April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
A2A Adenosine Receptor Attenuates Diabetes-Induced Retinal Inflammation and Neuronal Cell Death via Crosstalk With MAPK Pathways
Author Affiliations & Notes
  • A. S. Ibrahim
    Ophthalmology, Medical College of Georgia, Augusta, Georgia
    Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt
  • M. M. El-Shishtawy
    Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt
  • A. M. Rabie
    Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt
  • G. I. Liou
    Ophthalmology, Medical College of Georgia, Augusta, Georgia
  • Footnotes
    Commercial Relationships  A.S. Ibrahim, None; M.M. El-Shishtawy, None; A.M. Rabie, None; G.I. Liou, None.
  • Footnotes
    Support  Knights Templar, Egyptian Cultural and Educational Bureau, and MCG Vision Discovery Institute
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 5101. doi:
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      A. S. Ibrahim, M. M. El-Shishtawy, A. M. Rabie, G. I. Liou; A2A Adenosine Receptor Attenuates Diabetes-Induced Retinal Inflammation and Neuronal Cell Death via Crosstalk With MAPK Pathways. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5101.

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

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Abstract

Purpose: : In diabetic retinopathy, neuronal and vascular abnormalities are closely associated with inflammation. MAPK has been linked to inflammation and downstream events leading to neuronal cell death. We have recently demonstrated the anti-inflammatory effects of A2A adenosine receptor (A2AAR) in acute retinal inflammation. However, the role of adenosine signaling in chronic retinal inflammation, as occurring in diabetes, has not been investigated. In the present study, the role of adenosine, including the receptor subtypes and the underlying mechanism involving the crosstalk with MAPK pathways, during diabetes was examined.

Methods: : Experiments were performed in retinal microglial cells in the presence or absence of nonselective adenosine receptor (AR) agonist (NECA) and selective AR agonists/antagonists, and treated with or without Amadori-glycated albumin (AGA), which has been implicated as causal factors in diabetic complications. For in vivo study, streptozotocin-induced diabetic mice with A2AAR-/- or wild type background were used.

Results: : Microglial cells showed a 10-fold increase in TNF-α release after AGA treatment. Treatment with NECA (1 µM) potently inhibited AGA-induced TNF-α release (30%). A selective A2A antagonist ZM241385, but not A1, A2B, or A3 AR antagonists (CPX, MRS 1754, or MRS 1523, respectively) reversed the NECA-mediated TNF-α reduction. Consistently, treatment with A2AAR agonist CGS 21680 not only dampened AGA-induced TNF-α release, but also reduced AGA-induced ERK and p38 MAPK activation, demonstrating that CGS21680 inhibits TNF-α release via a negative crosstalk with MAPK signaling. To address the role of A2AAR in vivo, retinas from diabetic A2AAR-/- or wild type mice were compared. Retinas from diabetic A2AAR-/- mice showed extensive cell death and increased level of TNF-α, ICAM expression and ERK activation compared with their respective wild-type.

Conclusions: : The present study reveals that adenosine evokes endogenous protective mechanisms through A2AAR signaling for attenuating diabetes-induced retinal neuronal cell death. This study further indicates that the retinal protective effect of A2AAR is mediated primarily by abrogating inflammatory response associated with diabetes via a negative crosstalk with MAPK pathways. Thus, with discovery of new receptor-based therapy for diabetic retinopathy, A2AAR could be promising therapeutic target.

Keywords: diabetic retinopathy • inflammation • adenosine 
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