Neurological diseases account for approximately 30% of the total disease burden in Europe and neurodegenerative diseases account for a significant proportion of these (Olesen and Leonardi 2003). The neuromodulation system operated by adenosine has received an increasing attention as a potential novel target to manage neurodegenerative conditions, in view of its combined neuronal, glial and vascular effects (reviewed in Fredholm et al. 2005). This is best exemplified by the current development (phase IIb) These authors contributed equally to the experimental effort of this study.Abbreviations used: A1R, A1 receptor; A2AR, A2A receptor; BSA, bovine serum albumin; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; EPSP, excitatory post-synaptic potentials; IR, immunoreactivity; iNOS, inducible nitric oxide synthase; JNK, c-jun N-terminal kinase; LPS, lipopolysaccharide; LTP, long-term potentiation; MSX-3, 3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate; PBS, phosphate-buffered saline; SCH58261, 5-amino-7-2-phenylethyl.-2-2-furyl-pyrazolo[4,3-ex-1,2,4-triazolo-1,5-9-pyrimidine; SDS, sodium dodecyl sulfate; TBS, Tris-buffered saline; vGAT, vesicular GABA transporter; vGluT1 and vGluT2, glutamate transporters types 1 and 2; XAC, 8-{4-[(2-aminoethyl)amino]carbonylmethyl-oxyphenyl}xanthine. AbstractThe 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-1b 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-1b 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 mechani...

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Neurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A2A receptors (A2AR), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A2AR mRNA. This bolstered A2AR-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A2AR selectively in forebrain neurons. This shows that synaptic A2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.

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