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  1. Book ; Online ; E-Book: Homeostatic control of brain function

    Boison, Detlev / Masino, Susan A.

    2016  

    Author's details edited by Detlev Boison, PhD; Susan A. Masono
    Keywords Homeostasis / physiology ; Brain / physiology ; Brain Chemistry
    Language English
    Size 1 Online-Ressource (xiv, 642 Seiten), Illustrationen
    Publisher Oxford University Press
    Publishing place Oxford
    Publishing country United States
    Document type Book ; Online ; E-Book
    Remark Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
    HBZ-ID HT019008801
    ISBN 978-0-199-32230-5 ; 9780199322299 ; 0-199-32230-9 ; 0199322295
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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  2. Article: Specialty Grand Challenge for Brain Disease Mechanisms.

    Boison, Detlev

    Frontiers in molecular neuroscience

    2021  Volume 14, Page(s) 689903

    Language English
    Publishing date 2021-05-10
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2021.689903
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  3. Article ; Online: Bipolar mania and epilepsy pathophysiology and treatment may converge in purine metabolism: A new perspective on available evidence.

    Daniels, Scott D / Boison, Detlev

    Neuropharmacology

    2023  Volume 241, Page(s) 109756

    Abstract: Decreased ATPergic signaling is an increasingly recognized pathophysiology in bipolar mania disease models. In parallel, adenosine deficit is increasingly recognized in epilepsy pathophysiology. Under-recognized ATP and/or adenosine-increasing mechanisms ...

    Abstract Decreased ATPergic signaling is an increasingly recognized pathophysiology in bipolar mania disease models. In parallel, adenosine deficit is increasingly recognized in epilepsy pathophysiology. Under-recognized ATP and/or adenosine-increasing mechanisms of several antimanic and antiseizure therapies including lithium, valproate, carbamazepine, and ECT suggest a fundamental pathogenic role of adenosine deficit in bipolar mania to match the established role of adenosine deficit in epilepsy. The depletion of adenosine-derivatives within the purine cycle is expected to result in a compensatory increase in oxopurines (uric acid precursors) and secondarily increased uric acid, observed in both bipolar mania and epilepsy. Cortisol-based inhibition of purine conversion to adenosine-derivatives may be reflected in observed uric acid increases and the well-established contribution of cortisol to both bipolar mania and epilepsy pathology. Cortisol-inhibited conversion from IMP to AMP as precursor of both ATP and adenosine may represent a mechanism for treatment resistance common in both bipolar mania and epilepsy. Anti-cortisol therapies may therefore augment other treatments both in bipolar mania and epilepsy. Evidence linking (i) adenosine deficit with a decreased need for sleep, (ii) IMP/cGMP excess with compulsive hypersexuality, and (iii) guanosine excess with grandiose delusions may converge to suggest a novel theory of bipolar mania as a condition characterized by disrupted purine metabolism. The potential for disease-modification and prevention related to adenosine-mediated epigenetic changes in epilepsy may be mirrored in mania. Evaluating the purinergic effects of existing agents and validating purine dysregulation may improve diagnosis and treatment in bipolar mania and epilepsy and provide specific targets for drug development.
    MeSH term(s) Humans ; Bipolar Disorder/drug therapy ; Mania/drug therapy ; Hydrocortisone ; Uric Acid/therapeutic use ; Valproic Acid/therapeutic use ; Antimanic Agents/pharmacology ; Antimanic Agents/therapeutic use ; Purines/therapeutic use ; Epilepsy/drug therapy ; Adenosine Triphosphate ; Adenosine
    Chemical Substances Hydrocortisone (WI4X0X7BPJ) ; Uric Acid (268B43MJ25) ; Valproic Acid (614OI1Z5WI) ; Antimanic Agents ; Purines ; Adenosine Triphosphate (8L70Q75FXE) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2023-10-09
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2023.109756
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  4. Article ; Online: The metabolic basis of epilepsy.

    Rho, Jong M / Boison, Detlev

    Nature reviews. Neurology

    2022  Volume 18, Issue 6, Page(s) 333–347

    Abstract: The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures ... ...

