INHIBITORS OF P75-NTR PREVENT NEURONAL CELL DEATH, GLIAL ACTIVATION, AND PERICYTE DEATH, AND ARE EFFECTIVE THERAPEUTICS OF RETINAL NEURODEGENERATION AND RETINAL VASCULAR DISORDERS

BARCELONA PF; SAPIEHA M; SITARAS N; EL REMESY A; BAI Y; NEDEV H; DE LA ROSA EJ ; SARAGOVI HU

Montreal

Congreso; FRQS Vision Health Research Network 19th Annual Meeting; 2013

Vision Health Research Network

Goal: The p75NTR is a neurotrophin receptor that can carry out multiple and pleiotrophic actions, often opposite to each other. The signals and end-results depend on the cells in which p75NTR is expressed, the ligands which p75NTR might encounter, the level of physiological stress, and whether or not the tissue expressing p75NTR has been compromised. For example, during development p75NTR is responsible for neuronal pruning and death; and for neuronal survival in situations where neurotrophic support may be limiting. After birth, the p75NTR is expressed at very low levels in healthy tissue, but it is up-regulated in disease. Indeed, in many models of retinal diseases, p75NTR is up-regulated in glia and Muller cells (glaucoma, retinitis pigmentosa), and in pericytes and the neovasculature (diabetes, retinopathy of prematurity). We have used drug-like small molecule pharmacological antagonists of p75NTR, administered after disease onset, to study the mechanism of action of this receptor, its role in disease progression, and to validate p75NTR as a potential therapeutic target. Methodology: Animal models of disease are established : Optic Nerve Transection, Glaucoma Model and Intraocular Pressure, Induction of Diabetic Model, Model of Oxygen-induced retinopathy. Drug delivery is done by intravitreal injection 1-time after disease onset. Endpoints are measured by: Optical Coherence Tomography (FD-OCT), biochemical assays, and Immunohistochemistry. Neuronal survival is quantified by counting Fluorogold labeled cells, and histology. Results: We have shown that in glaucoma p75NTR up-regulated in glia and Muller cells is responsible for the production of neurotoxic factors TNF-a and a2M. Pharmacological inhibition of p75NTR during glaucoma normalizes these cytokines and prevents RGC death. Likewise, in a genetic model of Retinitis Pigmentosa pharmacological inhibition of p75NTR preserves the photoreceptors and the structure of the retina, and might also preserve the Pigmented Epithelium. During diabetic retinopathy, we have shown that p75NTR is etiological in the death of pericytes and leakiness in blood vessels. During diabetic retinopathy, pharmacological inhibition of p75NTR prevents vascular death and pericyte death, and prevents vascular edema. During retinopathy of prematurity, pharmacological inhibition of p75NTR prevents vaso-obliteration and the consequent vaso-proliferative rebound which is pathological. Conclusion : 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, the bioavailability of the multiple ligands of p75NTR (proNTFs and mature NTFs) during disease can also impact on the physiology. Using p75NTR antagonists, it may be possible to attempt novel therapies for diseases with neuro-glia-vascular components such as glaucoma or diabetes. Funding: Canadian Institutes of Health Research (CIHR) and Foundation Fighting Blindness (FFB Canada)