Publications by authors named "Detlev Boison"

159 Publications

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes.

Br J Pharmacol 2021 Oct;178 Suppl 1:S313-S411

Keele University, Keele, UK.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15542. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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http://dx.doi.org/10.1111/bph.15542DOI Listing
October 2021

Genetic variations of adenosine kinase as predictable biomarkers of efficacy of vagus nerve stimulation in patients with pharmacoresistant epilepsy.

J Neurosurg 2021 Sep 3:1-10. Epub 2021 Sep 3.

2Department of Brain Institute, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Epilepsy Research, Sanbo Brain Hospital, Capital Medical University, Beijing, China.

Objective: Vagus nerve stimulation (VNS) is an alternative treatment option for individuals with refractory epilepsy, with nearly 40% of patients showing no benefit after VNS and only 6%-8% achieving seizure freedom. It is presently unclear why some patients respond to treatment and others do not. Therefore, identification of biomarkers to predict efficacy of VNS is of utmost importance. The objective of this study was to explore whether genetic variations in genes involved in adenosine kinase (ADK), ecto-5'-nucleotidase (NT5E), and adenosine A1 receptor (A1R) are linked to outcome of VNS in patients with refractory epilepsy.

Methods: Thirty single-nucleotide polymorphisms (SNPs), including 9 in genes encoding ADK, 3 in genes encoding NT5E, and 18 in genes encoding A1R, were genotyped in 194 refractory epilepsy patients who underwent VNS. The chi-square test and binary logistic regression were used to determine associations between genetic differences and VNS efficacy.

Results: A significant association between ADK SNPs rs11001109, rs7899674, and rs946185 and seizure reduction with VNS was found. Regardless of sex, age, seizure frequency and type, antiseizure drug use, etiology, and prior surgical history, all patients (10/10 patients [100%]) with minor allele homozygosity at rs11001109 (genotype AA) or rs946185 (AA) achieved > 50% seizure reduction and 4 patients (4/10 [40%]) achieved seizure freedom. VNS therapy demonstrated higher efficacy among carriers of minor allele rs7899674 (CG + GG) (68.3% vs 48.8% for patients with major allele homozygosity).

Conclusions: Homozygous ADK SNPs rs11001109 (AA) and rs946185 (AA), as well as minor allele rs7899674 (CG + GG), may serve as useful biomarkers for prediction of VNS therapy outcome.
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http://dx.doi.org/10.3171/2021.3.JNS21141DOI Listing
September 2021

The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy.

Front Neurosci 2021 12;15:708304. Epub 2021 Jul 12.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States.

Adenosine is an inhibitory modulator of neuronal excitability. Neuronal activity results in increased adenosine release, thereby constraining excessive excitation. The exceptionally high neuronal activity of a seizure results in a surge in extracellular adenosine to concentrations many-fold higher than would be observed under normal conditions. In this review, we discuss the multifarious effects of adenosine signaling in the context of epilepsy, with emphasis on sudden unexpected death in epilepsy (SUDEP). We describe and categorize the beneficial, detrimental, and potentially deadly aspects of adenosine signaling. The good or beneficial characteristics of adenosine signaling in the context of seizures include: (1) its direct effect on seizure termination and the prevention of status epilepticus; (2) the vasodilatory effect of adenosine, potentially counteracting postictal vasoconstriction; (3) its neuroprotective effects under hypoxic conditions; and (4) its disease modifying antiepileptogenic effect. The bad or detrimental effects of adenosine signaling include: (1) its capacity to suppress breathing and contribute to peri-ictal respiratory dysfunction; (2) its contribution to postictal generalized EEG suppression (PGES); (3) the prolonged increase in extracellular adenosine following spreading depolarization waves may contribute to postictal neuronal dysfunction; (4) the excitatory effects of A receptor activation is thought to exacerbate seizures in some instances; and (5) its potential contributions to sleep alterations in epilepsy. Finally, the adverse effects of adenosine signaling may potentiate a deadly outcome in the form of SUDEP by suppressing breathing and arousal in the postictal period. Evidence from animal models suggests that excessive postictal adenosine signaling contributes to the pathophysiology of SUDEP. The goal of this review is to discuss the beneficial, harmful, and potentially deadly roles that adenosine plays in the context of epilepsy and to identify crucial gaps in knowledge where further investigation is necessary. By better understanding adenosine dynamics, we may gain insights into the treatment of epilepsy and the prevention of SUDEP.
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http://dx.doi.org/10.3389/fnins.2021.708304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311182PMC
July 2021

ATP and adenosine-Two players in the control of seizures and epilepsy development.

