title: ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy.
abstract: OBJECTIVE
  This study was undertaken to determine the effect of an adenosine kinase inhibitor (AKI) in diabetic retinopathy (DR). We have shown previously that adenosine signaling via A2A receptors (A2AAR) is involved in retinal protection from diabetes-induced inflammation. Here we demonstrate that AKI-enhanced adenosine signaling provides protection from DR in mice.
  
  
  METHODS
  We targeted AK, the key enzyme in adenosine metabolism, using a treatment regime with the selective AKI, ABT-702 (1.5mg/kg intraperitoneally twice a week) commencing at the beginning of streptozotocin-induced diabetes at the age of eight weeks. This treatment, previously demonstrated to increase free adenosine levels in vivo, was maintained until the age of 16 weeks. Retinal inflammation was evaluated using Western blot, Real-Time PCR and immuno-staining analyses. Role of A2AAR signaling in the anti-inflammation effect of ABT-702 was analyzed in Amadori-glycated-albumin (AGA)-treated microglial cells.
  
  
  RESULTS
  At 16 weeks, when diabetic mice exhibit significant signs of retinal inflammation including up-regulation of oxidative/nitrosative stress, A2AAR, ENT1, Iba1, TNF-α, ICAM1, retinal cell death, and down-regulation of AK, the ABT-702 treated group showed lower signs of inflammation compared to control animals receiving the vehicle. The involvement of adenosine signaling in the anti-inflammation effect of ABT-702 was supported by the TNF-α release blocking effect of A2AAR antagonist in AGA-treated microglial cells.
  
  
  CONCLUSIONS
  These results suggest a role for AK in regulating adenosine receptor signaling in the retina. Inhibition of AK potentially amplifies the therapeutic effects of site- and event-specific accumulation of extracellular adenosine, which is of highly translational impact.
authors.affiliation: Department of Ophthalmology, Georgia Regents University, 30909, USA.
authors.forename: Nehal M
authors.initials: NM
authors.lastname: Elsherbiny
authors.forename: Saif
authors.initials: S
authors.lastname: Ahmad
authors.forename: Mohammad
authors.initials: M
authors.lastname: Naime
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Elsherbini
authors.forename: Sadanand
authors.initials: S
authors.lastname: Fulzele
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Al-Gayyar
authors.forename: Laila A
authors.initials: LA
authors.lastname: Eissa
authors.forename: Mamdouh M
authors.initials: MM
authors.lastname: El-Shishtawy
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Liou
mesh_terms: D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D017127:Glycation End Products, Advanced; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D012173:Retinitis / Q000188:drug therapy* / Q000209:etiology; D012709:Serum Albumin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093423:Glycated Serum Albumin
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D004791:Enzyme Inhibitors; D033721:Equilibrative Nucleoside Transporter 1; D017127:Glycation End Products, Advanced; D009025:Morpholines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; C498476:SLC29A1 protein, mouse; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C416933:ABT 702; D000248:Adenosine Kinase; D000241:Adenosine; D000093423:Glycated Serum Albumin
keywords: Adenosine kinase; Diabetic retinopathy; Inflammation