Loss of A1 adenosine receptors in human temporal lobe epilepsy

Glass, Michelle; Faull, Richard L.M.; Bullock, Jocelyn Y.; Jansen, Karl; Mee, Edward; Walker, Elizabeth; Synek, Beth J.; Dragunow, Michael

doi:10.1016/0006-8993(95)01313-x

Cited by 120 publications

(77 citation statements)

References 49 publications

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“…Remarkably, and in agreement with upregulated ADK in epileptogenic hippocampus, in these studies basal adenosine levels sampled before the onset of seizures were lower in the epileptogenic hippocampus compared to the non-epileptic hippocampus (During and Spencer, 1992). Findings on A 1 R expression in human temporal lobe epilepsy are controversial; both downand upregulation of A 1 R have been described (Angelatou et al, 1993;Glass et al, 1996). Indeed, the incidence of spontaneous seizures in heterozygous A 1 R knockout mice described here (Fig.…”

Section: Clinical Findingssupporting

confidence: 86%

Adenosine dysfunction in astrogliosis: cause for seizure generation?

et al. 2007

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Epilepsy is characterized by both neuronal and astroglial dysfunction. The endogenous anticonvulsant adenosine, the level of which is largely controlled by astrocytes, might provide a critical link between astrocyte and neuron dysfunction in epilepsy. Here we studied astrogliosis, a hallmark of the epileptic brain, adenosine dysfunction and the emergence of spontaneous seizures in a comprehensive approach including a new mouse model of focal epileptogenesis, mutant mice with altered brain levels of adenosine, and mice lacking adenosine A 1 receptors. In wild type mice, following a focal epileptogenesis-precipitating injury, astrogliosis, upregulation of the adenosineremoving astrocytic enzyme adenosine kinase (ADK), and spontaneous seizures all coincided in a spatio-temporally restricted manner. Importantly, these spontaneous seizures were mimicked in untreated transgenic mice overexpressing ADK in brain or those lacking A 1 receptors. Conversely, mice with reduced forebrain ADK did not develop astrogliosis or spontaneous seizures. Our studies define ADK as critical upstream regulator of A 1 receptor mediated modulation of neuronal excitability and support the ADK hypothesis of epileptogenesis implicating that upregulation of ADK during astrogliosis provides a critical link between astrocyte and neuron dysfunction in epilepsy. These findings define ADK as rational target for therapeutic intervention.

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Section: Clinical Findingssupporting

confidence: 86%

Adenosine dysfunction in astrogliosis: cause for seizure generation?

et al. 2007

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“…Remarkably, and in agreement with upregulated ADK in epileptogenic hippocampus, in these studies basal adenosine levels sampled before the onset of seizures were lower in the epileptogenic hippocampus compared to the non-epileptic hippocampus (During and Spencer, 1992). Findings on A 1 R expression in human temporal lobe epilepsy are controversial; both down-and upregulation of A 1 R have been described (Angelatou et al, 1993;Glass et al, 1996). More recent findings from human studies suggest energetic dysfunction and mitochondrial dysfunction to be implicated in epileptogenesis (Kunz, 2002;Pan et al, 2005;Williamson et al, 2005).…”

Section: Adenosine In Human Epilepsysupporting

confidence: 74%

“…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: 94%

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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“…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: 89%

“…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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Loss of A1 adenosine receptors in human temporal lobe epilepsy

Cited by 120 publications

References 49 publications

Adenosine dysfunction in astrogliosis: cause for seizure generation?

Adenosine dysfunction in astrogliosis: cause for seizure generation?

The adenosine kinase hypothesis of epileptogenesis

The Antiepileptic Potential of Nucleosides

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