Adenosine dysfunction in astrogliosis: cause for seizure generation?

Li, Tianfu; Lan, Jing; Fredholm, Bertil B.; Simon, Roger P.; Boison, Detlev

doi:10.1017/s1740925x0800015x

Cited by 107 publications

(133 citation statements)

References 63 publications

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“…The antiseizure role of A 1 receptors was recently strengthened because (i) A 1 receptor knockout mice showed spontaneous hippocampal seizures and high sensitivity to status epilepticus [282,283] and (ii) seizure-activity-limiting effects of Ado (A 1 receptor)-induced attenuation of depolarizing GABA A receptor signaling has been demonstrated [284]. In addition, CCPA enhanced the antiseizure effect of carbamazepine in the mouse maximal electroshock seizure model [285].…”

Section: Adenosine Receptor Agonists and Antagonistsmentioning

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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Section: Adenosine Receptor Agonists and Antagonistsmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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show abstract

“…Astrocyte expansion and proliferation interferes with the normal reuptake of neurotransmitters and glia-neuron metabolic coupling and reduces inhibitory adenosinergic tone (Haydon and Carmignoto, 2006;Li et al, 2007;Devinsky et al, 2013). Microglia activation and proliferation can also promote hyperexcitability through neurotoxic and neuroinflammatory mechanisms (Allan et al, 2005;Block et al, 2007;Devinsky et al, 2013;Salter and Beggs, 2014).…”

Section: Introductionmentioning

confidence: 99%

Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy

et al. 2016

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Neuroinflammation is thought to contribute to the pathogenesis and maintenance of temporal lobe epilepsy, but the underlying cell and molecular mechanisms are not fully understood. The P2X7 receptor is an ionotropic receptor predominantly expressed on the surface of microglia, although neuronal expression has also been reported. The receptor is activated by the release of ATP from intracellular sources that occurs during neurodegeneration, leading to microglial activation and inflammasome-mediated interleukin 1␤ release that contributes to neuroinflammation.UsingareportermouseinwhichgreenfluorescentproteinisinducedinresponsetothetranscriptionofP2rx7,weshowthat expression of the receptor is selectively increased in CA1 pyramidal and dentate granule neurons, as well as in microglia in mice that developed epilepsy after intra-amygdala kainic acid-induced status epilepticus. P2X7 receptor levels were increased in hippocampal subfields in the mice and in resected hippocampus from patients with pharmacoresistant temporal lobe epilepsy. Cells transcribing P2rx7 in hippocampal slices from epileptic mice displayed enhanced agonist-evoked P2X7 receptor currents, and synaptosomes from these animals showed increased P2X7 receptor levels and altered calcium responses. A 5 d treatment of epileptic mice with systemic injections of the centrally available, potent, and specific P2X7 receptor antagonist JNJ-47965567 (30 mg/kg) significantly reduced spontaneous seizures during continuous video-EEG monitoring that persisted beyond the time of drug presence in the brain. Hippocampal sections from JNJ-47965567-treated animals obtained Ͼ5 d after treatment ceased displayed strongly reduced microgliosis and astrogliosis. The present study suggests that targeting the P2X7 receptor has anticonvulsant and possibly disease-modifying effects in experimental epilepsy.

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“…The extracellular concentration of adenosine increases during seizures, and it has been proposed that status epilepticus is a result of loss of adenosine signaling (4). Conversely, mice lacking A1 receptors exhibit a decreased threshold for seizure propagation (5)(6)(7). Adenosine can be generated in the cytosol of neurons as a consequence of the metabolic exhaustion and released directly, as adenosine, via the equilibrative nucleoside transporters (ENTs)-e.g., the ubiquitously expressed ENT1 and ENT2 (8,9).…”

mentioning

confidence: 99%

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity

Lovatt

Xu²,

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

249

221

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Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca 2+ photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.purinergic signaling | purine | glia | calcium signaling S everal lines of work over the past three decades have documented that adenosine acts as an endogenous anticonvulsant (1-3). The extracellular concentration of adenosine increases during seizures, and it has been proposed that status epilepticus is a result of loss of adenosine signaling (4). Conversely, mice lacking A1 receptors exhibit a decreased threshold for seizure propagation (5-7). Adenosine can be generated in the cytosol of neurons as a consequence of the metabolic exhaustion and released directly, as adenosine, via the equilibrative nucleoside transporters (ENTs)-e.g., the ubiquitously expressed ENT1 and ENT2 (8, 9). Alternatively, adenosine is released indirectly, as ATP followed by extracellular enzymatic catabolism to adenosine. The CNS expresses several ectoenzymes, including nucleoside triphosphate diphosphohydrolases (NTPDases; e.g., CD39, NTPDase-2), ectonucleotide pyrophosphatase/phosphodiesterases (e.g., autotaxin), and ecto-5′-nucleotidases (CD73/Nt5e, prostatic acid phosphatase, and alkaline phosphatase) (10-12). Although the regional and cellular activity patterns for each of these enzymes have not been fully explored, exogenous addition of ATP to ex vivo preparations has shown that all regions of the mammalian brain can dephosphorylate ATP to AMP through an ADP intermediate, whereas dephosphorylation of AMP to adenosine occurs primarily in the striatum and olfactory bulb (11). However, the presence of ectoenzymes does not prove that extracellular conversion of ATP to adenosine plays a physiological role, because extracellular adenosine is rapidly recirculated back into the cytosol by ENT1 and ENT2 (13). Further, ATP is released in small quantities during cell-cell signaling, and the effective diffusion of adenosine is limited because of the potent reuptake mechanisms (14). Thus, it is possible that extracellularly generated adenosine is transported back...

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Adenosine dysfunction in astrogliosis: cause for seizure generation?

Cited by 107 publications

References 63 publications

The Antiepileptic Potential of Nucleosides

The Antiepileptic Potential of Nucleosides

Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity

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