INHIBITORS OF P75NTR ARE EFFECTIVE THERAPEUTICS OF NEURODEGENERATION AND VASCULAR PERMEABILITY IN DIABETIC RETINOPATHY

BARCELONA PF; JMAEFF S; GALAN A; ESQUIVA G; CUENCA N; SARAGOVI HU

Montreal

Congreso; FRQS Vision Health Research Network 20th Annual Meeting; 2014

Vision Health Research Network

Goal: The p75NTR is a neurotrophin receptor that can carry out pleiotrophic actions, often opposite to each other. For example, during development p75NTR is responsible for neuronal pruning and death; and promotes neuronal survival in situations where neurotrophic support may be limiting. The signals and biological end-result depend on the cells in which p75NTR is expressed, the ligands which p75NTR might encounter, the level and type of physiological stress, and the relative levels of the p75NTR, and its ligand proNGF. Indeed, p75NTR is expressed at very low levels in healthy adult tissue, but it is up-regulated in many disease states. For example, Muller glial cells (glaucoma, retinitis pigmentosa), and around the neovasculature (retinopathy of prematurity) upregulate p75NTR. We have used drug-like pharmacological antagonists of p75NTR (small molecule inhibitor THX-B) or antagonists of the p75NTR ligand proNGF (neutralizing anti-proNGF mAb), administered therapeutically after disease onset. We studied the mechanism of action of p75NTR and its role in diabetes pathology, to potentially validate p75NTR as a druggable therapeutic target. Methodology: The animal model of type I diabetes is Streptozotocin (STZ) injections. Drug delivery is done by 1x intravitreal injection after disease onset. Endpoints are: Optical Coherence Tomography (FD-OCT), biochemical assays (western blot), and immunofluorescence in sections and flat-mounted retinas. Neuronal survival is quantified by TUNEL assay and by counting BRN3 labeled cells in whole retina. Vascular permeability and leakage is quantified by Evans Blue permeation. Time-dependent kinetic studies were done from 1 week to 6 weeks of diabetes. Results: We have shown that p75NTR is up-regulated in Muller glial cells, and it is responsible for the production of neurotoxic factors as TNF-α and α2M. p75NTR is also up-regulated in pericytes causing vascular dysfunction. Pharmacological inhibition of p75NTR or of the proNGF ligand normalizes cytokines level and prevents neuronal fiber loss, prevents RGC death and reduces vascular permeability and leakage. Conclusion (s): We propose that the p75NTR is a rheostat that dials in positive signals to support healthy tissue or negative signals to eliminate disease tissue. Some of the mechanisms are paracrine by regulation of glia and pericyte biology. In addition, increased p75NTR ligands (proNGF) during diabetes can also impact on the pathophysiology. Using p75NTR antagonists or proNGF antagonists, it may be possible to reset the system to homeostasis and ameliorate disorders with neuro-glia-vascular components such as diabetes. Funding: Supported by Canadian Institutes of Health Research (CIHR) and Foundation Fighting Blindness (FFB Canada)