Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

Boison, Detlev

doi:10.2174/156802611795347609

Cited by 46 publications

(26 citation statements)

References 294 publications

(327 reference statements)

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“…In rats, decreased ATP hydrolyzation was measured during the formation of a memory for an aversive event [13,14]. A1R and A2R related agents [34] as well as inhibitors of nucleoside metabolism [35] have been proposed as possible procognitive treatments for neurodegenerative disorders including Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

Superior working memory and behavioural habituation but diminished psychomotor coordination in mice lacking the ecto-5′-nucleotidase (CD73) gene

Zlomuzica

Burghoff

Schrader

et al. 2012

Purinergic Signalling

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Adenosine is an important neuromodulator in the central nervous system involved in the regulation of wakefulness, sleep, learning and memory, fear and anxiety as well as motor functions. Extracellular adenosine is synthesized by the cell-surface ectoenzyme ecto-5′-nucleotidase (CD73) from 5′-adenosine monophosphate. While CD73 is widely expressed throughout the mammalian brain, its specific role for behaviour is poorly understood. We examined spatial working memory, emotional responses, motor coordination and motor learning as well as behavioural habituation in mice with a targeted deletion of CD73. CD73 knockout (CD73−/−) mice exhibit enhanced spatial working memory in the Y-maze and enhanced long-term behavioural habituation in the open field. Furthermore, impaired psychomotor coordination on the accelerating rotarod was found in CD73−/− mice. No changes in motor learning and/ or anxiety-like behaviour were evident in CD73−/− mice.Our data provide evidence for a role of CD73 in the regulation of learning and memory and psychomotor coordination. Our results might be important for the evaluation of adenosine neuromodulators as possible treatments to ameliorate cognitive and motor deficits associated with neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Superior working memory and behavioural habituation but diminished psychomotor coordination in mice lacking the ecto-5′-nucleotidase (CD73) gene

Zlomuzica

Burghoff

Schrader

et al. 2012

Purinergic Signalling

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“…The modulatory role of Ado in different brain diseases involving epilepsy has been investigated extensively [31,32,[85][86][87], and some of the drugs that have effects on the adenosinergic system (e.g., ADK inhibitors) may also be used in the treatment of epileptic seizures [32,86]. However, nonAdo nucleosides, such as Guo, Ino and Urd, may also decrease the EC level of the excitatory neurotransmitter glutamate and/or increase GABAergic inhibition [88][89][90] and participate in pathophysiological processes of epilepsy [58][59][60][61][62][63][64].…”

Section: Modulatory Role Of Nucleosides On Epileptic Activitymentioning

confidence: 99%

“…Systemic application of ADK inhibitors as potential antiepileptic drugs is limited [86] by their cardiovascular and hypothermic side effects [141,206], their sedative effect and their CNS hemorrhaging effect [93]. In addition, Boison et al [207] demonstrated lethal hepatic steatosis in ADK knockout mice.…”

Section: The Specific Role Of Adenosine In Inflammationinduced Epilepsymentioning

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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“…A therapeutic alternative might be the direct modulation of the ambient level of adenosine, and this can be achieved by targeting enzymes or nucleoside transporters that control the extracellular levels of adenosine (19). A promising target is adenosine kinase (ADK), the key enzyme of the metabolic adenosine clearance pathway (20).…”

Section: Introductionmentioning

confidence: 99%

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Shen¹,

Singer²,

Lytle³

et al. 2012

J. Clin. Invest.

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An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A 2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia. IntroductionDespite extensive research over half a century, schizophrenia remains a major health concern, affecting more than one percent of the population. Two hypotheses, those of dopaminergic hyperfunction (1) and glutamatergic hypofunction (2), are widely accepted conceptual frameworks for understanding the pathophysiology of schizophrenia and for the development of drugs for the treatment of either dopamine-related or glutamate-related symptoms of the disease (2, 3). This study addresses a third hypothesis, the "adenosine hypothesis of schizophrenia," which has recently been proposed as a novel concept to integrate the dopaminergic hyperfunction and glutamatergic hypofunction hypotheses (4).The purine ribonucleoside adenosine modulates neurotransmission through activation of 4 types of G protein-coupled adenosine receptors (ARs), A 1 R, A 2A R, A 2B R, and A 3 R, which exert spatially distinct functions within the brain on presynaptic and postsynaptic sites (5, 6). Presynaptically, adenosine regulates the release of both dopamine and glutamate (7,8), whereas the output of dopaminergic and glutamatergic neurotransmission is regulated by heterodimerization of ARs with dopamine and glutamate receptors (9, 10). Through these mechanisms adenosine exerts upstream control over both dopaminergic and glutamatergic signaling. Consequently, any disruption in adenosine homeostasis is expected to affect those 2 transmitter systems, which play fundamental roles in the pathophysiology of schizophrenia. This regulatory function of adenosine might provide a missing link for the functional integration of the dopamine and glutamate hypotheses. Conventional antipsychotic

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Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

Cited by 46 publications

References 294 publications

Superior working memory and behavioural habituation but diminished psychomotor coordination in mice lacking the ecto-5′-nucleotidase (CD73) gene

Superior working memory and behavioural habituation but diminished psychomotor coordination in mice lacking the ecto-5′-nucleotidase (CD73) gene

The Antiepileptic Potential of Nucleosides

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

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