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Background and purpose  Blockade of adenosine A 2A  receptors (A 2A R) affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL)-1β. We investigated whether A 2A R controls the signaling of IL-1β and its deleterious effects in cultured hippocampal neurons.    Methods  Hippocampal neuronal cultures were treated with IL-1β and/or glutamate in the presence or absence of the selective A 2A R antagonist, SCH58261 (50 nmol/l). The effect of SCH58261 on the IL-1β-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) c-Jun N-terminal kinase (JNK) and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1β was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A 2A R blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1β, was studied using single-cell calcium imaging.    Results  IL-1β (10 to 100 ng/ml) enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 μg/ml), in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1β failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 μmol/l glutamate for 25 minutes (evaluated after 24 hours). It is likely that this resulted from the ability of IL-1β to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1β alone. The selective A 2A R antagonist, SCH58261 (50 nmol/l), prevented both the IL-1β-induced phosphorylation of JNK and p38, as well as the IL-1β-induced deregulation of calcium and the consequent enhanced neurotoxicity, whereas it had no effect on glutamate actions.    Conclusions  These results prompt the hypothesis that the neuroprotection afforded by A 2A R blockade might result from this particular ability of A 2A R to control IL-1β-induced exacerbation of excitotoxic neuronal damage, through the control of MAPK activation and late calcium deregulation.

journal of neuroinflammation

Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway