ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy

Nehal M. Elsherbiny, Saif Ahmad, Mohammad Naime, Ahmed M. Elsherbini, Sadanand Fulzele, Mohammed M. Al-Gayyar, Laila A. Eissa, Mamdouh M. El-Shishtawy, Gregory I. Liou

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Abstract

Aims 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. Main methods We targeted AK, the key enzyme in adenosine metabolism, using a treatment regime with the selective AKI, ABT-702 (1.5 mg/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 A 2AAR signaling in the anti-inflammation effect of ABT-702 was analyzed in Amadori-glycated-albumin (AGA)-treated microglial cells. Key findings At 16 weeks, when diabetic mice exhibit significant signs of retinal inflammation including up-regulation of oxidative/nitrosative stress, A 2AAR, 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. Significance 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.

Original languageEnglish (US)
Pages (from-to)78-88
Number of pages11
JournalLife sciences
Volume93
Issue number2-3
DOIs
StatePublished - Jul 30 2013

Fingerprint

Adenosine Kinase
Diabetic Retinopathy
Adenosine
Inflammation
Medical problems
Purinergic P1 Receptors
Oxidative stress
Experimental Diabetes Mellitus
Therapeutic Uses
Cell death
Streptozocin
Metabolism
Retina
ABT 702
Real-Time Polymerase Chain Reaction
Animals
Oxidative Stress
Cell Death
Up-Regulation
Down-Regulation

Keywords

  • Adenosine kinase
  • Diabetic retinopathy
  • Inflammation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Elsherbiny, N. M., Ahmad, S., Naime, M., Elsherbini, A. M., Fulzele, S., Al-Gayyar, M. M., ... Liou, G. I. (2013). ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy. Life sciences, 93(2-3), 78-88. https://doi.org/10.1016/j.lfs.2013.05.024

ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy. / Elsherbiny, Nehal M.; Ahmad, Saif; Naime, Mohammad; Elsherbini, Ahmed M.; Fulzele, Sadanand; Al-Gayyar, Mohammed M.; Eissa, Laila A.; El-Shishtawy, Mamdouh M.; Liou, Gregory I.

In: Life sciences, Vol. 93, No. 2-3, 30.07.2013, p. 78-88.

Research output: Contribution to journalArticle

Elsherbiny, NM, Ahmad, S, Naime, M, Elsherbini, AM, Fulzele, S, Al-Gayyar, MM, Eissa, LA, El-Shishtawy, MM & Liou, GI 2013, 'ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy', Life sciences, vol. 93, no. 2-3, pp. 78-88. https://doi.org/10.1016/j.lfs.2013.05.024
Elsherbiny, Nehal M. ; Ahmad, Saif ; Naime, Mohammad ; Elsherbini, Ahmed M. ; Fulzele, Sadanand ; Al-Gayyar, Mohammed M. ; Eissa, Laila A. ; El-Shishtawy, Mamdouh M. ; Liou, Gregory I. / ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy. In: Life sciences. 2013 ; Vol. 93, No. 2-3. pp. 78-88.
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AU - Fulzele, Sadanand

AU - Al-Gayyar, Mohammed M.

AU - Eissa, Laila A.

AU - El-Shishtawy, Mamdouh M.

AU - Liou, Gregory I.

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AB - Aims 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. Main methods We targeted AK, the key enzyme in adenosine metabolism, using a treatment regime with the selective AKI, ABT-702 (1.5 mg/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 A 2AAR signaling in the anti-inflammation effect of ABT-702 was analyzed in Amadori-glycated-albumin (AGA)-treated microglial cells. Key findings At 16 weeks, when diabetic mice exhibit significant signs of retinal inflammation including up-regulation of oxidative/nitrosative stress, A 2AAR, 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. Significance 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.

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