Prog Neurobiol 2021 Sep 16;204:102105. Epub 2021 Jun 16.

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland; FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland. Electronic address:

Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a clinical challenge. Over one third of patients remain resistant to current pharmacological interventions. Moreover, even when effective in suppressing seizures, current medications are merely symptomatic without significantly altering the course of the disease. Much effort is therefore invested in identifying new treatments with novel mechanisms of action, effective in drug-refractory epilepsy patients, and with the potential to modify disease progression. Compelling evidence has demonstrated that the purines, ATP and adenosine, are key mediators of the epileptogenic process. Extracellular ATP concentrations increase dramatically under pathological conditions, where it functions as a ligand at a host of purinergic receptors. ATP, however, also forms a substrate pool for the production of adenosine, via the action of an array of extracellular ATP degrading enzymes. ATP and adenosine have assumed largely opposite roles in coupling neuronal excitability to energy homeostasis in the brain. This review integrates and critically discusses novel findings regarding how ATP and adenosine control seizures and the development of epilepsy. This includes purine receptor P1 and P2-dependent mechanisms, release and reuptake mechanisms, extracellular and intracellular purine metabolism, and emerging receptor-independent effects of purines. Finally, possible purine-based therapeutic strategies for seizure suppression and disease modification are discussed.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102105DOI Listing
September 2021

Specialty Grand Challenge for Brain Disease Mechanisms.

Authors:
Detlev Boison

Front Mol Neurosci 2021 10;14:689903. Epub 2021 May 10.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States.

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http://dx.doi.org/10.3389/fnmol.2021.689903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141592PMC
May 2021

Adenosine kinase: An epigenetic modulator in development and disease.

Neurochem Int 2021 07 5;147:105054. Epub 2021 May 5.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurosurgery, New Jersey Medical School, Rutgers University, Newark, NJ 07102, USA; Brain Health Institute, Rutgers University, Piscataway, NJ 08854, USA. Electronic address:

Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5'-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). The two isoforms are developmentally regulated and are differentially expressed in distinct subcellular compartments with ADK-L localized in the nucleus and ADK-S localized in the cytoplasm. The nuclear localization of ADK-L and its biochemical link to the transmethylation pathway suggest a specific role for gene regulation via epigenetic mechanisms. Recent evidence reveals an adenosine receptor-independent role of ADK in determining the global methylation status of DNA and thereby contributing to epigenomic regulation. Here we summarize recent progress in understanding the biochemical interactions between adenosine metabolism by ADK-L and epigenetic modifications linked to transmethylation reactions. This review will provide a comprehensive overview of ADK-associated changes in DNA methylation in developmental, as well as in pathological conditions including brain injury, epilepsy, vascular diseases, cancer, and diabetes. Challenges in investigating the epigenetic role of ADK for therapeutic gains are briefly discussed.
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http://dx.doi.org/10.1016/j.neuint.2021.105054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178237PMC
July 2021

Developmental Role of Adenosine Kinase in the Cerebellum.

eNeuro 2021 May-Jun;8(3). Epub 2021 Jun 2.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854

Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhibitor 5-iodotubericine (5-ITU) reduced DNA synthesis of granular neuron precursors in a concentration-dependent manner In the developing CB, immunohistochemical studies indicated ADK-L is expressed in immature Purkinje cells and granular neuron precursors, whereas in adulthood, ADK is absent from Purkinje cells, but widely expressed in mature granule neurons and their molecular layer (ML) processes. Furthermore, ADK-L is expressed in developing and mature Bergmann glia in the Purkinje cell layer, and in astrocytes in major cerebellar cortical layers. Together, our data demonstrate an association between neuronal ADK expression and developmental processes of the CB, which supports a functional role of ADK-L in the plasticity of the CB.
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http://dx.doi.org/10.1523/ENEURO.0011-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174006PMC
July 2021

Adenosine Kinase Expression Determines DNA Methylation in Cancer Cell Lines.

ACS Pharmacol Transl Sci 2021 Apr 16;4(2):680-686. Epub 2021 Feb 16.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, United States.

