Reduction of A1 adenosine receptors in rat hippocampus after kainic acid-induced limbic seizures

Ekonomou, Antigoni; Sperk, Günther; Kostopoulos, George; Angelatou, Fevronia

doi:10.1016/s0304-3940(00)00954-x

Cited by 53 publications

(44 citation statements)

References 21 publications

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“…Thus, it is compelling to conclude that under conditions of brain injury, hypoxia, or inflammation, which all cause both upregulation of A 2A Rs (Cunha, 2005) as well as acute increase in adenosine (Dunwiddie and Masino, 2001), an adenosine-based mechanism contributes to astrogliosis. This notion is further supported by findings that stimulation of A 1 Rs, which are downregulated during epileptogenesis (Ekonomou et al, 2000;Rebola et al, 2003;Rebola et al, 2005), leads to a reduction of astrocyte proliferation (Rathbone et al, 1991).…”

Section: Astrogliosismentioning

confidence: 58%

“…Synaptic activation of A 2A receptors can subsequently downregulate A 1 receptors or its responses (Ciruela et al, 2006;Lopes et al, 1999). Thus, synaptic stimulation of A 2A receptors under high frequency conditions in epileptic circuits could lead to downregulation of A 1 receptors, a finding confirmed in chronic epilepsy (Ekonomou et al, 2000;Glass et al, 1996;Rebola et al, 2003). An additional layer of complexity in adenosine receptor function is created by heteromerization with each other (e.g.…”

Section: Adenosine a 2a Receptorsmentioning

confidence: 93%

“…These findings demonstrate that upregulation of ADK in chronic epilepsy is implicated in epileptogenesis by reducing the adenosine tone at the A 1 R. Upregulation of ADK was also found in chronically kindled rats and in the rat pilocarpine model of epilepsy (D. Boison, unpublished observations). Upregulation of ADK in chronic epilepsy is paralleled by changes in G-protein coupled receptor expression such as downregulation of A 1 Rs (Ekonomou et al, 2000;Rebola et al, 2003;Rebola et al, 2005), reorganization of cannabinoid type 1 receptors (Falenski et al, 2007), or increases in GABA B receptor expression (Kokaia et al, 2001;Morimoto et al, 2004).…”

Section: Biphasic Regulation Of Adenosine Kinase Expressionmentioning

confidence: 99%

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The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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Section: Astrogliosismentioning

confidence: 58%

Section: Adenosine a 2a Receptorsmentioning

confidence: 93%

Section: Biphasic Regulation Of Adenosine Kinase Expressionmentioning

confidence: 99%

See 1 more Smart Citation

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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“…For example, low or moderate Ado concentrations in the human cerebral cortex and hippocampus correlate well with the medium to high A 1 receptor expression in these brain regions [30,56] suggesting the involvement of Ado and its receptors in the modulation of hippocampal and cortical activity in pathological conditions such as epilepsy. It has also been supported by the demonstration of an epilepsy-induced decrease in A 1 receptor expression in chronic seizures [67,[158][159][160]228] and adaptive changes in Ado receptors after seizures [111]. Activation of A 2B receptors by elevated Ado levels may induce the release of proinflammatory interleukin-6 (IL-6) from astrocytes leading to increased expression of A 1 receptors and their functions in the brain [229,230], which may explain (i) the increase of A 1 receptor expression after seizures parallel with increasing Ado level and (ii) the higher level of IL-6 in the brain areas (e.g., in the hippocampus and cortex) of epileptic patients and rats [186,[231][232][233], which may have a protective effect against subsequent seizures [230].…”

Section: Adenosine Receptor Agonists and Antagonistsmentioning

confidence: 90%

“…The expression of ADK by glial fibrillary acidic protein (GFAP)-positive astrocytes and the overexpression of ADK in parallel with the formation of astrogliosis has been observed [27,65,93,156]. Additionally, although A 1 receptors may reduce astrogliosis [157], expression of astrocytic A 1 receptors may be reduced by epileptogenesis [158][159][160][161]. A 2A receptors are upregulated by high Ado levels [27]; thus, the crucial role of Ado receptor expression in astrogliosis, the astrogliosisinduced increase in ADK activity and the disruption of Ado homeostasis have been suggested in epilepsy [151,156,162,163].…”

Section: Modulation Of Adenosine Levels and Epileptic Activity By Metmentioning

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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Ectonucleotidases and synaptic plasticity: Implications in physiological and pathological conditions

Bonan

Schetinger

Battastini

et al. 2001

Drug Development Research

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Several studies have suggested a role of extracellular ATP in synaptic plasticity. The signaling actions induced by extracellular ATP are directly correlated to the activity of a group of ectonucleotidases, which includes an ecto-ATPase (EC 3.6.1.3), an ATP diphosphohydrolase (apyrase, EC 3.6.1.5), and a 5′-nucleotidase (EC 3.1.3.5). These ectoenzymes trigger enzymatic conversion of ATP to adenosine, an important neuromodulator. Our studies have shown that ectonucleotidase activities are modulated in physiological and pathological situations able to induce synaptic plasticity, such as memory, epilepsy, and ischemia. Synaptosomal ectonucleotidase activities from hippocampus and entorhinal cortex were inhibited after the training session in a step-down inhibitory avoidance task in rats. Considering that adenosine has anticonvulsant effects, ectonucleotidase activities were determined after the induction of epilepsy by several animal models, such as pilocarpine, kainic acid, and kindling models. ATP diphosphohydrolase and 5′-nucleotidase activities from synaptosomes of hippocampus and cerebral cortex of rats significantly and differently increased after induction of status epilepticus by pilocarpine, kainic acid, or kindling models. Furthermore, significant changes have been observed in ATP diphosphohydrolase and 5′-nucleotidase after ischemia and reperfusion in hippocampal synaptosomes of rats. The demonstration that ectonucleotidases presented the activities altered after a memory task, or the induction of animal models of epilepsy or ischemia-reperfusion, suggests that these enzymes can act in the regulation of synaptic activity, controlling ATP and adenosine levels, depending on the synaptic plasticity developed, in physiological or pathological conditions. Drug Dev. Res. 52:57-65, 2001.

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Reduction of A1 adenosine receptors in rat hippocampus after kainic acid-induced limbic seizures

Cited by 53 publications

References 21 publications

The adenosine kinase hypothesis of epileptogenesis

The adenosine kinase hypothesis of epileptogenesis

The Antiepileptic Potential of Nucleosides

Ectonucleotidases and synaptic plasticity: Implications in physiological and pathological conditions

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