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New Nrf2-Inducer Compound ITH12674 Slows the Progression of Retinitis Pigmentosa in the Mouse Model rd10
Laura Campello1,2, Oksana Kutsyr1, Agustina Noailles1
1Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain.
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.
Insights
A novel compound, ITH12674, demonstrated significant neuroprotection in a mouse model of retinitis pigmentosa. This Nrf2 inducer slowed retinal degeneration, preserving vision and photoreceptor integrity, suggesting a new therapeutic avenue.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Oxidative stress and inflammation are key drivers of retinal degenerative diseases.
- ITH12674 is a novel compound that activates Nrf2, exhibiting antioxidant, anti-inflammatory, and neuroprotective properties.
- Retinitis pigmentosa (RP) is a group of inherited retinal diseases causing progressive vision loss.
Purpose of the Study:
- To investigate the therapeutic potential of ITH12674 in slowing retinal degeneration in rd10 mice, an animal model of RP.
- To evaluate the effects of ITH12674 on retinal function, photoreceptor survival, and inflammatory markers.
Main Methods:
- rd10 mice were treated with ITH12674 (1 or 10 mg/Kg) or placebo from P16 to P30.
- Retinal function and visual acuity were assessed using electroretinography and optomotor tests.
- Photoreceptor morphology, oxidative stress, inflammation, and microglia reactivity were analyzed using immunohistochemistry, Western blot, and flow cytometry.
Main Results:
- Treatment with 10 mg/Kg ITH12674 preserved visual function, evidenced by improved scotopic a- and b-waves and enhanced visual acuity.
- The compound maintained cone photoreceptor morphology and synaptic connectivity.
- ITH12674 reduced markers of inflammation (TNF-α, NF-κB) and microglia activation, while increasing p38 MAPK and Atg12-Atg5 complex expression.
Conclusions:
- ITH12674 demonstrates significant neuroprotective effects in a mouse model of retinitis pigmentosa.
- Nrf2 inducer compounds represent a promising therapeutic strategy for combating retinal neurodegeneration.
- Further chemical optimization of ITH12674 is underway to enhance its neuroprotective potential for retinal diseases.
