title: IκB kinase-β inhibitor IMD-0354 beneficially suppresses retinal vascular permeability in streptozotocin-induced diabetic mice.
abstract: OBJECTIVE
  The purpose of the present study is to evaluate the effect of selective IKK-β inhibition by IMD-0354 on inflammation, apoptosis, and angiogenesis in diabetic retinopathy (DR).
  
  
  METHODS
  Six weeks after administration of a streptozotocin (STZ) injection, before diabetic retinopathy (DR) was evident, one group of STZ-induced diabetic mice was systemically administered with IMD-0354 (30 mg/kg) daily for another 6 weeks. Ten weeks after the STZ injection, with DR already present, another group of STZ-induced diabetic mice was administered IMD-0354 for 2 weeks. As controls, nondiabetic mice of the same age were treated with IMD-0354 for 6 weeks, and diabetic mice were treated with 10 μL of dimethyl sulfoxide (DMSO) for 6 weeks. Using these groups of mice, the following effects of IMD-0354 were analyzed: (1) inhibition of nuclear factor-κB (NF-κB) activation, (2) retinal morphology, (3) apoptotic signaling by cleaved caspase-3, (4) retinal vascular permeability, (5) angiogenesis of the retina, and (6) retinal production of VEGF.
  
  
  RESULTS
  Systemic administration of IMD-0354 for 6 weeks to week-6 diabetic mice caused significant reduction in the loss of retinal ganglion cells and apoptotic signaling, with preservation of retinal vascular integrity and suppression of retinal VEGF expression. When inhibition of NF-κB activation treatment started after the onset of STZ-induced DR (week 10), IMD-0354 was still effective in preventing further DR progression while the vascular integrity was preserved.
  
  
  CONCLUSIONS
  The present data indicate that NF-κB activation is the key step in the development of DR. Its suppression by IMD-0354 may present a promising therapeutic strategy for DR, especially in the early stages of the disease.
authors.affiliation: Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Anton
authors.initials: A
authors.lastname: Lennikov
authors.affiliation: Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Hiraoka
authors.affiliation: Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Abe
authors.affiliation: Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Institute of Medicinal Molecular Design (IMMD), Inc., Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujikawa
authors.affiliation: Institute of Medicinal Molecular Design (IMMD), Inc., Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.affiliation: Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohguro
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D018450:Disease Progression; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001549:Benzamides; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse
keywords: IKK-2; IKK-β; IMD-0354; NF-κB; diabetes; inflammation; retina