title: Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction.
abstract: The blockade of adenosine A(2A) receptors (A2AR) affords a robust neuroprotection in different noxious brain conditions. However, the mechanisms underlying this general neuroprotection are unknown. One possible mechanism could be the control of neuroinflammation that is associated with brain damage, especially because A2AR efficiently control peripheral inflammation. Thus, we tested if the intracerebroventricular injection of a selective A2AR antagonist (SCH58261) would attenuate the changes in the hippocampus triggered by intraperitoneal administration of lipopolysaccharide (LPS) that induces neuroinflammation through microglia activation. LPS administration triggers an increase in inflammatory mediators like interleukin-1β that causes biochemical changes (p38 and c-jun N-terminal kinase phosphorylation and caspase 3 activation) contributing to neuronal dysfunction typified by decreased long-term potentiation, a form of synaptic plasticity. Long-term potentiation, measured 30 min after the tetanus, was significantly lower in LPS-treated rats compared with control-treated rats, while SCH58261 attenuated the LPS-induced change. The LPS-induced increases in phosphorylation of c-jun N-terminal kinase and p38 and activation of caspase 3 were also prevented by SCH58261. Significantly, SCH58261 also prevented the LPS-induced recruitment of activated microglial cells and the increase in interleukin-1β concentration in the hippocampus, indicating that A2AR activation is a pivotal step in mediating the neuroinflammation triggered by LPS. These results indicate that A2AR antagonists prevent neuroinflammation and support the hypothesis that this mechanism might contribute for the ability of A2AR antagonists to control different neurodegenerative diseases known to involve neuroinflammation.
authors.affiliation: Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Nelson
authors.initials: N
authors.lastname: Rebola
authors.forename: Ana Patrícia
authors.initials: AP
authors.lastname: Simões
authors.forename: Paula M
authors.initials: PM
authors.lastname: Canas
authors.forename: Angelo R
authors.initials: AR
authors.lastname: Tomé
authors.forename: Geanne M
authors.initials: GM
authors.lastname: Andrade
authors.forename: Claire E
authors.initials: CE
authors.lastname: Barry
authors.forename: Paula M
authors.initials: PM
authors.lastname: Agostinho
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology / Q000627:therapeutic use; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D043705:Receptor, Adenosine A2A; D012118:Resorcinols; C511080:Sch 725681