The adenosine hypothesis of epilepsy

O'Brien, D.R.

doi:10.1016/0306-9877(88)90007-2

Cited by 9 publications

(5 citation statements)

References 23 publications

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“…Although the binding and signaling mechanism of nonAdo nucleosides (Urd, Guo and Ino) as well as their exact effect on epileptic activity have not been established yet, the available data suggest an expansion of the adenosinergic/purinergic hypothesis in relation to epileptic activity [93,423]; therefore, we discussed that not only Ado but also endogenous Urd, Guo and Ino might have a crucial role in the modulation of the epileptic activity and sensitivity to epileptic seizures. Consequently, even if we have only sporadic data on the distribution and function of metabolic enzymes of Urd, Guo and Ino under different pathological conditions (e.g., epilepsy) in brain areas, we cannot exclude the possibility that their metabolic enzyme inhibitors are potential antiepileptic drugs, which increase the levels of non-Ado nucleosides.…”

Section: New Developmentsmentioning

confidence: 97%

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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Section: New Developmentsmentioning

confidence: 97%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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“…Adenosine and other purines are known modulators of neuronal excitability and seizure activity in experimental animals and humans (Dunwiddie, 1980 ; Turski et al, 1985 ; O’Brien, 1988 ; Arvin et al, 1989 ; During and Spencer, 1992 ; Boison et al, 1999 ; Huber et al, 2001 ; Zuchora et al, 2001 ; Anschel et al, 2004 ; Boison, 2005 , 2006 , 2008 , 2009 ; Cunha, 2005 ; Vianna et al, 2005 ; Pagonopoulou et al, 2006 ; Li et al, 2007 , 2011 ; Boison and Stewart, 2009 ; Van Dycke et al, 2010 , 2011 ; Hargus et al, 2012 ). In rats, adenosine injections directly onto the epileptic focus (Anschel et al, 2004 ) or the hippocampus improve seizure control (Van Dycke et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Role of adenosine in the antiepileptic effects of deep brain stimulation

Miranda

Hamani

Almeida

et al. 2014

Front. Cell. Neurosci.

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Despite the effectiveness of anterior thalamic nucleus (AN) deep brain stimulation (DBS) for the treatment of epilepsy, mechanisms responsible for the antiepileptic effects of this therapy remain elusive. As adenosine modulates neuronal excitability and seizure activity in animal models, we hypothesized that this nucleoside could be one of the substrates involved in the effects of AN DBS. We applied 5 days of stimulation to rats rendered chronically epileptic by pilocarpine injections and recorded epileptiform activity in hippocampal slices. We found that slices from animals given DBS had reduced hippocampal excitability and were less susceptible to develop ictal activity. In live animals, AN DBS significantly increased adenosine levels in the hippocampus as measured by microdialysis. The reduced excitability of DBS in vitro was completely abolished in animals pre-treated with A1 receptor antagonists and was strongly potentiated by A1 receptor agonists. We conclude that some of the antiepileptic effects of DBS may be mediated by adenosine.

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Section: Discussionmentioning

confidence: 99%

“…Adenosinergic activities are tightly linked to the etiological and pathophysiological outcomes of seizures and epilepsy ( Ashraf et al, 2021 ; Faingold et al, 2016 ; Kommajosyula et al, 2016 ; Masino et al, 2014 ; O'Brien, 1988 ; Shen et al, 2014 ). Acute and chronic seizures can trigger repeated adenosine surges and increase adenosine tone in the brain, which can act as an endogenous anticonvulsant and also reset neuron network stability by affecting neurotransmission at the synapse ( Masino et al, 2014 ; O'Brien, 1988 ). It is increasingly established that two main systems are contributing to the extracellular adenosine that engages the adenosine modulation system in the brain: the activity of equilibrative nucleoside transporters (ENTs) and of ADK mostly associated with a global A 1 R function and CD73-mediated formation of ATP-derived adenosine tightly associated with A 2A R activation ( Cunha, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Further, due to the complexity of the adenosinergic actions in the CNS and diverse and wide distributions of A 1 R and A 2A R across brain regions ( O'Brien, 1988 ; Chen et al, 2014 ; Fredholm et al, 2005 ; Chen et al, 2013 ), the application of adenosinergic interventions to prevent SUDEP deserves deeper discussion. In the hippocampus, A 1 R suppresses the ictal firing of excitatory neurons; conversely, hippocampal A 2A R activation is proconvulsant and proseizure ( Zeraati et al, 2006 ; El Yacoubi et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

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Adenosine-A2A Receptor Signaling Plays a Crucial Role in Sudden Unexpected Death in Epilepsy

et al. 2022

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Adenosinergic activities are suggested to participate in SUDEP pathophysiology; this study aimed to evaluate the adenosine hypothesis of SUDEP and specifically the role of adenosine A2A receptor (A2AR) in the development of a SUDEP mouse model with relevant clinical features. Using a combined paradigm of intrahippocampal and intraperitoneal administration of kainic acid (KA), we developed a boosted-KA model of SUDEP in genetically modified adenosine kinase (ADK) knockdown (Adk+/-) mice, which has reduced ADK in the brain. Seizure activity was monitored using video-EEG methods, and in vivo recording of local field potential (LFP) was used to evaluate neuronal activity within the nucleus tractus solitarius (NTS). Our boosted-KA model of SUDEP was characterized by a delayed, postictal sudden death in epileptic mice. We demonstrated a higher incidence of SUDEP in Adk+/- mice (34.8%) vs. WTs (8.0%), and the ADK inhibitor, 5-Iodotubercidin, further increased SUDEP in Adk+/- mice (46.7%). We revealed that the NTS level of ADK was significantly increased in epileptic WTs, but not in epileptic Adk+/- mutants, while the A2AR level in NTS was increased in epileptic (WT and Adk+/-) mice vs. non-epileptic controls. The A2AR antagonist, SCH58261, significantly reduced SUDEP events in Adk+/- mice. LFP data showed that SCH58261 partially restored KA injection-induced suppression of gamma oscillation in the NTS of epileptic WT mice, whereas SCH58261 increased theta and beta oscillations in Adk+/- mutants after KA injection, albeit with no change in gamma oscillations. These LFP findings suggest that SCH58261 and KA induced changes in local neuronal activities in the NTS of epileptic mice. We revealed a crucial role for NTS A2AR in SUDEP pathophysiology suggesting A2AR as a potential therapeutic target for SUDEP risk prevention.

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The adenosine hypothesis of epilepsy

Cited by 9 publications

References 23 publications

The Antiepileptic Potential of Nucleosides

The Antiepileptic Potential of Nucleosides

Role of adenosine in the antiepileptic effects of deep brain stimulation

Adenosine-A2A Receptor Signaling Plays a Crucial Role in Sudden Unexpected Death in Epilepsy

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