March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Amelioration Of Endotoxin-induced Uveitis Treated With An Ikb Kinase Inhibitor, Imd-0354 In Rats
Author Affiliations & Notes
  • Anton Lennikov
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
  • Nobuyoshi Kitaichi
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
    Department of ophthalmology, Health Sciences University of Hokkaido, Sapporo, Japan
  • Kosuke Noda
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
  • Ryo Ando
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
  • Zhenyu Dong
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
  • Kenichi Namba
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
  • Kenichi Namba
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
  • Shigeaki Ohno
    Department of Ocular Inflammation and Immunology,
    Hokkaido University, Sapporo, Japan
  • Susumu Ishida
    Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology,
    Hokkaido University, Sapporo, Japan
  • Footnotes
    Commercial Relationships  Anton Lennikov, None; Nobuyoshi Kitaichi, None; Kosuke Noda, None; Ryo Ando, None; Zhenyu Dong, None; Kenichi Namba, None; Kenichi Namba, None; Shigeaki Ohno, None; Susumu Ishida, None
  • Footnotes
    Support  Japan Society for the Promotion of Science (JSPS); Ministry of Education, Culture, Sports, Science, and Technology (MEXT); and the Mishima Memorial Foundation, Japan.
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 6276. doi:https://doi.org/
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      Anton Lennikov, Nobuyoshi Kitaichi, Kosuke Noda, Ryo Ando, Zhenyu Dong, Kenichi Namba, Kenichi Namba, Shigeaki Ohno, Susumu Ishida; Amelioration Of Endotoxin-induced Uveitis Treated With An Ikb Kinase Inhibitor, Imd-0354 In Rats. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6276. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose:
 

Endotoxin-induced uveitis (EIU) is an animal model for acute ocular inflammation. Nuclear factor-kappa B (NF-ΚB) plays a key role to induce inflammation. Inactive NF-ΚB complexed with inhibitor of kappa B (IΚB) and activated by degradation of IΚB by IΚB kinases (IKKs). IMD-0354 is one of the IKK inhibitors which down-regulates NF-ΚB activation. In the present study, we examined whether administration of new IKKβ inhibitor IMD-0354 has therapeutic effects on EIU in rats.

 
Methods:
 

Six-week-old male Lewis rats were used. EIU was induced by subcutaneous injection of 200 μg of LPS from Escherichia Coli. Immediately, rats were administered 30, 10, 3 or 0 mg/kg of body weight of IMD-0354 intraperitoneally. At 24 hours after LPS injection, the aqueous humor was collected. Total aqueous protein concentrations were quantified and cell numbers were counted. Also eyes were fixed with PFA 4% via intracardial injection and immunohistochemically stained with anti-NFΚB antibodies.

 
Results:
 

Aqueous protein concentrations were 92.5±5.3, 101.5±11.7, 112.6±3.2 and 117.3±3.0 µg/ml in rats treated with 30, 10, 3 or 0 mg/kg of IMD-0354, respectively. It was significantly lower in rats treated with 30 mg/kg and 10 mg/kg of IMD-0354 compared with controls (P<0.01). Mean aqueous protein concentration was 21.5±4.7 in naïve rats. The numbers of inflammatory cells in aqueous humor were 46.4±16.8, 68.25±30.1, 128.41±54.9, and 133.3±44.0 in rats treated with 30, 10, 3 or 0 mg/kg of IMD-0354, respectively. Significantly fewer aqueous inflammatory cells were counted in rats treated with 30 and 10 mg/kg of IMD-0354 than controls (P<0.05). NF-ΚBp65 positive nuclei (yellow) in ciliary body were detected as 249.0±27.8 in untreated eyes (Image 1,B), but only 146.6±3.0 in 30 mg/kg IMD-0354-treated rats (Image 1,A) (P<0.01). No NF-ΚBp65 positive nuclei were detected in Naïve eyes (Image 1,C).

 
Conclusions:
 

It was demonstrated that acute intraocular inflammation was ameliorated by inhibition of IKK/NF-ΚB pathway. IMD-1041, a prodrug for IMD-0354, also showed similar anti-inflammatory effect with oral application in EIU model (Data is not shown).Therefore IKKβ phosphorylation inhibitor might be a promising substance for treatment of uveitis and other intraocular inflammation.  

 
Keywords: inflammation • uveitis-clinical/animal model • enzymes/enzyme inhibitors 
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