Effect of topical administration of the microneurotrophin BNN27 in the diabetic rat retina
Diabetic retinopathy (DR) is a complex eye disease associated with diabetes mellitus. It is characterized by three pathophysiological components, namely microangiopathy, neurodegeneration, and inflammation. We recently reported that intraperitoneal administration of BNN27, a novel neurosteroidal microneurotrophin, reversed the diabetes-induced neurodegeneration and inflammation in rats treated with streptozotocin (STZ), by activating the NGF TrkA and p75 receptors. The aim of the present study was to investigate the efficacy of BNN27 to protect retinal neurons when applied topically as eye drops in the same model.
The STZ rat model of DR was employed. BNN27 was administered as eye drops to diabetic Sprague-Dawley rats for 7 days, 4 weeks post-STZ (70 mg/kg) injection. Immunohistochemistry and western blot analyses were employed to examine the viability of retinal neurons in control, diabetic, and diabetic-treated animals and the involvement of the TrkA receptor and its downstream signaling ERK1/2 kinases, respectively.
BNN27 reversed the STZ-induced attenuation of the immunoreactive brain nitric oxide synthetase (bNOS)- and tyrosine hydroxylase (TH)-expressing amacrine cells and neurofilament (NFL)-expressing ganglion cell axons in a dose-dependent manner. In addition, BNN27 activated/phosphorylated the TrkA receptor and its downstream prosurvival signaling pathway, ERK1/2 kinases.
The results of this study provide solid evidence regarding the efficacy of BNN27 as a neuroprotectant to the diabetic retina when administered topically, and suggest that its pharmacodynamic and pharmacokinetic profiles render it a putative therapeutic for diabetic retinopathy.
KeywordsRetinal disease Nerve growth factor TrkA receptor Neurodegeneration Neuroprotection ERK1/2 kinases
KT conceived, designed the experiments, interpreted the data, wrote the manuscript, and supervised the project and is the guarantor of this study. RIA performed experiments, analyzed and interpreted the data, and wrote the manuscript with KT. SL performed experiments, and analyzed and interpreted the data. SP and NM performed experiments and analyzed the data. IC interpreted data and edited the manuscript. AG edited the manuscript. All authors significantly revised, edited, and read the final version of the manuscript.
This study was co-financed by a grant to K.T from the European Union (European Social Fund-ESF) and Greek National Funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) – Research Funding Program: ARISTEIA II.
Compliance with ethical standards
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Conflict of interest
Dr. Achille Gravanis is the co-founder of Bionature EA LTD, proprietor of compound BNN27 (patented with the WO 2008/1555 34 A2 number at the World Intellectual Property Organization). Dr. Ioannis Charalampopoulos has a patent WO 2008/1555 34 A2 with royalties paid. All other authors have no conflict of interest.
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