Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis

Garcı́a-Borreguero, Diego; Guitart, Xavier; García-Malo, Celia; Cano-Pumarega, Irene; Granizo, Juan José; Ferré, Sergi

doi:10.1016/j.sleep.2018.02.002

Cited by 51 publications

(28 citation statements)

References 18 publications

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“…As expected, the increased sensitivity of corticostriatal terminals observed in the experimental animal could be counteracted by blocking the constitutive signaling of A2AR, with A2AR inverse agonists or CB1R agonists, or by activating A1R, by moderately increasing extracellular levels of adenosine with an inhibitor of the adenosine transporter. There is in fact preliminary clinical evidence for the successful application of these strategies in RLS patients [63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Control of glutamate release by complexes of adenosine and cannabinoid receptors

et al. 2020

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Background: It has been hypothesized that heteromers of adenosine A 2A receptors (A2AR) and cannabinoid CB 1 receptors (CB1R) localized in glutamatergic nerve terminals mediate the integration of adenosine and endocannabinoid signaling involved in the modulation of striatal excitatory neurotransmission. Previous studies have demonstrated the existence of A2AR-CB1R heteromers in artificial cell systems. A dependence of A2AR signaling for the Gi protein-mediated CB1R signaling was described as one of its main biochemical characteristics. However, recent studies have questioned the localization of functionally significant A2AR-CB1R heteromers in striatal glutamatergic terminals. Results: Using a peptide-interfering approach combined with biophysical and biochemical techniques in mammalian transfected cells and computational modeling, we could establish a tetrameric quaternary structure of the A2AR-CB1R heterotetramer. This quaternary structure was different to the also tetrameric structure of heteromers of A2AR with adenosine A 1 receptors or dopamine D 2 receptors, with different heteromeric or homomeric interfaces. The specific quaternary structure of the A2A-CB1R, which depended on intermolecular interactions involving the long C-terminus of the A2AR, determined a significant A2AR and Gs protein-mediated constitutive activation of adenylyl cyclase. Using heteromer-interfering peptides in experiments with striatal glutamatergic terminals, we could then demonstrate the presence of functionally significant A2AR-CB1R heteromers with the same biochemical characteristics of those studied in mammalian transfected cells. First, either an A2AR agonist or an A2AR antagonist allosterically counteracted Gimediated CB1R agonist-induced inhibition of depolarization-induced glutamate release. Second, co-application of both an A2AR agonist and an antagonist cancelled each other effects. Finally, a CB1R agonist inhibited glutamate release dependent on a constitutive activation of A2AR by a canonical Gs-Gi antagonistic interaction at the adenylyl cyclase level.

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Section: Discussionmentioning

confidence: 99%

Control of glutamate release by complexes of adenosine and cannabinoid receptors

et al. 2020

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“…In fact, we recently reported encouraging results with the nonselective ENT1/ENT2 inhibitor dipyridamole in an open trial with RLS patients. 68 At the preclinical level, as predicted, an A 1 R antagonist produced hypersensitivity of corticostriatal terminals and reduced the frequency of optogenetic stimulation necessary to induce corticostriatal glutamate release. 65 Furthermore, dipyridamole, by increasing the striatal extracellular concentration of adenosine and the activation of presynaptic A 1 R, was able to counteract optogenetic-induced glutamate release in both naive rats and in rats with BID.…”

Section: Neuroprotective Role Of the Presynaptic Striatal A1r-a2ar Hementioning

confidence: 64%

Functional and Neuroprotective Role of Striatal Adenosine A_2AReceptor Heterotetramers

Ferré

Ciruela

2019

Journal of Caffeine and Adenosine Research

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In the striatum, adenosine A 2A receptors (A 2A R) are mainly expressed within the soma and dendrites of the striatopallidal neuron. A predominant proportion of these striatal postsynaptic A 2A R form part of the macromolecular complexes that include A 2A R-dopamine D 2 receptor (D 2 R) heteromers, G olf and G i/o proteins, and the effector adenylyl cyclase (AC), subtype AC5. The A 2A R-D 2 R heteromers have a tetrameric structure, constituted by A 2A R and D 2 R homomers. By means of reciprocal antagonistic allosteric interactions and antagonistic interactions at the effector level between adenosine and dopamine, the A 2A R-D 2 R heterotetramer-AC5 complex acts an integrative molecular device, which determines a switch between the adenosine-facilitated activation and the dopamine-facilitated inhibition of the striatopallidal neuron. Striatal adenosine also plays an important presynaptic modulatory role, driving the function of corticostriatal terminals. This control is mediated by adenosine A 1 receptors (A 1 R) and A 2A R, which establish intermolecular interactions forming A 1 R-A 2A R heterotetramers. Here, we review the functional role of both presynaptic and postsynaptic striatal A 2A R heterotetramers as well as their possible neuroprotective role. We hypothesize that alterations in the homomer/heteromer stoichiometry (i.e., increase or decrease in the proportion of A 2A R forming homomers or heteromers) are pathogenetically involved in neurological disorders, specifically in Parkinson's disease and restless legs syndrome.

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“…40 This hypoadenosinergic state provides a mechanism that explains PLMs, secondary to the hypersensitivity of corticostriatal terminals, 34 but also hyperarousal, secondary to A1 receptor downregulation in the cortex, basal forebrain, or hypothalamus. 35 The therapeutic effect of dipyridamole, a drug that blocks the human equilibrative nucleoside transporter 1 (ENT-1) reuptake mechanisms and thereby increases extracellular adenosine, provides validity for this hypothesis 41 (Fig 1).…”

Section: Neurotransmitter Dysfunctionmentioning

confidence: 97%

“…Dipyridamole, a drug that blocks ENT-1 reuptake mechanisms and thereby increases extracellular adenosine, resulted in an improvement in RLS symptoms and in the mean periodic leg movement index. 41 Several studies have investigated the effect of alternative and complementary nonpharmacological treatments. Repetitive transcranial magnetic stimulation is a noninvasive treatment used to alter cortex excitability.…”

Section: Emerging Treatmentsmentioning

confidence: 99%

Emerging Concepts of the Pathophysiology and Adverse Outcomes of Restless Legs Syndrome

Romero-Peralta

Cano-Pumarega

Garcı́a-Borreguero

2020

Chest

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Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis

Cited by 51 publications

References 18 publications

Control of glutamate release by complexes of adenosine and cannabinoid receptors

Control of glutamate release by complexes of adenosine and cannabinoid receptors

Functional and Neuroprotective Role of Striatal Adenosine A_2AReceptor Heterotetramers

Emerging Concepts of the Pathophysiology and Adverse Outcomes of Restless Legs Syndrome

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Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis

Cited by 51 publications

References 18 publications

Control of glutamate release by complexes of adenosine and cannabinoid receptors

Control of glutamate release by complexes of adenosine and cannabinoid receptors

Functional and Neuroprotective Role of Striatal Adenosine A2AReceptor Heterotetramers

Emerging Concepts of the Pathophysiology and Adverse Outcomes of Restless Legs Syndrome

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Functional and Neuroprotective Role of Striatal Adenosine A_2AReceptor Heterotetramers