A NOVEL THERAPEUTIC TARGET FOR NEURODEGENERATION AND VASCULAR DAMAGE IN RETINOPATHIES

BARCELONA PF

Mar del Plata

Congreso; SAN 2017 (XXXII Congreso Anual de Sociedad Argentina de Investigacion en Neurociencias; 2017

Sociedad Argentina de Investigacion en Neurociencias

A novel therapeutic target for neurodegeneration and vascular damage in Retinopathies. Propose: The p75NTR is a neurotrophin receptor, which promotes neuronal pruning and death. In the healthy adult retina, p75NTR and proNGF are expressed at very low levels, but they are up regulated in many neovascular and neurodegenerative diseases. Here, we studied the mechanism of action of p75NTR and its ligand in the modulation of vascular and neurodegenerative events on Retinopathies. Methods: Drug-like pharmacological antagonists of p75NTR or biological antagonists of proNGF (anti-proNGF mAb), were administered after disease onset of retinopathy animal models. Drug delivery was performed using various rout of administration. At optimized endpoints we quantify retinal structure by FD-OCT, p75NTR signals by measured TNFα, receptor and ligand kinetics expression by IF, in situ hibridization and biochemical analyses. Neuronal survival was analyzed by TUNEL assay and by counting of BRN3 labeled cells in whole retina. Finally, vascular permeability were quantified by Evans Blue extravasation. Results: p75NTR was up-regulated in Muller glial cells, and it was responsible for promoting production of neurotoxic cytokines such as TNFα and α2M which kill RGCs. In vasculature p75NTR also was up-regulated. The kinetics of p75NTR expression correlated with the disease progression. Pharmacological inhibition of p75NTR or proNGF normalized the levels of neurotoxic cytokines, prevented neuronal fiber loss and RGC death and reduced vascular permeability and decreased retinal avascular area and neovascularization. Conclusion: In retinopathies, the p75NTR mechanisms showed a paracrine regulation on glia and vasculature, impacting on health RGC. Using p75NTR or proNGF antagonists, it was possible to ameliorate the neuronal as well as the vascular components. These studies validate p75NTR as a druggable therapeutic target for retinopathies and potentially for other diseases of the nervous system.