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JP4-039, a Mitochondria-Targeted Nitroxide, Mitigates the Effect of Apoptosis and Inflammatory Cell Migration in the
Jennifer O Adeghate1, Michael W Epperly2, Katherine Anne Davoli1
1Department of Ophthalmology, University of Pittsburgh School of Medicine and UPMC Vision Institute, UPMC Mercy Pavilion, Pittsburgh, PA 15219, USA.
Abstract:
We hypothesize that the injection of JP4-039, a mitochondria-targeted nitroxide, prior to irradiation of the mouse retina may decrease apoptosis and reduce neutrophil and macrophage migration into the retina. In our study, we aimed to examine the effects of JP4-039 in the mouse retina using fluorescent microscopy, a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and flow cytometry. Forty-five mice and one eye per mouse were used. In Group 1, fluorescent microscopy was used to determine retinal uptake of 10 µL (0.004 mg/µL) of intravitreally injected BODIPY-labeled JP4-039 at 0, 15, and 60 min after injection. In Group 2, the TUNEL assay was performed to investigate the rate of apoptosis after irradiation in addition to JP4-039 injection, compared to controls. In Group 3, flow cytometry was used to determine the extent of inflammatory cell migration into the retina after irradiation in addition to JP4-039 injection, compared to controls. Maximal retinal uptake of JP4-039 was 15 min after intravitreal injection (p < 0.0001). JP4-039-treated eyes had lower levels of retinal apoptosis (35.8 ± 2.5%) than irradiated controls (49.0 ± 2.7%; p = 0.0066) and demonstrated reduced migration of N1 cells (30.7 ± 11.7% vs. 77.7 ± 5.3% controls; p = 0.004) and M1 cells (76.6 ± 4.2 vs. 88.1 ± 3.7% controls, p = 0.04). Pretreatment with intravitreally injected JP4-039 reduced apoptosis and inflammatory cell migration in the irradiated mouse retina, marking the first confirmed effect of this molecule in retinal tissue. Further studies may allow for safety profiling and potential use for patients with radiation retinopathy.
Insights
Mitochondria-targeted JP4-039, when injected into the mouse eye before radiation, significantly reduced retinal cell death and inflammatory cell infiltration. This study confirms JP4-039
Area of Science:
- Ophthalmology and Vision Science
- Radiation Biology
- Mitochondrial Medicine
Background:
- Radiation therapy can cause retinal damage, leading to apoptosis and inflammation.
- Mitochondria-targeted antioxidants may offer protective effects against radiation-induced injury.
- JP4-039 is a novel mitochondria-targeted nitroxide with potential radioprotective properties.
Purpose of the Study:
- To investigate the efficacy of JP4-039 in mitigating radiation-induced retinal damage in a mouse model.
- To assess the impact of JP4-039 on retinal apoptosis and inflammatory cell infiltration post-irradiation.
Main Methods:
- Mice received intravitreal injections of JP4-039 or a control solution.
- Retinal uptake of fluorescently labeled JP4-039 was assessed using fluorescent microscopy.
- Apoptosis was quantified using the TUNEL assay, and inflammatory cell migration (neutrophils and macrophages) was analyzed by flow cytometry.
Main Results:
- Maximal retinal uptake of JP4-039 was observed at 15 minutes post-injection.
- JP4-039 treatment significantly reduced retinal apoptosis compared to irradiated controls (35.8% vs. 49.0%).
- JP4-039 significantly decreased the migration of N1 (neutrophil) and M1 (macrophage) cells into the retina.
Conclusions:
- Pretreatment with intravitreally injected JP4-039 effectively reduces apoptosis and inflammatory cell infiltration in the irradiated mouse retina.
- This study provides the first evidence of JP4-039's protective effects in retinal tissue.
- JP4-039 shows promise as a therapeutic agent for preventing radiation retinopathy, warranting further safety and efficacy studies.
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