    Abstract The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures have long been known to permanently alter neuronal circuitry and to cause excitotoxic injury and aberrant inflammation. Furthermore, pathological changes in bioenergetics and metabolism are considered downstream consequences of epileptic seizures that begin at the synaptic level. However, as we highlight in this Review, evidence is also emerging that primary derangements in cellular or mitochondrial metabolism can result in seizure genesis and lead to spontaneous recurrent seizures. Basic and translational research indicates that the relationships between brain metabolism and epileptic seizures are complex and bidirectional, producing a vicious cycle that compounds the deleterious consequences of seizures. Metabolism-based treatments such as the high-fat, antiseizure ketogenic diet have become mainstream, and metabolic substrates and enzymes have become attractive molecular targets for seizure prevention and recovery. Moreover, given that metabolism is crucial for epigenetic as well as inflammatory changes, the idea that epileptogenesis can be both negatively and positively influenced by metabolic changes is rapidly gaining ground. Here, we review evidence that supports both pathophysiological and therapeutic roles for brain metabolism in epilepsy.
    MeSH term(s) Brain/pathology ; Energy Metabolism/physiology ; Epilepsy ; Humans ; Seizures/drug therapy ; Seizures/etiology ; Status Epilepticus
    Language English
    Publishing date 2022-03-31
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 2491514-2
    ISSN 1759-4766 ; 1759-4758
    ISSN (online) 1759-4766
    ISSN 1759-4758
    DOI 10.1038/s41582-022-00651-8
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  5. Article ; Online: ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain.

    Yegutkin, Gennady G / Boison, Detlev

    Pharmacological reviews

    2022  Volume 74, Issue 3, Page(s) 797–822

    Abstract: Adenosine is an evolutionary ancient metabolic regulator linking energy state to physiologic processes, including immunomodulation and cell proliferation. Tumors create an adenosine-rich immunosuppressive microenvironment through the increased release of ...

    Abstract Adenosine is an evolutionary ancient metabolic regulator linking energy state to physiologic processes, including immunomodulation and cell proliferation. Tumors create an adenosine-rich immunosuppressive microenvironment through the increased release of ATP from dying and stressed cells and its ectoenzymatic conversion into adenosine. Therefore, the adenosine pathway becomes an important therapeutic target to improve the effectiveness of immune therapies. Prior research has focused largely on the two major ectonucleotidases, ectonucleoside triphosphate diphosphohydrolase 1/cluster of differentiation (CD)39 and ecto-5'-nucleotidase/CD73, which catalyze the breakdown of extracellular ATP into adenosine, and on the subsequent activation of different subtypes of adenosine receptors with mixed findings of antitumor and protumor effects. New findings, needed for more effective therapeutic approaches, require consideration of redundant pathways controlling intratumoral adenosine levels, including the alternative NAD-inactivating pathway through the CD38-ectonucleotide pyrophosphatase phosphodiesterase (ENPP)1-CD73 axis, the counteracting ATP-regenerating ectoenzymatic pathway, and cellular adenosine uptake and its phosphorylation by adenosine kinase. This review provides a holistic view of extracellular and intracellular adenosine metabolism as an integrated complex network and summarizes recent data on the underlying mechanisms through which adenosine and its precursors ATP and ADP control cancer immunosurveillance, tumor angiogenesis, lymphangiogenesis, cancer-associated thrombosis, blood flow, and tumor perfusion. Special attention is given to differences and commonalities in the purinome of different cancers, heterogeneity of the tumor microenvironment, subcellular compartmentalization of the adenosine system, and novel roles of purine-converting enzymes as targets for cancer therapy. SIGNIFICANCE STATEMENT: The discovery of the role of adenosine as immune checkpoint regulator in cancer has led to the development of novel therapeutic strategies targeting extracellular adenosine metabolism and signaling in multiple clinical trials and preclinical models. Here we identify major gaps in knowledge that need to be filled to improve the therapeutic gain from agents targeting key components of the adenosine metabolic network and, on this basis, provide a holistic view of the cancer purinome as a complex and integrated network.
    MeSH term(s) Adenosine/metabolism ; Adenosine Triphosphate ; Humans ; Neoplasms/drug therapy ; Signal Transduction ; Tumor Microenvironment
    Chemical Substances Adenosine Triphosphate (8L70Q75FXE) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2022-01-09
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 209898-2
    ISSN 1521-0081 ; 0031-6997
    ISSN (online) 1521-0081
    ISSN 0031-6997
    DOI 10.1124/pharmrev.121.000528
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  6. Article ; Online: Altered mnemonic functions and resistance to N-METHYL-d-Aspartate receptor antagonism by forebrain conditional knockout of glycine transporter 1.

