Adenosine uptake inhibitors

Noji, Tohru; Karasawa, Akira; Kusaka, Hideaki

doi:10.1016/j.ejphar.2004.05.003

Cited by 67 publications

(70 citation statements)

References 188 publications

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“…Adenosine is first taken up by neurons and astrocytes through the equilibrative nucleoside transporters and concentrative transporters, and it is then either phosphorylated to AMP by adenosine kinase or converted to inosine by adenosine deaminase. In addition, adenosine can be metabolized by adenosine deaminase in the extracellular matrix (Baldwin et al 2004;Dunwiddie and Masino 2001;Fredholm et al 2005;Noji et al 2004). To determine the involvement of adenosine uptake (by the equilibrative nucleoside transporters: ENT1 and ENT2), adenosine phosphorylation (by adenosine kinase), and adenosine metabolism (by adenosine deaminase) in the regulation of extracellular adenosine in BF, we tested the effects of specific blockers for these enzymes on the amplitude of the evEPSC amplitude in MCPO/SI cholinergic neurons.…”

Section: Resultsmentioning

confidence: 99%

Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

Hawryluk

Ferrari

Keating

et al. 2012

Journal of Neurophysiology

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Hawryluk JM, Ferrari LL, Keating SA, Arrigoni E. Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons. J Neurophysiol 107: 2769 -2781, 2012. First published February 22, 2012 doi:10.1152/jn.00528.2011.-Adenosine has been proposed as an endogenous homeostatic sleep factor that accumulates during waking and inhibits wake-active neurons to promote sleep. It has been specifically hypothesized that adenosine decreases wakefulness and promotes sleep recovery by directly inhibiting wake-active neurons of the basal forebrain (BF), particularly BF cholinergic neurons. We previously showed that adenosine directly inhibits BF cholinergic neurons. Here, we investigated 1) how adenosine modulates glutamatergic input to BF cholinergic neurons and 2) how adenosine uptake and adenosine metabolism are involved in regulating extracellular levels of adenosine. Our experiments were conducted using whole cell patch-clamp recordings in mouse brain slices. We found that in BF cholinergic neurons, adenosine reduced the amplitude of AMPAmediated evoked glutamatergic excitatory postsynaptic currents (EPSCs) and decreased the frequency of spontaneous and miniature EPSCs through presynaptic A 1 receptors. Thus we have demonstrated that in addition to directly inhibiting BF cholinergic neurons, adenosine depresses excitatory inputs to these neurons. It is therefore possible that both direct and indirect inhibition may synergistically contribute to the sleep-promoting effects of adenosine in the BF. We also found that blocking the influx of adenosine through the equilibrative nucleoside transporters or inhibiting adenosine kinase and adenosine deaminase increased endogenous adenosine inhibitory tone, suggesting a possible mechanism through which adenosine extracellular levels in the basal forebrain are regulated. magnocellular preoptic nucleus; substantia innominata; adenosine A 1 receptors; electrophysiology; excitatory postsynaptic currents; in vitro; mice IN THE LAST EIGHTY YEARS, a large number of studies have been directed toward identifying the endogenous sleep factors that could build during the waking period to drive the need for sleep and then be dissipated by sleep itself (Achermann

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Section: Resultsmentioning

confidence: 99%

Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

Hawryluk

Ferrari

Keating

et al. 2012

Journal of Neurophysiology

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“…The Ado uptake inhibitor, midazolam, depresses excitatory synaptic transmissions in the hippocampus [220]. In addition, Ado uptake inhibitors have less severe adverse effects compared to Ado receptor agonists [221,222]. Some controversial results were described in relation to nucleoside transporter inhibition, e.g., papaverine may have pro-and anticonvulsant effects in different models [134,213,217,[223][224][225].…”

Section: Inhibition Of Nucleoside Transportersmentioning

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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“…Equilibrative nucleoside transporters (ENTs) passively transport adenosine across cell membranes in either directions depending on the intra and extracellular adenosine concentration through facilitated diffusion (Noji et al, 2004). These transporters are largely responsible for adenosine uptake from the extracellular space in control conditions, but have been proposed to mediate adenosine release from neurons and astrocytes (Bender and Hertz, 1986;Brundege and Dunwiddie, 1996).…”

Section: Hypoxia-induced Adenosine Release From Astrocytes Is Negativmentioning

confidence: 99%

Adenosine released by astrocytes contributes to hypoxia‐induced modulation of synaptic transmission

Martı́n

Fernández

Perea

et al. 2006

Glia

187

160

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Astrocytes play a critical role in brain homeostasis controlling the local environment in normal as well as in pathological conditions, such as during hypoxic/ischemic insult. Since astrocytes have recently been identified as a source for a wide variety of gliotransmitters that modulate synaptic activity, we investigated whether the hypoxia-induced excitatory synaptic depression might be mediated by adenosine release from astrocytes. We used electrophysiological and Ca 21 imaging techniques in hippocampal slices and transgenic mice, in which ATP released from astrocytes is specifically impaired, as well as chemiluminescent and fluorescence photometric Ca 21 techniques in purified cultured astrocytes. In hippocampal slices, hypoxia induced a transient depression of excitatory synaptic transmission mediated by activation of presynaptic A1 adenosine receptors. The glia-specific metabolic inhibitor fluorocitrate (FC) was as effective as the A1 adenosine receptor antagonist CPT in preventing the hypoxia-induced excitatory synaptic transmission reduction. Furthermore, FC abolished the extracellular adenosine concentration increase during hypoxia in astrocyte cultures. Several lines of evidence suggest that the increase of extracellular adenosine levels during hypoxia does not result from extracellular ATP or cAMP catabolism, and that astrocytes directly release adenosine in response to hypoxia. Adenosine release is negatively modulated by external or internal Ca 21 concentrations. Moreover, adenosine transport inhibitors did not modify the hypoxia-induced effects, suggesting that adenosine was not released by facilitated transport. We conclude that during hypoxia, astrocytes contribute to regulate the excitatory synaptic transmission through the release of adenosine, which acting on A1 adenosine receptors reduces presynaptic transmitter release. Therefore, adenosine release from astrocytes serves as a protective mechanism by down regulating the synaptic activity level during demanding conditions such as transient hypoxia.

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Adenosine uptake inhibitors

Cited by 67 publications

References 188 publications

Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

The Antiepileptic Potential of Nucleosides

Adenosine released by astrocytes contributes to hypoxia‐induced modulation of synaptic transmission

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