the pharmacological profile needed to address the neurodegenerative and inflammatory parameters that characterize DR. Our results advocate that this novel microneurotrophin, BNN27, has the potential to become a “lead” molecule for the treatment for DR.
Language English
Subject Neurotrofic receptors
Issue date 2018-07-18
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work
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