The use of real-time PCR with fluorogenic probes for the rapid selection of mutant neuroectodermal grafts

Zumsteg, Valérie; Boison, Detlev

doi:10.1016/s0165-0270(02)00186-3

Cited by 3 publications

(1 citation statement)

References 21 publications

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“…(5) A pathological increase of ADK enzyme activity in epileptic hippocampus would be an explanation for the efficacy of antiepileptic drugs that inhibit ADK. ADK inhibition was demonstrated to potentiate local extracellular adenosine levels at cell and tissue sites, which are undergoing accelerated adenosine release Kowaluk and Jarvis, 2000), and cultured cells with a complete lack of ADK released substantial amounts of adenosine (Huber et al, 2001;Zumsteg and Boison, 2002). (6) Finally, the contribution of ADK expression to chronic seizure activity would favor the development of local adenosine-based therapeutic interventions for chronic epilepsy, e.g., by grafting of adenosine-releasing cells and/or by pharmacological inhibition of ADK.…”

Section: Adenosine Levels In Brainmentioning

confidence: 99%

Overexpression of Adenosine Kinase in Epileptic Hippocampus Contributes to Epileptogenesis

Gouder¹,

Scheurer²,

Fritschy³

et al. 2004

J. Neurosci.

201

245

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Endogenous adenosine in the brain is thought to prevent the development and spread of seizures via a tonic anticonvulsant effect. Brain levels of adenosine are primarily regulated by the activity of adenosine kinase. To establish a link between adenosine kinase expression and seizure activity, we analyzed the expression of adenosine kinase in the brain of control mice and in a kainic acid-induced mouse model of mesial temporal lobe epilepsy. Immunohistochemical analysis of brain sections of control mice revealed intense staining for adenosine kinase, mainly in astrocytes, which were more or less evenly distributed throughout the brain, as well as in some neurons, particularly in olfactory bulb, striatum, and brainstem. In contrast, hippocampi lesioned by a unilateral kainic acid injection displayed profound astrogliosis and therefore a significant increase in adenosine kinase immunoreactivity accompanied by a corresponding increase of enzyme activity, which paralleled chronic recurrent seizure activity in this brain region. Accordingly, seizures and interictal spikes were suppressed by the injection of a low dose of the adenosine kinase inhibitor 5-iodotubercidin. We conclude that overexpression of adenosine kinase in discrete parts of the epileptic hippocampus may contribute to the development and progression of seizure activity.

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Section: Adenosine Levels In Brainmentioning

confidence: 99%

Overexpression of Adenosine Kinase in Epileptic Hippocampus Contributes to Epileptogenesis

Gouder¹,

Scheurer²,

Fritschy³

et al. 2004

J. Neurosci.

201

245

View full text Add to dashboard Cite

show abstract

Astrogliosis in epilepsy leads to overexpression of adenosine kinase, resulting in seizure aggravation

Fedele¹,

Gouder²,

Güttinger³

et al. 2005

Brain

Self Cite

170

192

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Adenosine kinase (ADK) is considered to be the key regulator of the brain's endogenous anticonvulsant, adenosine. In adult brain, ADK is primarily expressed in a subpopulation of astrocytes and striking upregulation of ADK in these cells has been associated with astrogliosis after kainic acid-induced status epilepticus (KASE) in the kainic acid mouse model of temporal lobe epilepsy. To investigate the causal relationship between KASE-induced astrogliosis, upregulation of ADK and seizure activity, we have developed a novel mouse model [the Adktm1(-/-)-Tg(UbiAdk) mouse] lacking the endogenous astrocytic enzyme due to a targeted disruption of the endogenous gene, but containing an Adk transgene under the control of a human ubiquitin promoter. Mutant Adktm1(-/-)-Tg(UbiAdk) mice were characterized by increased brain ADK activity and constitutive overexpression of transgenic ADK throughout the brain, with particularly high levels in hippocampal pyramidal neurons. This ADK overexpression was associated with increased baseline levels of locomotion. Most importantly, two-thirds of the mutant mice analysed exhibited spontaneous seizure activity in the hippocampus and cortex. This was the direct consequence of transgene expression, since this seizure activity could be prevented by systemic application of the ADK inhibitor 5-iodotubercidin. Intrahippocampal injection of kainate in the mutant mice resulted in astrogliosis to the same extent as that observed in wild-type mice despite the absence of endogenous astrocytic ADK. Therefore, KASE-induced upregulation of endogenous ADK in wild-type mice is a consequence of astrogliosis. However, seizures in kainic acid-injected mutants displayed increased intra-ictal spike frequency compared with wild-type mice, indicating that, once epilepsy is established, increased levels of ADK aggravate seizure severity. We therefore conclude that therapeutic strategies that augment the adenosine system after astrogliosis-induced upregulation of ADK constitute a neurochemical rationale for the prevention of seizures in epilepsy.

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Adenosine and Epilepsy: From Therapeutic Rationale to New Therapeutic Strategies

2005

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Adenosine, as the brain's endogenous anticonvulsant, is considered to be responsible for seizure arrest and postictal refractoriness. On the other hand, deficiencies within the adenosine-based neuromodulatory system may contribute to epileptogenesis. Based on these natural mechanisms and on findings that adenosine and its analogs can suppress pharmacoresistant seizures, a new field of adenosine-based therapies has emerged, including the use of adenosine receptor agonists and adenosine transport inhibitors, or the inhibition of adenosine kinase, which is thought to be the key enzyme for the regulation of intra- and extracellular adenosine levels. However, most of these pharmacological approaches are limited by strong systemic side effects ranging from a decrease of heart rate, blood pressure, and body temperature to sedation. Recently, new strategies have been developed aimed at the local reconstitution of the inhibitory adenosinergic tone by intracerebral implantation of cells engineered to release adenosine. Adenosine-releasing cells or devices implanted into or near a seizure focus offer new hopes for a side effect-free therapy for pharmacoresistant epilepsy.

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The use of real-time PCR with fluorogenic probes for the rapid selection of mutant neuroectodermal grafts

Cited by 3 publications

References 21 publications

Overexpression of Adenosine Kinase in Epileptic Hippocampus Contributes to Epileptogenesis

Overexpression of Adenosine Kinase in Epileptic Hippocampus Contributes to Epileptogenesis

Astrogliosis in epilepsy leads to overexpression of adenosine kinase, resulting in seizure aggravation

Adenosine and Epilepsy: From Therapeutic Rationale to New Therapeutic Strategies

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