Adenosine receptors in the nervous system: pathophysiological implications

Ribeiro, Joaquim A.; Sebastião, Ana M.; Mendonça, Alexandre de

doi:10.1016/s0301-0082(02)00155-7

Cited by 457 publications

(382 citation statements)

References 159 publications

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“…In addition, A 2A receptor activation may inhibit A 1 receptors [98,249,250]. As a consequence, the increased risk of excitation and the consequent excitation-induced pathological processes may increase the sensitivity to epileptic seizures in elderly people [57,251,252].…”

Section: Adenosine Receptor Agonists and Antagonistsmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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Section: Adenosine Receptor Agonists and Antagonistsmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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“…Both receptors have a role in miscellaneous biological processes, particularly the cAMPprotein kinase A signaling cascade and the fine-tuning of glutamatergic information flow (Schiffmann et al, 2007;van Calker and Biber, 2005). They are considered to be modulators of glial function, neuronal communication and neuronal activity, and to be involved in sleep and arousal, and cognition, as well as different psychiatric disorders, including anxiety and other mood disorders (Ribeiro et al, 2003;Cunha et al, 2008;Freitag et al, 2010). In mice, genetic knockout of adenosine A 1 or A 2A receptors has been linked to increased anxiety (Ledent et al, 1997;Johansson et al, 2001), implicating the corresponding genes or, more precisely, polymorphisms within these genes, as promising candidates for increased anxiety reactions.…”

Section: Introductionmentioning

confidence: 99%

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

Rogers

Hohoff

Heatherley

et al. 2010

Neuropsychopharmacol

181

139

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Caffeine, a widely consumed adenosine A 1 and A 2A receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine. Participants were 162 non-/low (NL) and 217 medium/high (MH) caffeine consumers. In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. Caffeine intake was prohibited for 16 h before the first dose of caffeine/placebo. Results showed greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake (indeed coffee intake was higher), in the rs5751876 TT genotype group, and a reduced anxiety response in MH vs NL participants irrespective of genotype. Apart from the almost completely linked ADORA2A SNP rs3761422, no other of eight ADORA2A and seven ADORA1 SNPs studied were found to be clearly associated with effects of caffeine on anxiety, alertness, or headache. Placebo administration in MH participants decreased alertness and increased headache. Caffeine did not increase alertness in NL participants. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.

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“…The endogenous purine nucleoside adenosine regulates a variety of physiological processes, including neuronal survival (Ribeiro et al, 2002) and suppression of inflammation (Cronstein, 1994). The biological effects of adenosine are mediated by four different subtypes of G-protein-coupled cell surface receptors (A1, A2a, A2b, and A3), all of which have been shown to regulate the synthesis and release of immunomodulatory molecules, including cytokines, matrix metalloproteinases (MMPs), and reactive oxygen species (Boyle et al, 1996;Hasko et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Tsutsui¹,

Schnermann²,

Noorbakhsh³

et al. 2004

J. Neurosci.

293

259

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The neuromodulator adenosine regulates immune activation and neuronal survival through specific G-protein-coupled receptors expressed on macrophages and neurons, including the A1 adenosine receptor (A1AR). Here we show that A1AR null (A1AR Ϫ/Ϫ ) mice developed a severe progressive-relapsing form of experimental allergic encephalomyelitis (EAE) compared with their wild-type (A1AR ϩ/ϩ ) littermates. Worsened demyelination, axonal injury, and enhanced activation of microglia/macrophages were observed in A1AR Ϫ/Ϫ animals. In addition, spinal cords from A1AR Ϫ/Ϫ mice demonstrated increased proinflammatory gene expression during EAE, whereas anti-inflammatory genes were suppressed compared with A1AR ϩ/ϩ animals. Macrophages from A1AR Ϫ/Ϫ animals exhibited increased expression of the proinflammatory genes, interleukin-1␤, and matrix metalloproteinase-12 on immune activation when matched with A1AR ϩ/ϩ control cells. A1AR Ϫ/Ϫ macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. The A1AR was downregulated in microglia in A1AR ϩ/ϩ mice during EAE accompanied by neuroinflammation, which recapitulated findings in multiple sclerosis (MS) patients. Caffeine treatment augmented A1AR expression on microglia, with ensuing reduction of EAE severity, which was further enhanced by concomitant treatment with the A1AR agonist, adenosine amine congener. Thus, modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for MS and other demyelinating diseases.

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Adenosine receptors in the nervous system: pathophysiological implications

Cited by 457 publications

References 159 publications

The Antiepileptic Potential of Nucleosides

The Antiepileptic Potential of Nucleosides

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

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