New Nrf2-Inducer Compound ITH12674 Slows the Progression of Retinitis Pigmentosa in the Mouse Model rd10

Background/Aims: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. Methods: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood−brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. Results: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. Conclusion: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.This work was supported by grants from Bayer (Grats4Targets), from the Spanish Ministry of Economy and Competitiveness (MINECO-FEDER BFU2015-67139-R), Spanish Ministry of Education (FPU14/03166, FPU13/03737 and FPU16/04114), Instituto de Salud Carlos III co-financed by the European Regional Development’s funds (FEDER) (RETICS-FEDER RD16/0008/0016, Programa Miguel Servet II (CP16/00014) and research project (grant PI17/01700)), Asociación Retina Asturias, Fundación La Caixa, CaixaImpulse program (grant CI17-00048), Comunidad Autónoma de Madrid (grant B2017/BMD-3827), Generalitat Valenciana (PROMETEO/2016/158 and ACIF/2016/055) Generalitat Valenciana-FEDER IDIFEDER/2017/064