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Cell Death Dis ; 8(7): e2922, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28703796

RESUMO

ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Retinose Pigmentar/patologia , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/análise , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/química , Células Fotorreceptoras/citologia , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/metabolismo , Precursores de Proteínas/análise , Precursores de Proteínas/metabolismo , Purinas/química , Purinas/farmacologia , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Retinose Pigmentar/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ureia/análogos & derivados , Ureia/química , Ureia/farmacologia
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