The adenosine kinase hypothesis of epileptogenesis

Boison, Detlev

doi:10.1016/j.pneurobio.2007.12.002

Cited by 208 publications

(221 citation statements)

References 154 publications

(206 reference statements)

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“…Recently an "astrocytic basis for epilepsy" was proposed based on findings that Ca 2+ homeostasis in astrocytes plays a key role in the hyper-synchronization of epileptic bursts (Tian et al, 2005). Here we provide experimental evidence in support of the "ADK hypothesis of epileptogenesis" (Boison, 2008b), which is based on astrogliotic upregulation of the key adenosine-removing enzyme ADK.…”

Section: Discussionsupporting

confidence: 60%

“…This in turn causes adenosine deficiency, increased neuronal excitability and seizure generation. This hypothesis (Boison, 2008b) is based on previous work correlating astrogliosis and upregulation of ADK with the emergence of spontaneous seizures (Gouder et al, 2004;Fedele et al, 2005;Li et al, 2008). Here we expand these previous studies by providing a comprehensive analysis of the spatio-temporal requirements of ADK dysregulation in a new mouse model of focal CA3-selective epileptogenesis (Li et al, 2008).…”

Section: Objectivementioning

confidence: 63%

“…after establishment of the initial precipitating injury) significantly reduced the degree of CA3-selective astrogliosis, prevented upregulation of ADK, and -most importantly -prevented the occurrence of CA3-selective seizures 3 weeks after acute brain injury (Li et al, 2008). The beneficial mechanisms how chronic augmentation of brain adenosine in the nanomolar range as achieved by cell-based brain implants (Huber et al, 2001) lead to a reduction of astrogliosis and to lack of ADK upregulation need to be distinguished from the mechanisms of acute rises in adenosine to micromolar levels (Fredholm et al, 2005a) as a response to injury that are thought to trigger astrogliosis (Boison, 2008b). More work is needed to fully understand the mechanistic differences of opposing downstream-effects of chronic low-level increases in adenosine versus acute high-level increases in adenosine.…”

mentioning

confidence: 99%

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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: Discussionsupporting

confidence: 60%

Section: Objectivementioning

confidence: 63%

mentioning

confidence: 99%

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Adenosine dysfunction in astrogliosis: cause for seizure generation?

et al. 2007

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“…As A 1 R agonists have peripheral cardiac and central sedative side-effects, adenosine kinase inhibitors (Fig. 29.1 ) have been used to indirectly increase Ado levels (Boison 2008 ) . These drugs were shown to have anticonvulsant properties .…”

Section: Epilepsymentioning

confidence: 99%

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

Kovács

Dobolyi

2012

Adenosine

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Nucleosides have a wide range of physiological and pathophysiological roles in the human brain as modulators of a variety of neural functions. For example, adenosine, inosine, guanosine, and uridine participate in the mechanisms underlying memory, cognition, sleep, pain, depression, schizophrenia, epilepsy, Alzheimer's disease, Huntington's disease, and Parkinson's disease. Consequently, increasing attention is now being given to the speci fi c role of nucleosides in physiological and pathological processes in the human brain. Different elements of nucleoside system, including nucleoside concentrations, metabolic enzyme activity, and expression of nucleoside transporters and receptors, may be changed under normal and pathological conditions. The alterations suggest that interlinked elements of the nucleoside system are functioning in a tightly concerted manner.Nucleoside levels, activity of nucleoside metabolic enzymes, and expression of nucleoside transporters and receptors are unevenly distributed in the brain, suggesting that nucleosides have different roles in functionally distinct human brain areas. The aim of this chapter is to summarize our present knowledge of the anatomical distribution of nucleoside system in the human brain, placing emphasis on potential therapeutic pharmacological strategies.

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“…The recent identification of focal adenosine deficiency as major cause for seizure generation [11,12] provides a neurochemical rationale for focal adenosine augmentation therapies (AATs). Focal AATs can be accomplished by implanting adenosine releasing devices or cells into the vicinity of an epileptogenic focus [13].…”

Section: Introductionmentioning

confidence: 99%

Silk polymer-based adenosine release: Therapeutic potential for epilepsy

et al. 2008

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Adenosine augmentation therapies (AAT) make rational use of the brain's own adenosine-based seizure control system and hold promise for the therapy of refractory epilepsy. In an effort to develop an AAT compatible with future clinical application, we developed a novel silk protein-based release system for adenosine. Adenosine releasing brain implants with target release doses of 0, 40, 200, and 1,000 ng adenosine/day were prepared by embedding adenosine-containing microspheres into nanofilm-coated silk fibroin scaffolds. In vitro, the respective polymers released 0, 33.4, 170.5, and 819.0 ng adenosine/day over 14 days. The therapeutic potential of the implants was validated in a dose-response study in the rat model of kindling epileptogenesis. Four days prior to the onset of kindling, adenosine-releasing polymers were implanted into the infrahippocampal cleft and progressive acquisition of kindled seizures was monitored over a total of 48 stimulations. We document a dose-dependent retardation of seizure acquisition. In recipients of polymers releasing 819 ng adenosine/day, kindling epileptogenesis was delayed by one week corresponding to 18 kindling stimulations. Histological analysis of brain samples confirmed correct location of implants and electrodes. We conclude that silk-based delivery of around 1,000 ng adenosine/day is a safe and efficient strategy to suppress seizures.

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The adenosine kinase hypothesis of epileptogenesis

Cited by 208 publications

References 154 publications

Adenosine dysfunction in astrogliosis: cause for seizure generation?

Adenosine dysfunction in astrogliosis: cause for seizure generation?

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

Silk polymer-based adenosine release: Therapeutic potential for epilepsy

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