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Title: | Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway | Authors: | Simões, Ana Patrícia Duarte, João A Agasse, Fabienne Canas, Paula M. Tomé, Ângelo R. Agostinho, Paula Cunha, Rodrigo A. |
Keywords: | Adenosine; A2A receptor; Interleukin 1β; Neurodegeneration; p38 MAPK; Calcium | Issue Date: | 20-Aug-2012 | Publisher: | Springer Nature | Project: | POCTI/BIA-BCM-59980/2004 PTDC/SAU-NEU/108668/2008 |
Serial title, monograph or event: | Journal of Neuroinflammation | Volume: | 9 | Issue: | 1 | Abstract: | Background and purpose: Blockade of adenosine A2A receptors (A2AR) 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 A2AR 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 A2AR 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 A2AR 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 A2AR 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 A2AR blockade might result from this particular ability of A2AR to control IL-1β-induced exacerbation of excitotoxic neuronal damage, through the control of MAPK activation and late calcium deregulation. | URI: | http://hdl.handle.net/10316/109901 | ISSN: | 1742-2094 | DOI: | 10.1186/1742-2094-9-204 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais FCTUC Ciências da Vida - Artigos em Revistas Internacionais FMUC Medicina - Artigos em Revistas Internacionais |
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