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Prior research has demonstrated the therapeutic potential of peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist fenofibrate on diabetic retinopathy. In the present study, a novel non-fibrate PPAR alpha agonist, A190, was designed with higher potency and selectivity than fenofibrate in PPAR alpha agonism. A190 was encapsulated in biodegradable microparticles (A190-MP) to ensure sustained drug release, with detection in the retina up to 6 months following a single intravitreal injection. A190-MP alleviated retinal dysfunction as shown by electroretinography in Vldlr- /- (wet-AMD model) and Abca4- /- /Rdh8- /- (dry-AMD model) mice. A190-MP also attenuated the decreases in cone photoreceptor density and outer nuclear layer thickness as demonstrated by optical coherence tomography and histology. Moreover, A190-MP reduced vascular leakage and neovascularization in Vldlr- /- mice, suggesting an anti-inflammatory and anti-angiogenic effect. A190-MP upregulated expression of PPAR alpha, PGC1 alpha, and TOMM20 in the retina of Vldlr- /- and Abca4- /- /Rdh8- /- mice. A190MP also improved retinal mitochondrial function as shown by Seahorse analysis using retinal biopsy. In vitro, A190 attenuated oxidative stress and preserved cell viability in a photoreceptor-derived cell line exposed to 4HNE and improved mitochondrial function, via a PPAR alpha-dependent mechanism. These findings revealed sustained therapeutic effects of A190-MP in wet and dry AMD models, through improving mitochondrial function by activating PPAR alpha.
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JOURNAL OF CONTROLLED RELEASE
ISSN: 0168-3659
Year: 2025
Volume: 380
Page: 910-926
1 0 . 5 0 0
JCR@2023
CAS Journal Grade:1
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ESI Highly Cited Papers on the List: 0 Unfold All
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