Ecto-5'-Nucleotidase (CD73)-Mediated Formation of Adenosine Is Critical for the Striatal Adenosine A2A Receptor Functions

Augusto, Elisabete; Matos, Marco; Sévigny, Jean; El‐Tayeb, Ali; Bynoe, Margaret S.; Müller, Christian; Cunha, Rodrigo A.; Chen, Jiang‐Fan

doi:10.1523/jneurosci.5817-12.2013

Cited by 144 publications

(135 citation statements)

References 83 publications

(16 reference statements)

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“…Ecto-5′-nucleotidase (CD73) is the major adenosine producing enzyme in the extracellular space (Augusto et al, 2013; Chu et al, 2014; Cunha et al, 1992; Koszalka et al, 2004) and implicated in reactive synaptogenesis (Lie et al, 1999; Schoen et al, 1999). Interestingly, increased CD73 expression was found in the dentate gyrus molecular layer in human resective surgery specimen from TLE patients, implicating TLE-associated reactive synaptogenesis in this brain region (Lie et al, 1999).…”

Section: Disruption Of Adenosine Homeostasismentioning

confidence: 99%

Adenosinergic signaling in epilepsy

Boison

2016

Neuropharmacology

115

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Despite the introduction of at least 20 new antiepileptic drugs (AEDs) into clinical practice over the past decades, about one third of all epilepsies remain refractory to conventional forms of treatment. In addition, currently used AEDs have been developed to suppress neuronal hyperexcitability, but not necessarily to address pathogenic mechanisms involved in epilepsy development or progression (epileptogenesis). For those reasons endogenous seizure control mechanisms of the brain may provide alternative therapeutic opportunities. Adenosine is a well characterized endogenous anticonvulsant and seizure terminator of the brain. Several lines of evidence suggest that endogenous adenosine-mediated seizure control mechanisms fail in chronic epilepsy, whereas therapeutic adenosine augmentation effectively prevents epileptic seizures, even those that are refractory to conventional AEDs. New findings demonstrate that dysregulation of adenosinergic mechanisms are intricately involved in the development of epilepsy and its comorbidities, whereas adenosine-associated epigenetic mechanisms may play a role in epileptogenesis. The first goal of this review is to discuss how maladaptive changes of adenosinergic mechanisms contribute to the expression of seizures (ictogenesis) and the development of epilepsy (epileptogenesis) by focusing on pharmacological (adenosine receptor dependent) and biochemical (adenosine receptor independent) mechanisms as well as on enzymatic and transport based mechanisms that control the availability (homeostasis) of adenosine. The second goal of this review is to highlight innovative adenosine-based opportunities for therapeutic intervention aimed at reconstructing normal adenosine function and signaling for improved seizure control in chronic epilepsy. New findings suggest that transient adenosine augmentation can have lasting epigenetic effects with disease modifying and antiepileptogenic outcome.

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Section: Disruption Of Adenosine Homeostasismentioning

confidence: 99%

Adenosinergic signaling in epilepsy

Boison

2016

Neuropharmacology

115

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“…The series of arm entries was recorded visually and an alternation was defined as entries in all three arms on consecutive occasions. The percentage of alternation was calculated as follows: total of alternations / (total arm entries -2), as we previously described (Augusto et al, 2013). The experimenter conducting behavioral analysis was blinded to treatment conditions.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Western blot analysis as we described previously (Augusto et al, 2013;Matos et al, 2015;Rebola et al, 2005a). Briefly, after determination of protein concentration, samples were diluted with five volumes of SDS-PAGE buffer.…”

Section: Western Blot Analysismentioning

confidence: 99%

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

Ren

Liu

et al. 2016

Experimental Neurology

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“…On the other hand, A 2A receptors facilitate glutamate release, and their association with ectonucleotidase, CD73, implies A 2A receptors are activated under pathological conditions when excess extracellular ATP is found (Augusto et al, 2013). Hence A 2A receptor antagonists such as caffeine limit the pathology of neurodegenerative disorders such as AD and PD.…”

Section: P2 Receptors Determine the Eventual Effect Of Extracellular Atpmentioning

confidence: 99%

The two-hit hypothesis for neuroinflammation: role of exogenous ATP in modulating inflammation in the brain

Fiebich¹,

Akter²,

Akundi³

2014

Front. Cell. Neurosci.

100

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Brain inflammation is a common occurrence following responses to varied insults such as bacterial infections, stroke, traumatic brain injury and neurodegenerative disorders. A common mediator for these varied inflammatory responses is prostaglandin E2 (PGE2), produced by the enzymatic activity of cyclooxygenases (COX) 1 and 2. Previous attempts to reduce neuronal inflammation through COX inhibition, by use of nonsteroidal anti-inflammatory drugs (NSAIDs), have met with limited success. We are proposing the two-hit model for neuronal injury—an initial localized inflammation mediated by PGE2 (first hit) and the simultaneous release of adenosine triphosphate (ATP) by injured cells (second hit), which significantly enhances the inflammatory response through increased synthesis of PGE2. Several evidences on the role of exogenous ATP in inflammation have been reported, including contrary instances where extracellular ATP reduces inflammatory events. In this review, we will examine the current literature on the role of P2 receptors, to which ATP binds, in modulating inflammatory reactions during neurodegeneration. Targeting the P2 receptors, therefore, provides a therapeutic alternative to reduce inflammation in the brain. P2 receptor-based anti-inflammatory drugs (PBAIDs) will retain the activities of essential COX enzymes, yet will significantly reduce neuroinflammation by decreasing the enhanced production of PGE2 by extracellular ATP.

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Ecto-5'-Nucleotidase (CD73)-Mediated Formation of Adenosine Is Critical for the Striatal Adenosine A2A Receptor Functions

Abstract: Adenosine is a neuromodulator acting through inhibitory

Cited by 144 publications

References 83 publications

Adenosinergic signaling in epilepsy

Adenosinergic signaling in epilepsy

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

The two-hit hypothesis for neuroinflammation: role of exogenous ATP in modulating inflammation in the brain

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