DNA methylation has a major role in cancer, and its inhibitors are used therapeutically. DNA methylation depends on methyl group flux through the transmethylation pathway, which forms adenosine. We hypothesized that an adenosine kinase isoform with nuclear expression (ADK-L) determines global DNA methylation in cancer cells. We quantified ADK-L expression (Western Blot) and global DNA methylation as percent 5-methyldeoxycytidine (5mdC, LC-MS/MS) in three cancer lines (HeLa, HepG2, and U373). ADK-L expression and global DNA methylation correlated positively with the highest levels in HeLa cells compared to U373 and HepG2 cells. To determine whether ADK increases global DNA methylation and to validate its potential therapeutics, we treated HeLa cells with potent ADK inhibitors MRS4203 and MRS4380 (IC 88 and 140 nM, respectively). Both nucleosides, but not a structurally related poor ADK inhibitor, significantly reduced global DNA methylation in HeLa cells in a concentration-dependent manner. Thus, ADK-L is a potential target for the therapeutic manipulation of DNA methylation levels in cancer.
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http://dx.doi.org/10.1021/acsptsci.1c00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033756PMC
April 2021

Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice.

Nat Commun 2021 04 9;12(1):2113. Epub 2021 Apr 9.

Sleep and Circadian Neuroscience Institute (SCNi), Department of Pharmacology, University of Oxford, Oxford, UK.

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A/A receptor signalling through the activation of the Ca -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.
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http://dx.doi.org/10.1038/s41467-021-22179-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035342PMC
April 2021

Possible Role of Adenosine in COVID-19 Pathogenesis and Therapeutic Opportunities.

Front Pharmacol 2020 26;11:594487. Epub 2020 Nov 26.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States.

The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) requires urgent clinical interventions. Crucial clinical needs are: 1) prevention of infection and spread of the virus within lung epithelia and between people, 2) attenuation of excessive lung injury in Advanced Respiratory Distress Syndrome, which develops during the end stage of the disease, and 3) prevention of thrombosis associated with SARS-CoV-2 infection. Adenosine and the key adenosine regulators adenosine deaminase (ADA), adenosine kinase (ADK), and equilibrative nucleoside transporter 1 may play a role in COVID-19 pathogenesis. Here, we highlight 1) the non-enzymatic role of ADA by which it might out-compete the virus (SARS-CoV-2) for binding to the CD26 receptor, 2) the enzymatic roles of ADK and ADA to increase adenosine levels and ameliorate Advanced Respiratory Distress Syndrome, and 3) inhibition of adenosine transporters to reduce platelet activation, thrombosis and improve COVID-19 outcomes. Depending on the stage of exposure to and infection by SARS-CoV-2, enhancing adenosine levels by targeting key adenosine regulators such as ADA, ADK and equilibrative nucleoside transporter 1 might find therapeutic use against COVID-19 and warrants further investigation.
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http://dx.doi.org/10.3389/fphar.2020.594487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726428PMC
November 2020

Suppression of phrenic nerve activity as a potential predictor of imminent sudden unexpected death in epilepsy (SUDEP).

Neuropharmacology 2021 02 16;184:108405. Epub 2020 Nov 16.

Department of Neurosurgery, Robert Wood Johnson and New Jersey Medical Schools, Rutgers University, Piscataway, NJ, 08854, USA; Brain Health Institute, Rutgers University, Piscataway, NJ, 08854, USA; Rutgers Neurosurgery H.O.P.E. Center, Department of Neurosurgery, Rutgers University, New Brunswick, NJ, 08901, USA. Electronic address:

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with refractory epilepsy. Centrally-mediated respiratory dysfunction has been identified as one of the principal mechanisms responsible for SUDEP. Seizures generate a surge in adenosine release. Elevated adenosine levels suppress breathing. Insufficient metabolic clearance of a seizure-induced adenosine surge might be a precipitating factor in SUDEP. In order to deliver targeted therapies to prevent SUDEP, reliable biomarkers must be identified to enable prompt intervention. Because of the integral role of the phrenic nerve in breathing, we hypothesized that suppression of phrenic nerve activity could be utilized as predictive biomarker for imminent SUDEP. We used a rat model of kainic acid-induced seizures in combination with pharmacological suppression of metabolic adenosine clearance to trigger seizure-induced death in tracheostomized rats. Recordings of EEG, blood pressure, and phrenic nerve activity were made concomitant to the seizure. We found suppression of phrenic nerve burst frequency to 58.9% of baseline (p < 0.001, one-way ANOVA) which preceded seizure-induced death; importantly, irregularities of phrenic nerve activity were partly reversible by the adenosine receptor antagonist caffeine. Suppression of phrenic nerve activity may be a useful biomarker for imminent SUDEP. The ability to reliably detect the onset of SUDEP may be instrumental in the timely administration of potentially lifesaving interventions.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199795PMC
February 2021

Adenosine kinase: A key regulator of purinergic physiology.

