Adenosine receptor activation ameliorates type 1 diabetes

Zoltán H. Németh, David Bleich, Balázs Csóka, Pál Pacher, Jon G. Mabley, Leonóra Himer, E. Sylvester Vizi, Edwin A. Deitch, Csaba Szabó, Bruce N. Cronstein, György Haskó

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Growing evidence indicates that adenosine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD-1 mice was induced by multiple-low-dose-streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) prevented diabetes development in both MLDS-challenged mice and in cyclophosphamide- treated NOD mice. The effect of NECA was reversed by the selective A 2B receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2, 6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS 1754). The selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and A3 receptor agonist N6-(3-iodobenzyl)- adenosine-5′-N-methyluronamide (IB-MECA) were less efficacious in ameliorating the course of diabetes. NECA inhibited diabetes in A2A receptor KO mice and the selective A2A receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5′-N-ethyl-carboxamidoadenosine (CGS21680) had no effect in normal mice, indicating a lack of role of A 2A receptors. NECA failed to prevent cytokine-induced β-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-α, MIP-1α, IL-12, and IFN-γ in pancreata, endotoxin, or anti-CD3-stimulated splenic cells, and T helper 1 lymphocytes, indicating that the beneficial effect of NECA was due to immunomodulation. These results demonstrate that adenosine receptor ligands are potential candidates for the treatment of type 1 diabetes.

Original languageEnglish
Pages (from-to)2379-2388
Number of pages10
JournalFASEB Journal
Issue number10
Publication statusPublished - Aug 1 2007



  • Immune
  • Inflammation
  • Islet

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Németh, Z. H., Bleich, D., Csóka, B., Pacher, P., Mabley, J. G., Himer, L., Vizi, E. S., Deitch, E. A., Szabó, C., Cronstein, B. N., & Haskó, G. (2007). Adenosine receptor activation ameliorates type 1 diabetes. FASEB Journal, 21(10), 2379-2388.