    Singer, P / Yee, B K / Feldon, J / Iwasato, T / Itohara, S / Grampp, T / Prenosil, G / Benke, D / Möhler, H / Boison, D

    Neuroscience

    2009  Volume 161, Issue 2, Page(s) 635–654

    Abstract: ... that inhibition of glycine transporter 1 (GlyT1) constitutes an effective means to boost N-methyl-d-aspartate ...

    Abstract Converging evidence from pharmacological and molecular studies has led to the suggestion that inhibition of glycine transporter 1 (GlyT1) constitutes an effective means to boost N-methyl-d-aspartate receptor (NMDAR) activity by increasing the extra-cellular concentration of glycine in the vicinity of glutamatergic synapses. However, the precise extent and limitation of this approach to alter cognitive function, and therefore its potential as a treatment strategy against psychiatric conditions marked by cognitive impairments, remain to be fully examined. Here, we generated mutant mice lacking GlyT1 in the entire forebrain including neurons and glia. This conditional knockout system allows a more precise examination of GlyT1 downregulation in the brain on behavior and cognition. The mutation was highly effective in attenuating the motor-stimulating effect of acute NMDAR blockade by phencyclidine, although no appreciable elevation in NMDAR-mediated excitatory postsynaptic currents (EPSC) was observed in the hippocampus. Enhanced cognitive performance was observed in spatial working memory and object recognition memory while spatial reference memory and associative learning remained unaltered. These findings provide further credence for the potential cognitive enhancing effects of brain GlyT1 inhibition. At the same time, they indicated potential phenotypic differences when compared with other constitutive and conditional GlyT1 knockout lines, and highlighted the possibility of a functional divergence between the neuronal and glia subpopulations of GlyT1 in the regulation of learning and memory processes. The relevance of this distinction to the design of future GlyT1 blockers as therapeutic tools in the treatment of cognitive disorders remains to be further investigated.
    MeSH term(s) Amphetamine/pharmacology ; Animals ; Down-Regulation ; Excitatory Postsynaptic Potentials ; Female ; Glycine/metabolism ; Glycine Plasma Membrane Transport Proteins/biosynthesis ; Glycine Plasma Membrane Transport Proteins/genetics ; Hippocampus/physiology ; Learning ; Male ; Memory ; Mice ; Mice, Knockout ; Motor Activity/drug effects ; Mutation ; Phencyclidine/pharmacology ; Prosencephalon/drug effects ; Prosencephalon/metabolism ; Prosencephalon/physiology ; Psychomotor Performance ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/biosynthesis ; Recognition, Psychology ; Synaptic Transmission
    Chemical Substances Glycine Plasma Membrane Transport Proteins ; Receptors, N-Methyl-D-Aspartate ; Slc6a9 protein, mouse ; Amphetamine (CK833KGX7E) ; Phencyclidine (J1DOI7UV76) ; Glycine (TE7660XO1C)
    Language English
    Publishing date 2009-03-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 196739-3
    ISSN 1873-7544 ; 0306-4522
    ISSN (online) 1873-7544
    ISSN 0306-4522
    DOI 10.1016/j.neuroscience.2009.03.056
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  7. Article ; Online: Astrocyte-neuron circuits in epilepsy.

    Purnell, Benton S / Alves, Mariana / Boison, Detlev

    Neurobiology of disease

    2023  Volume 179, Page(s) 106058

    Abstract: The epilepsies are a diverse spectrum of disease states characterized by spontaneous seizures and associated comorbidities. Neuron-focused perspectives have yielded an array of widely used anti-seizure medications and are able to explain some, but not ... ...

