PMID- 23112571
OWN - NLM
STAT- MEDLINE
DCOM- 20130129
LR  - 20220310
IS  - 1090-0535 (Electronic)
IS  - 1090-0535 (Linking)
VI  - 18
DP  - 2012
TI  - Amelioration of endotoxin-induced uveitis treated with an IkappaB kinase beta inhibitor 
      in rats.
PG  - 2586-97
AB  - PURPOSE: Endotoxin-induced uveitis (EIU) is an animal model for acute ocular 
      inflammation. Several substances play major roles in the development of 
      inflammatory changes in EIU, including tumor necrosis factor-alpha (TNF-alpha), 
      interleukin (IL)-1beta, and IL-6. These inflammatory cytokines trigger the 
      degradation of IkappaB by activating IkappaB kinases (IKKs). Released nuclear factor 
      kappaB (NFkappaB) subsequently translocates to the nucleus, where NFkappaB expresses its 
      proinflammatory function. IMD-0354, 
      N-(3,5-Bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide, selectively 
      inhibits IKKbeta, particularly when induced by proinflammatory cytokines, such as 
      TNF-alpha and IL-1beta. In the present study, we examined whether IKKbeta inhibition has 
      therapeutic effects on EIU by using IMD-0354 and its prodrug IMD-1041. METHODS: 
      Six-week-old male Lewis rats were used. EIU was induced with subcutaneous 
      injections of 200 mug of lipopolysaccharide (LPS) from Escherichia coli that had 
      been diluted in 0.1 ml of phosphate-buffered saline. IMD-0354 was administered 
      intraperitoneally at 30, 10, 3, or 0 mg/kg, suspended in 1.0 ml of 0.5% 
      carboxymethyl cellulose sodium. The prodrug IMD-1041 (100 mg/kg) was also 
      administered orally. The rats were euthanized 24 h after LPS injection, and EIU 
      severity was evaluated histologically. The number of infiltrating cells and the 
      protein, TNF-alpha, and monocyte chemoattractant protein-1 (MCP-1) concentrations in 
      the aqueous humor were determined. TNF-alpha and MCP-1 concentrations were quantified 
      with enzyme-linked immunosorbent assay. Eye sections were also stained with 
      anti-NFkappaB and phosphorylated I-kappaBalpha antibodies. RESULTS: The number of 
      infiltrating cells in aqueous humor was 53.6+/-9.8x10(5), 72.5+/-17.0x10(5), 
      127.25+/-32.0x10(5), and 132.0+/-25.0x10(5) cells/ml in rats treated with 30, 10, 3, 
      or 0 mg/kg of IMD-0354, respectively. The total protein concentrations of aqueous 
      humor were 92.6+/-3.1 mg/ml, 101.5+/-6.8 mg/ml, 112.6+/-1.9 mg/ml, and 117.33+/-1.8 mg/ml 
      in rats treated with 30, 10, 3, and 0 mg/kg of IMD-0354, respectively. 
      Infiltrating cells and protein concentrations were significantly decreased by 
      treatment with IMD-0354 (p<0.01). IMD-0354 treatment significantly reduced the 
      concentration of TNF-alpha (p<0.05) and MCP-1 (p<0.01) in aqueous humor. The number 
      of NFkappaB positive nuclei was reduced when treated with IMD-0354. Furthermore, 
      IMD-0354-treated EIU rats showed only background levels of phosphorylated I-kappaBalpha; 
      however, it was strongly expressed in the iris-ciliary body cell cytoplasm of the 
      IMD-0354 untreated EIU rats. Oral administration of IMD-1041 also decreased the 
      cell number (p<0.01) and protein concentration (p<0.05) of aqueous humor in EIU. 
      CONCLUSIONS: Acute uveitis was ameliorated by inhibition of IKKbeta in rats. 
      IMD-0354 and its prodrug IMD-1041 seem to be promising candidates for treating 
      intraocular inflammation/uveitis.
FAU - Lennikov, Anton
AU  - Lennikov A
AD  - Laboratory of Ocular Cell Biology and Visual Science, Department of 
      Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
FAU - Kitaichi, Nobuyoshi
AU  - Kitaichi N
FAU - Noda, Kousuke
AU  - Noda K
FAU - Ando, Ryo
AU  - Ando R
FAU - Dong, Zhenyu
AU  - Dong Z
FAU - Fukuhara, Junichi
AU  - Fukuhara J
FAU - Kinoshita, Satoshi
AU  - Kinoshita S
FAU - Namba, Kenichi
AU  - Namba K
FAU - Mizutani, Miho
AU  - Mizutani M
FAU - Fujikawa, Tomoyuki
AU  - Fujikawa T
FAU - Itai, Akiko
AU  - Itai A
FAU - Ohno, Shigeaki
AU  - Ohno S
FAU - Ishida, Susumu
AU  - Ishida S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121020
PL  - United States
TA  - Mol Vis
JT  - Molecular vision
JID - 9605351
RN  - 0 (Benzamides)
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Endotoxins)
RN  - 0 (NF-kappa B)
RN  - 0 (Prodrugs)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 76145IS906 (N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Aqueous Humor/*drug effects/immunology
MH  - Benzamides/*pharmacology/therapeutic use
MH  - Chemokine CCL2/genetics/immunology
MH  - Dose-Response Relationship, Drug
MH  - Endotoxins
MH  - Gene Expression/drug effects
MH  - I-kappa B Kinase/*antagonists & inhibitors/metabolism
MH  - Injections, Intraperitoneal
MH  - Male
MH  - NF-kappa B/genetics/immunology
MH  - Neutrophil Infiltration/drug effects
MH  - Phosphorylation/drug effects
MH  - Prodrugs/*pharmacology/therapeutic use
MH  - Protein Kinase Inhibitors/*pharmacology/therapeutic use
MH  - Rats
MH  - Rats, Inbred Lew
MH  - Tumor Necrosis Factor-alpha/genetics/immunology
MH  - Uveitis/chemically induced/*drug therapy/immunology/pathology
PMC - PMC3482174
EDAT- 2012/11/01 06:00
MHDA- 2013/01/30 06:00
PMCR- 2012/01/01
CRDT- 2012/11/01 06:00
PHST- 2012/05/05 00:00 [received]
PHST- 2012/11/18 00:00 [accepted]
PHST- 2012/11/01 06:00 [entrez]
PHST- 2012/11/01 06:00 [pubmed]
PHST- 2013/01/30 06:00 [medline]
PHST- 2012/01/01 00:00 [pmc-release]
AID - 268 [pii]
PST - ppublish
SO  - Mol Vis. 2012;18:2586-97. Epub 2012 Oct 20.