Biochem Pharmacol 2021 05 6;187:114321. Epub 2020 Nov 6.

Global Medical Affairs, AbbVie, Inc., United States.

Adenosine (ADO) is an essential biomolecule for life that provides critical regulation of energy utilization and homeostasis. Adenosine kinase (ADK) is an evolutionary ancient ribokinase derived from bacterial sugar kinases that is widely expressed in all forms of life, tissues and organ systems that tightly regulates intracellular and extracellular ADO concentrations. The facile ability of ADK to alter ADO availability provides a "site and event" specificity to the endogenous protective effects of ADO in situations of cellular stress. In addition to modulating the ability of ADO to activate its cognate receptors (P1 receptors), nuclear ADK isoform activity has been linked to epigenetic mechanisms based on transmethylation pathways. Previous drug discovery research has targeted ADK inhibition as a therapeutic approach to manage epilepsy, pain, and inflammation. These efforts generated multiple classes of highly potent and selective inhibitors. However, clinical development of early ADK inhibitors was stopped due to apparent mechanistic toxicity and the lack of suitable translational markers. New insights regarding the potential role of the nuclear ADK isoform (ADK-Long) in the epigenetic modulation of maladaptive DNA methylation offers the possibility of identifying novel ADK-isoform selective inhibitors and new interventional strategies that are independent of ADO receptor activation.
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http://dx.doi.org/10.1016/j.bcp.2020.114321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096637PMC
May 2021

Ketogenic diet, neuroprotection, and antiepileptogenesis.

Epilepsy Res 2020 11 19;167:106444. Epub 2020 Aug 19.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, United States; Department of Neurosurgery, New Jersey Medical School, Rutgers University, Newark, NJ 07102, United States; Rutgers Neurosurgery H.O.P.E. Center, Department of Neurosurgery, Rutgers University, New Brunswick, NJ 08901, United States. Electronic address:

High fat, low carbohydrate ketogenic diets (KD) have been in use for the treatment of epilepsy for almost a hundred years. Remarkably, seizures that are resistant to conventional anti-seizure drugs can in many cases be controlled by the KD therapy, and it has been shown that many patients with epilepsy become seizure free even after discontinuation of the diet. These findings suggest that KD combine anti-seizure effects with disease modifying effects. In addition to the treatment of epilepsy, KDs are now widely used for the treatment of a wide range of conditions including weight reduction, diabetes, and cancer. The reason for the success of metabolic therapies is based on the synergism of at least a dozen different mechanisms through which KDs provide beneficial activities. Among the newest findings are epigenetic mechanisms (DNA methylation and histone acetylation) through which KD exerts long-lasting disease modifying effects. Here we review mechanisms through which KD can affect neuroprotection in the brain, and how a combination of those mechanisms with epigenetic alterations can attenuate and possibly reverse the development of epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655615PMC
November 2020

Hyperexcitability and seizures in the THY-Tau22 mouse model of tauopathy.

Neurobiol Aging 2020 10 20;94:265-270. Epub 2020 Jun 20.

University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France. Electronic address:

Epileptic seizures constitute a significant comorbidity of Alzheimer's disease (AD), which are recapitulated in transgenic mouse models of amyloidogenesis. Here, we sought to evaluate the potential role of tau pathology regarding seizure occurrence. To this end, we performed intra-hippocampal electroencephalogram (EEG) recordings and PTZ (pentylenetetrazol) seizure threshold tests in THY-Tau22 transgenic mice of AD-like tau pathology. We demonstrate that despite a lack of spontaneous epileptiform activity in Tau22 mice, the animals display increased PTZ-induced seizure susceptibility and mortality. The increased propensity for induced seizures in THY-Tau22 mutants correlates with astrogliosis and increased expression of adenosine kinase, consistent with increased network excitability. These data support an impact of tau pathology toward AD-associated seizures and suggest that tau pathology may contribute to seizure generation in AD independent of Aβ pathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483348PMC
October 2020

Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation.

Front Mol Neurosci 2020 5;13:97. Epub 2020 Jun 5.

RS Dow Neurobiology Laboratories, Department of Translational Neuroscience, Legacy Research Institute, Portland, OR, United States.

