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  • Given the powerful and ubiquitous


    Given the powerful and ubiquitous nature of adenosine action within the CNS, basal levels of extracellular adenosine are carefully regulated and are estimated to be in the region of 30–300 nM (Fredholm et al., 2001). The two main pathways for the control of extracellular adenosine involve phosphorylation of cytosolic adenosine to AMP, which is mediated by adenosine kinase (ADK), or deamination by adenosine deaminase (ADA) resulting in the formation of inosine. In rat brain, Km values are ∼2 μM for ADK and ∼17 μM for ADA (Phillips and Newsholme, 1979). This suggests that under normal physiological conditions adenosine is metabolised primarily via the action of ADK, with the contribution of ADA increasing as the extracellular adenosine concentration is elevated, for example, during metabolic stress (Lloyd and Fredholm, 1995, Latini and Pedata, 2001). These Km values also suggest that adenosine kinase is the primary regulator of intracellular, and, most likely by virtue of the ubiquitous equilibrative nucleoside transporters (King et al., 2006), basal extracellular adenosine concentration (Boison, 2006). Accordingly, inhibition of ADK, but not ADA, in hippocampal slices increased extracellular levels of adenosine and depressed excitatory synaptic transmission in an A1R-dependent manner (Pak et al., 1994, Lloyd and Fredholm, 1995). More recently, hippocampal grafts of ADK-deficient myoblasts, fibroblasts or embryonic stem BD 1047 dihydrobromide sale raised extracellular adenosine levels in vivo and were able to retard kindling-induced seizure activity in rats (Boison, 2006, Boison, 2007). Thus, ADK is a key regulator of the concentration, and hence effects, of extracellular adenosine. In this study we have examined the role of ADK in an in vitro model of electrically-evoked epileptiform activity. We show that inhibition of ADK, which is located primarily in GFAP-positive astrocytes, elevates synaptic adenosine and greatly suppresses glutamatergic excitatory synaptic transmission in both control and nominally Mg2+-free aCSF in an A1R-dependent manner. In addition, seizure activity evoked by brief, high-frequency stimulation was greatly attenuated. These data suggest that not only do astrocytes and ADK play a pivotal role in the regulation of synaptic adenosine under both physiological and pathological conditions, they also imply that basal ADK activity is permissive to seizure activity. Thus, factors influencing the activity or levels of ADK are therefore likely to have important consequences for activity-dependent neuronal function, such as synaptic plasticity, whilst targeting ADK may provide novel therapies for epilepsy and other neurological disorders.
    Materials and methods
    Introduction The neuromodulator adenosine is critical for not only the maintenance of brain homeostasis but also the regulation of complex behaviours via its interaction with other neurotransmitters (Fuxe et al., 1998, Fredholm et al., 2005, Ribeiro and Sebastião, 2009). Rather than playing a central role in information processing, the influence of adenosine on cognitive processes is modulatory in nature, mediated primarily via its action on inhibitory A1 receptors (A1Rs) and excitatory A2A receptors (A2ARs) expressed in neurons. Evidence for a critical involvement of adenosine in learning and memory is based on behavioural data derived from animals as well as humans (for a review, see Boison et al., 2012). In particular, adenosine receptor (AR) antagonists are effective in ameliorating memory deficits in several animal models of degenerative diseases (e.g., Takahashi et al., 2008, Cunha and Agostinho, 2010). However, a clear consensus is lacking regarding whether similar pharmacological manipulations may yield pro-cognitive effects in normal unperturbed subjects (see Table 3 of Boison et al., 2012). Amongst these, the mixed A1R/A2AR antagonist, caffeine, has been more consistently reported to enhance performance on memory tests in normal animals, and it is commonly believed that such pro-cognitive effects stem primarily from an increase in arousal mediated via blockade of A2AR signals in the nucleus accumbens (Fredholm et al., 1999, Nehlig, 2010). In agreement, selective genetic disruption of A2AR in striatal neurons is sufficient to enhance working memory and to facilitate reversal learning (Wei et al., 2011).