Adenosine A_2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction

Abstract

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...

Caffeine acts through neuronal adenosine A 2A receptors to prevent mood and memory dysfunction triggered by chronic stress

“…This result excludes a major participation by peripheral adenosine receptors (22) and does not support a prominent role for glial A 2A R in controlling CUS-induced alterations, as occurs in animal models of Parkinson's disease (25) or upon treatment with lipopolysaccharide (17). However, the data are compatible with A 2A R having a key role in glutamatergic terminals defining the synaptic dysfunction underlying the behavioral alterations associated with repeated stress (26,27).…”

“…The only molecular targets for caffeine at nontoxic doses are the main adenosine receptors in the brain, namely the inhibitory A 1 receptors (A 1 R) and the facilitatory A 2A receptors (A 2A R) (9). A 2A R blockade affords robust protection against noxious brain conditions (10), an effect that might result from the ability of neuronal A 2A R to control aberrant plasticity (11,12) and synaptotoxicity (13)(14)(15) or from A 2A R's impact on astrocytes (16) or microglia (17). The protection provided by A 2A R blockade prompts the hypothesis that A 2A R antagonism may underlie the beneficial effects of caffeine on chronic stress, in accordance with the role of synaptic (18,19) or glial dysfunction (20) in mood disorders.…”

The Antiepileptic Potential of Nucleosides

“…All of these effects may increase epileptic activity by decreased Ado-induced inhibition via A 1 receptors. An A 2A receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3-c)1,2,4-triazolo(1,5-c)-pyrimidine (SCH 58261) prevented the LPS-induced increase in the IL-1 concentration in the hippocampus [152,197], whereas the A 2A receptor agonist (2-(4-(2-carboxyethyl)-phenylamino)-5'-N-ethylcarboxamido-adenosine (CGS 21680) decreased the release of TNF- [198]. Because glial cells contain Ado receptors [152,[199][200][201] the adenosinergic system may decrease inflammation-induced epilepsy via A 1 receptors.…”

“…However, more detailed studies are necessary to reveal this novel possibility. In addition, the anti-inflammatory effects of not only Ado [197,198,201,424] but also of Urd and Ino have been demonstrated [403,[424][425][426]; thus, investigation of the effect of Urd and Ino on inflammationinduced exacerbation of epileptic activity [192,193] may also be an interesting and promising novel drug discovery target in epilepsy research.…”

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

“…While adenosine analogues and A 2A R agonists can limit endotoxemic or septic injury in lung [15,16], liver [17], brain [18] and heart [19][20][21], the roles of intrinsic A 2A R activity are less clear. Receptor deletion fails to modify inflammatory markers/injury in some studies [22], reportedly worsens endotoxemic injury in heart [23] and lung [15,24] and improves survival in models of polymicrobial sepsis [25,26].…”