title: Sustained inhibition of neovascularization in vldlr-/- mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-κB pathway.
abstract: Cerium oxide nanoparticles (nanoceria) are direct antioxidants; they inhibit pathological neovascularization following a single intravitreal injection into new born very low density lipoprotein receptor knockout (vldlr(-/-)) mice. However, the long-term therapeutic effects and mechanisms of nanoceria action on regression of the existing pathologic neovascularization in the eyes are unknown. We intravitreally injected P28 vldlr(-/-) mice and extended the endpoint for analysis until P70. The data demonstrate that nanoceria sustained their therapeutic function up to 6 weeks. Multiple parameters for nanoceria effects were examined including: regression of existing abnormal blood vessels, reduction of vascular leakage, down-regulation of the expression of vascular endothelial growth factor (VEGF), acrolein, glial fibrillary acidic protein (GFAP) and caspase 3 as well as up-regulation of the expression of rod- and cone-opsin genes. Regulation of ASK1-P38/JNK-NF-κB signaling pathway by nanoceria was investigated. Our data demonstrated that a single intravitreal injection of nanoceria in P28 vldlr(-/-) mice produced sustained regression of existing oxidative stress-induced neovascularizations, prevented blood vessel leakage and inhibited apoptosis via down-regulation of the ASK1-P38/JNK-NF-κB signaling pathway.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: xue-cai@ouhsc.edu.
authors.forename: Xue
authors.initials: X
authors.lastname: Cai
authors.forename: Sudipta
authors.initials: S
authors.lastname: Seal
authors.forename: James F
authors.initials: JF
authors.lastname: McGinnis
mesh_terms: D000818:Animals; D002563:Cerium / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D053758:Nanoparticles; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D014822:Vitreous Body; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D011973:Receptors, LDL; C036053:VLDL receptor; D002563:Cerium; C030583:ceric oxide; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5
keywords: Nanoceria; Neovascularization; Retinal degeneration; Signal transduction; vldlr(−/−) mouse