New Nrf2-Inducer Compound ITH12674 Slows the Progression of Retinitis Pigmentosa in the Mouse Model rd10.
Por:
Campello L, Kutsyr O, Noailles A, Michalska P, Fernández-Sánchez L, Martínez-Gil N, Ortuño-Lizarán I, Sánchez-Sáez X, de Juan E, Lax P, León R, García AG, Cuenca N and Maneu V
Publicada:
7 feb 2020
Resumen:
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-a and NF-?B; (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.
Filiaciones:
Campello L:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Kutsyr O:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
Noailles A:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
Michalska P:
Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain
Fernández-Sánchez L:
Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, Alicante, Spain
Martínez-Gil N:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
Ortuño-Lizarán I:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
Sánchez-Sáez X:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
de Juan E:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
:
Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain
García AG:
Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain
:
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
Maneu V:
Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, Alicante, Spain,
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