    Abstract The epilepsies are a diverse spectrum of disease states characterized by spontaneous seizures and associated comorbidities. Neuron-focused perspectives have yielded an array of widely used anti-seizure medications and are able to explain some, but not all, of the imbalance of excitation and inhibition which manifests itself as spontaneous seizures. Furthermore, the rate of pharmacoresistant epilepsy remains high despite the regular approval of novel anti-seizure medications. Gaining a more complete understanding of the processes that turn a healthy brain into an epileptic brain (epileptogenesis) as well as the processes which generate individual seizures (ictogenesis) may necessitate broadening our focus to other cell types. As will be detailed in this review, astrocytes augment neuronal activity at the level of individual neurons in the form of gliotransmission and the tripartite synapse. Under normal conditions, astrocytes are essential to the maintenance of blood-brain barrier integrity and remediation of inflammation and oxidative stress, but in epilepsy these functions are impaired. Epilepsy results in disruptions in the way astrocytes relate to each other by gap junctions which has important implications for ion and water homeostasis. In their activated state, astrocytes contribute to imbalances in neuronal excitability due to their decreased capacity to take up and metabolize glutamate and an increased capacity to metabolize adenosine. Furthermore, due to their increased adenosine metabolism, activated astrocytes may contribute to DNA hypermethylation and other epigenetic changes that underly epileptogenesis. Lastly, we will explore the potential explanatory power of these changes in astrocyte function in detail in the specific context of the comorbid occurrence of epilepsy and Alzheimer's disease and the disruption in sleep-wake regulation associated with both conditions.
    MeSH term(s) Humans ; Astrocytes/metabolism ; Epilepsy/metabolism ; Neurons/metabolism ; Adenosine/metabolism ; Glutamic Acid/metabolism
    Chemical Substances Adenosine (K72T3FS567) ; Glutamic Acid (3KX376GY7L)
    Language English
    Publishing date 2023-03-01
    Publishing country United States
    Document type Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 1211786-9
    ISSN 1095-953X ; 0969-9961
    ISSN (online) 1095-953X
    ISSN 0969-9961
    DOI 10.1016/j.nbd.2023.106058
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  8. Article ; Online: New insights into the mechanisms of the ketogenic diet.

    Boison, Detlev

    Current opinion in neurology

    2017  Volume 30, Issue 2, Page(s) 187–192

    Abstract: Purpose of review: High-fat, low-carbohydrate ketogenic diets have been used for almost a century for the treatment of epilepsy. Used traditionally for the treatment of refractory pediatric epilepsies, in recent years the use of ketogenic diets has ... ...

    Abstract Purpose of review: High-fat, low-carbohydrate ketogenic diets have been used for almost a century for the treatment of epilepsy. Used traditionally for the treatment of refractory pediatric epilepsies, in recent years the use of ketogenic diets has experienced a revival to include the treatment of adulthood epilepsies as well as conditions ranging from autism to chronic pain and cancer. Despite the ability of ketogenic diet therapy to suppress seizures refractory to antiepileptic drugs and reports of lasting seizure freedom, the underlying mechanisms are poorly understood. This review explores new insights into mechanisms mobilized by ketogenic diet therapies.
    Recent findings: Ketogenic diets act through a combination of mechanisms, which are linked to the effects of ketones and glucose restriction, and to interactions with receptors, channels, and metabolic enzymes. Decanoic acid, a component of medium-chain triclycerides, contributes to seizure control through direct α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition, whereas drugs targeting lactate dehydrogenase reduce seizures through inhibition of a metabolic pathway. Ketogenic diet therapy also affects DNA methylation, a novel epigenetic mechanism of the diet.
    Summary: Ketogenic diet therapy combines several beneficial mechanisms that provide broad benefits for the treatment of epilepsy with the potential to not only suppress seizures but also to modify the course of the epilepsy.
    MeSH term(s) Anticonvulsants/therapeutic use ; Decanoic Acids/therapeutic use ; Diet, Ketogenic ; Epilepsy/drug therapy ; Humans ; Seizures/drug therapy
    Chemical Substances Anticonvulsants ; Decanoic Acids ; decanoic acid (4G9EDB6V73)
    Language English
    Publishing date 2017-01-27
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1182686-1
    ISSN 1473-6551 ; 1350-7540
    ISSN (online) 1473-6551
    ISSN 1350-7540
    DOI 10.1097/WCO.0000000000000432
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  9. Article: The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine.

    Boison, Detlev

    Frontiers in molecular neuroscience

    2016  Volume 9, Page(s) 26

    Abstract: Epilepsy, one of the most prevalent neurological conditions, presents as a complex disorder of network homeostasis characterized by spontaneous non-provoked seizures and associated comorbidities. Currently used antiepileptic drugs have been designed to ... ...

