title: Inhibition of cerebral vascular inflammation by brain endothelium-targeted oligodeoxynucleotide complex.
abstract: The present study generated a novel DNA complex to specifically target endothelial NF-κB to inhibit cerebral vascular inflammation. This DNA complex (GS24-NFκB) contains a DNA decoy which inhibits NF-κB activity, and a DNA aptamer (GS-24), a ligand of transferrin receptor (TfR), which allows for targeted delivery of the DNA decoy into cells. The results indicate that GS24-NFκB was successfully delivered into a murine brain-derived endothelial cell line, bEND5, and inhibited inflammatory responses induced by tumor necrosis factor α (TNF-α) or oxygen-glucose deprivation/re-oxygenation (OGD/R) via down-regulation of the nuclear NF-κB subunit, p65, as well as its downstream inflammatory cytokines, inter-cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). The inhibitory effect of the GS24-NFκB was demonstrated by a significant reduction in TNF-α or OGD/R induced monocyte adhesion to the bEND5 cells after GS24-NFκB treatment. Intravenous (i.v.) injection of GS24-'NFκB (15mg/kg) was able to inhibit the levels of phoseph-p65 and VCAM-1 in brain endothelial cells in a mouse lipopolysaccharide (LPS)-induced inflammatory model in vivo. In conclusion, our approach using DNA nanotechnology for DNA decoy delivery could potentially be utilized for inhibition of inflammation in ischemic stroke and other neuro-inflammatory diseases affecting cerebral vasculature.
authors.affiliation: Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Daniah
authors.initials: D
authors.lastname: Al-Waili
authors.affiliation: Department of Pediatrics, University of Cincinnati & Cincinnati Children's Hospital Medical Center, USA.
authors.forename: Aishlin
authors.initials: A
authors.lastname: Hassan
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, University of Cincinnati & Cincinnati Children's Hospital Medical Center, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xin
authors.affiliation: Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA. Electronic address: haojn@ucmail.uc.edu.
authors.forename: Jiukuan
authors.initials: J
authors.lastname: Hao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D052157:Aptamers, Nucleotide / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D005947:Glucose / Q000172:deficiency; D006041:Goats; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha; D020293:Vasculitis, Central Nervous System / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D052157:Aptamers, Nucleotide; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose
keywords: NF-κB; aptamer; endothelial cells; inflammation; lipopolysaccharide; oxygen-glucose deprivation