Role of Adenosine Receptors in Epileptic Seizures

Rombo, Diogo M.; Ribeiro, J.A.; Sebastião, Ana M.

doi:10.1007/978-3-319-90808-3_13

Cited by 6 publications

(2 citation statements)

References 288 publications

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“…such as 2-chloro-N 6 -cyclopentyl-adenosine (CCPA) or N 6 -cyclohexyladenosine (CHA), possess anticonvulsant actions in a variety of acute and chronic models of epilepsy, which are prevented by A 1 R antagonists such as 8-cyclopentyl-1,3-dimethylxanthine (DPX) or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 58 Importantly, so far available information shows that A 1 R activation is not only capable of preventing seizure occurrence when administered before the trigger but also to abort an already emerging seizure event, thus working as a true anticonvulsant substance.…”

Section: Role Of Ars In Synaptic Function Synaptic Plasticity and Synaptotoxicity In Epilepsymentioning

confidence: 99%

Role of Adenosine in Epilepsy and Seizures

Tescarollo

Rombo

DeLiberto

et al. 2020

Journal of Caffeine and Adenosine Research

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Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles. It not only controls seizures (ictogenesis), but also plays a major role in processes that turn a normal brain into an epileptic brain (epileptogenesis). It is involved in the control of abnormal synaptic plasticity and neurodegeneration and plays a major role in the expression of comorbid symptoms and complications of epilepsy, such as sudden unexpected death in epilepsy (SUDEP). Given the important role of adenosine in epilepsy, therapeutic strategies are in development with the goal to utilize adenosine augmentation not only for the suppression of seizures but also for disease modification and epilepsy prevention, as well as strategies to block adenosine A 2A receptor overfunction associated with neurodegeneration. This review provides a comprehensive overview of the role of adenosine in epilepsy.

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Section: Role Of Ars In Synaptic Function Synaptic Plasticity and Synaptotoxicity In Epilepsymentioning

confidence: 99%

Role of Adenosine in Epilepsy and Seizures

Tescarollo

Rombo

DeLiberto

et al. 2020

Journal of Caffeine and Adenosine Research

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“…A great deal of studies have examined the mechanisms behind the anti-epileptic effects of adenosine and demonstrated that adenosine or adenosine analogues are effective in suppressing epileptic seizures, and this mainly through activation of adenosine A 1 receptors. Several excellent reviews have been published in recent years describing the current knowledge on the role of adenosine in epilepsy and its therapeutic potential (see references [ 8 , 9 , 10 ]). The aim of this review is to specifically focus on the inhibitory A 1 receptors and their downstream signaling pathways, giving an overview of the consequential neuronal effects and how these effects contribute to the seizure suppressing role of adenosine.…”

Section: Introductionmentioning

confidence: 99%

The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

Spanoghe

Larsen

Craey

et al. 2020

IJMS

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Adenosine acts as an endogenous anticonvulsant and seizure terminator in the brain. Many of its anticonvulsive effects are mediated through the activation of the adenosine A1 receptor, a G protein-coupled receptor with a wide array of targets. Activating A1 receptors is an effective approach to suppress seizures. This review gives an overview of the neuronal targets of the adenosine A1 receptor focusing in particular on signaling pathways resulting in neuronal inhibition. These include direct interactions of G protein subunits, the adenyl cyclase pathway and the phospholipase C pathway, which all mediate neuronal hyperpolarization and suppression of synaptic transmission. Additionally, the contribution of the guanyl cyclase and mitogen-activated protein kinase cascades to the seizure-suppressing effects of A1 receptor activation are discussed. This review ends with the cautionary note that chronic activation of the A1 receptor might have detrimental effects, which will need to be avoided when pursuing A1 receptor-based epilepsy therapies.

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Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

et al. 2022

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Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3- b ]pyridine derivatives as non-nucleoside A 1 agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3- b ]pyridine derivative), displayed good binding affinity to the rA 1 AR ( K i = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3- b ]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives ( 6a - s ) in relation to AR binding was also evaluated. A significant loss of activity against rA 1 /rA 2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA 1 ARs ( K i < 10 nM) than rA 2A . Compound 6c had the best rA 1 affinity ( K i = 0.076 nM). Novel compounds ( 6d , 6k , 6l , 6m , 6n , 6o , 6p) were highly selective towards rA 1 AR ( K i between 0.179 and 21.0 nM). Based on their high selectivity for A 1 ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA 1 AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3- b ]pyridines ( 7a , 7d , 7c ) from amino-3,5-dicyanopyridine derivatives ( 6a , 6f , 6g ).

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Role of Adenosine Receptors in Epileptic Seizures

Cited by 6 publications

References 288 publications

Role of Adenosine in Epilepsy and Seizures

Role of Adenosine in Epilepsy and Seizures

The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

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