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author:

Cui, Yi (Cui, Yi.) [1] | Poudel, Sagun (Poudel, Sagun.) [2] | Xu, Nuo (Xu, Nuo.) [3] | Zhou, Kelu (Zhou, Kelu.) [4] | Cheng, Rui (Cheng, Rui.) [5] | Liang, Wentao (Liang, Wentao.) [6] | Yuan, Tian (Yuan, Tian.) [7] | Zhao, Long (Zhao, Long.) [8] | Qin, Chaolong (Qin, Chaolong.) [9] | Stevens, Katelyn G. (Stevens, Katelyn G..) [10] | Duerfeldt, Adam S. (Duerfeldt, Adam S..) [11] | Hu, Jianzhang (Hu, Jianzhang.) [12] | Xu, Qingguo (Xu, Qingguo.) [13] | Ma, Jian-xing (Ma, Jian-xing.) [14]

Indexed by:

EI SCIE

Abstract:

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.

Keyword:

AMD Neuroprotection Ocular drug delivery PLGA PPAR alpha Sustained-release

Community:

  • [ 1 ] [Cui, Yi]Fujian Med Univ, Dept Ophthalmol, Union Hosp, Fuzhou 350001, Peoples R China
  • [ 2 ] [Hu, Jianzhang]Fujian Med Univ, Dept Ophthalmol, Union Hosp, Fuzhou 350001, Peoples R China
  • [ 3 ] [Cui, Yi]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA
  • [ 4 ] [Xu, Nuo]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA
  • [ 5 ] [Zhou, Kelu]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA
  • [ 6 ] [Cheng, Rui]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA
  • [ 7 ] [Liang, Wentao]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA
  • [ 8 ] [Yuan, Tian]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA
  • [ 9 ] [Ma, Jian-xing]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA
  • [ 10 ] [Poudel, Sagun]Virginia Commonwealth Univ, Dept Pharmaceut, Richmond, VA 23298 USA
  • [ 11 ] [Zhao, Long]Virginia Commonwealth Univ, Dept Pharmaceut, Richmond, VA 23298 USA
  • [ 12 ] [Qin, Chaolong]Virginia Commonwealth Univ, Dept Pharmaceut, Richmond, VA 23298 USA
  • [ 13 ] [Xu, Qingguo]Virginia Commonwealth Univ, Dept Pharmaceut, Richmond, VA 23298 USA
  • [ 14 ] [Xu, Nuo]Fuzhou Univ, Fujian Med Univ, Fujian Prov Hosp, Dept Ophthalmol,Shengli Clin Med Coll,Affiliated P, Fuzhou 350001, Peoples R China
  • [ 15 ] [Stevens, Katelyn G.]Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55414 USA
  • [ 16 ] [Duerfeldt, Adam S.]Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55414 USA
  • [ 17 ] [Xu, Qingguo]Virginia Commonwealth Univ, Ctr Pharmaceut Engn, Massey Canc Ctr, Dept Ophthalmol Pediat Biomed Engn, Richmond, VA 23298 USA
  • [ 18 ] [Xu, Qingguo]Virginia Commonwealth Univ, Inst Struct Biol Drug Discovery & Dev ISB3D, Massey Canc Ctr, Richmond, VA 23298 USA

Reprint 's Address:

  • [Hu, Jianzhang]Fujian Med Univ, Dept Ophthalmol, Union Hosp, Fuzhou 350001, Peoples R China;;[Ma, Jian-xing]Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27101 USA

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Source :

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

Cited Count:

WoS CC Cited Count:

SCOPUS Cited Count:

ESI Highly Cited Papers on the List: 0 Unfold All

WanFang Cited Count:

Chinese Cited Count:

30 Days PV: 0

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