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ProNGF signaling through p75 NTR  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 p75 NTR  in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75 NTR  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  α  2 -macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75 NTR  was assessed in organotypic retinal cultures from  rd10  and  RhoP  mouse models. Retinal explants treated with p75 NTR  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 TNF α  secretion. Use of p75 NTR  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 p75 NTR /proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.

p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa