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Published on: May 10, 2018
Adenosine receptor activation ameliorates type 1 diabetes
Zoltán H Németh1, David Bleich, Balázs Csóka
1Department of Surgery, UMDNJ-New Jersey Medical School, 185 South Orange Ave., University Heights, Newark, NJ 07103, USA.
Abstract:
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 A2B 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 A2A receptors. NECA failed to prevent cytokine-induced beta-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-alpha, MIP-1alpha, IL-12, and IFN-gamma 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.
Insights
Adenosine receptor agonist NECA shows promise for treating type 1 diabetes by modulating immune responses, not by protecting beta cells directly. This suggests new therapeutic avenues for autoimmune diabetes.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Autoimmune diseases, including type 1 diabetes, are increasingly recognized as potential targets for adenosine receptor-based therapies.
- Adenosine receptors play a crucial role in regulating immune responses and metabolic processes.
Purpose of the Study:
- To investigate the role of adenosine receptors in the pathogenesis of type 1 diabetes.
- To evaluate the therapeutic potential of adenosine receptor agonists in preclinical models of type 1 diabetes.
Main Methods:
- Type 1 diabetes was induced in CD-1 mice using multiple low-dose streptozotocin (MLDS) and in nonobese diabetic (NOD) mice via cyclophosphamide injection.
- The effects of the nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) and selective receptor agonists/antagonists were assessed in vivo and in vitro.
- Immune cell responses and cytokine expression were analyzed to elucidate the mechanism of action.
Main Results:
- NECA significantly prevented diabetes development in both MLDS-induced and cyclophosphamide-treated NOD mice.
- The protective effect of NECA was dependent on A2B receptor activity and was independent of A2A receptor function.
- NECA suppressed the expression of key pro-inflammatory cytokines (TNF-alpha, MIP-1alpha, IL-12, IFN-gamma) in immune cells, indicating an immunomodulatory mechanism rather than direct beta-cell protection.
Conclusions:
- Adenosine receptor ligands, particularly NECA, demonstrate significant potential for the treatment of type 1 diabetes.
- The therapeutic benefits are primarily mediated through immunomodulation, targeting pro-inflammatory pathways involved in autoimmune diabetes.
- Targeting adenosine receptors represents a promising strategy for developing novel therapies for type 1 diabetes.
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