    Abstract Epilepsy, one of the most prevalent neurological conditions, presents as a complex disorder of network homeostasis characterized by spontaneous non-provoked seizures and associated comorbidities. Currently used antiepileptic drugs have been designed to suppress neuronal hyperexcitability and thereby to suppress epileptic seizures. However, the current armamentarium of antiepileptic drugs is not effective in over 30% of patients, does not affect the comorbidities of epilepsy, and does not prevent the development and progression of epilepsy (epileptogenesis). Prevention of epilepsy and its progression remains the Holy Grail for epilepsy research and therapy development, requiring novel conceptual advances to find a solution to this urgent medical need. The methylation hypothesis of epileptogenesis suggests that changes in DNA methylation are implicated in the progression of the disease. In particular, global DNA hypermethylation appears to be associated with chronic epilepsy. Clinical as well as experimental evidence demonstrates that epilepsy and its progression can be prevented by biochemical manipulations and those that target previously unrecognized epigenetic functions contributing to epilepsy development and maintenance of the epileptic state. This mini-review will discuss, epigenetic mechanisms implicated in epileptogenesis and biochemical interactions between adenosine and glycine as a conceptual advance to understand the contribution of maladaptive changes in biochemistry as a major contributing factor to the development of epilepsy. New findings based on biochemical manipulation of the DNA methylome suggest that: (i) epigenetic mechanisms play a functional role in epileptogenesis; and (ii) therapeutic reconstruction of the epigenome is an effective antiepileptogenic therapy.
    Language English
    Publishing date 2016-04-13
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2016.00026
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  10. Article ; Online: Adenosinergic signaling in epilepsy.

    Boison, Detlev

    Neuropharmacology

    2016  Volume 104, Page(s) 131–139

    Abstract: Despite the introduction of at least 20 new antiepileptic drugs (AEDs) into clinical practice over the past decades, about one third of all epilepsies remain refractory to conventional forms of treatment. In addition, currently used AEDs have been ... ...

    Abstract Despite the introduction of at least 20 new antiepileptic drugs (AEDs) into clinical practice over the past decades, about one third of all epilepsies remain refractory to conventional forms of treatment. In addition, currently used AEDs have been developed to suppress neuronal hyperexcitability, but not necessarily to address pathogenic mechanisms involved in epilepsy development or progression (epileptogenesis). For those reasons endogenous seizure control mechanisms of the brain may provide alternative therapeutic opportunities. Adenosine is a well characterized endogenous anticonvulsant and seizure terminator of the brain. Several lines of evidence suggest that endogenous adenosine-mediated seizure control mechanisms fail in chronic epilepsy, whereas therapeutic adenosine augmentation effectively prevents epileptic seizures, even those that are refractory to conventional AEDs. New findings demonstrate that dysregulation of adenosinergic mechanisms are intricately involved in the development of epilepsy and its comorbidities, whereas adenosine-associated epigenetic mechanisms may play a role in epileptogenesis. The first goal of this review is to discuss how maladaptive changes of adenosinergic mechanisms contribute to the expression of seizures (ictogenesis) and the development of epilepsy (epileptogenesis) by focusing on pharmacological (adenosine receptor dependent) and biochemical (adenosine receptor independent) mechanisms as well as on enzymatic and transport based mechanisms that control the availability (homeostasis) of adenosine. The second goal of this review is to highlight innovative adenosine-based opportunities for therapeutic intervention aimed at reconstructing normal adenosine function and signaling for improved seizure control in chronic epilepsy. New findings suggest that transient adenosine augmentation can have lasting epigenetic effects with disease modifying and antiepileptogenic outcome. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
    MeSH term(s) 5'-Nucleotidase/metabolism ; Adenosine/metabolism ; Adenosine Kinase/genetics ; Adenosine Kinase/metabolism ; Animals ; Anticonvulsants/pharmacology ; Anticonvulsants/therapeutic use ; Astrocytes/metabolism ; Epilepsy/enzymology ; Epilepsy/metabolism ; Epilepsy/therapy ; Genetic Therapy ; Homeostasis ; Humans ; Nucleoside Transport Proteins/metabolism ; Receptors, Purinergic P1/metabolism ; Signal Transduction
    Chemical Substances Anticonvulsants ; Nucleoside Transport Proteins ; Receptors, Purinergic P1 ; adenosine transporter ; Adenosine Kinase (EC 2.7.1.20) ; 5'-Nucleotidase (EC 3.1.3.5) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2016-05
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2015.08.046
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