Epileptogenesis is a common consequence of brain insults, however, the prevention or delay of the epileptogenic process remains an important unmet medical challenge. Overexpression of glycine transporter 1 (GlyT1) is proposed as a pathological hallmark in the hippocampus of patients with temporal lobe epilepsy (TLE), and we previously demonstrated in rodent epilepsy models that augmentation of glycine suppressed chronic seizures and altered acute seizure thresholds. In the present study we evaluated the effect of the GlyT1 inhibitor, sarcosine (aka N-methylglycine), on epileptogenesis and also investigated possible mechanisms. We developed a modified rapid kindling model of epileptogenesis in rats combined with seizure score monitoring to evaluate the antiepileptogenic effect of sarcosine. We used immunohistochemistry and Western blot analysis for the evaluation of GlyT1 expression and epigenetic changes of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the epileptogenic hippocampi of rats, and further evaluated expression changes in enzymes involved in the regulation of DNA methylation, ten-eleven translocation methylcytosine dioxygenase 1 (TET1), DNA-methyltransferase 1 (DNMT1), and DNMT3a. Our results demonstrated: (i) experimental evidence that sarcosine (3 g/kg, i.p. daily) suppressed kindling epileptogenesis in rats; (ii) the sarcosine-induced antiepileptogenic effect was accompanied by a suppressed hippocampal GlyT1 expression as well as a reduction of hippocampal 5mC levels and a corresponding increase in 5hmC; and (iii) sarcosine treatment caused differential expression changes of TET1 and DNMTs. Together, these findings suggest that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation. Thus, manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.
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http://dx.doi.org/10.3389/fnmol.2020.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291815PMC
June 2020

Role of Adenosine in Epilepsy and Seizures.

J Caffeine Adenosine Res 2020 Jun 4;10(2):45-60. Epub 2020 Jun 4.

Deptartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.

Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles. It not only controls seizures (ictogenesis), but also plays a major role in processes that turn a normal brain into an epileptic brain (epileptogenesis). It is involved in the control of abnormal synaptic plasticity and neurodegeneration and plays a major role in the expression of comorbid symptoms and complications of epilepsy, such as sudden unexpected death in epilepsy (SUDEP). Given the important role of adenosine in epilepsy, therapeutic strategies are in development with the goal to utilize adenosine augmentation not only for the suppression of seizures but also for disease modification and epilepsy prevention, as well as strategies to block adenosine A receptor overfunction associated with neurodegeneration. This review provides a comprehensive overview of the role of adenosine in epilepsy.
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http://dx.doi.org/10.1089/caff.2019.0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301316PMC
June 2020

Adenosine kinase inhibition promotes proliferation of neural stem cells after traumatic brain injury.

Brain Commun 2020 20;2(1):fcaa017. Epub 2020 Feb 20.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.

Traumatic brain injury (TBI) is a major public health concern and remains a leading cause of disability and socio-economic burden. To date, there is no proven therapy that promotes brain repair following an injury to the brain. In this study, we explored the role of an isoform of adenosine kinase expressed in the cell nucleus (ADK-L) as a potential regulator of neural stem cell proliferation in the brain. The rationale for this hypothesis is based on coordinated expression changes of ADK-L during foetal and postnatal murine and human brain development indicating a role in the regulation of cell proliferation and plasticity in the brain. We first tested whether the genetic disruption of ADK-L would increase neural stem cell proliferation after TBI. Three days after TBI, modelled by a controlled cortical impact, transgenic mice, which lack ADK-L (ADK) in the dentate gyrus (DG) showed a significant increase in neural stem cell proliferation as evidenced by significant increases in doublecortin and Ki67-positive cells, whereas animals with transgenic overexpression of ADK-L in dorsal forebrain neurons (ADK-L) showed an opposite effect of attenuated neural stem cell proliferation. Next, we translated those findings into a pharmacological approach to augment neural stem cell proliferation in the injured brain. Wild-type C57BL/6 mice were treated with the small molecule adenosine kinase inhibitor 5-iodotubercidin for 3 days after the induction of TBI. We demonstrate significantly enhanced neural stem cell proliferation in the DG of 5-iodotubercidin-treated mice compared to vehicle-treated injured animals. To rule out the possibility that blockade of ADK-L has any effects in non-injured animals, we quantified baseline neural stem cell proliferation in ADK mice, which was not altered, whereas baseline neural stem cell proliferation in ADK-L mice was enhanced. Together these findings demonstrate a novel function of ADK-L involved in the regulation of neural stem cell proliferation after TBI.
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http://dx.doi.org/10.1093/braincomms/fcaa017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158236PMC
February 2020

Compartmentalization of adenosine metabolism in cancer cells and its modulation during acute hypoxia.

J Cell Sci 2020 05 29;133(10). Epub 2020 May 29.

MediCity Research Laboratory, University of Turku, 20520 Turku, Finland

Extracellular adenosine mediates diverse anti-inflammatory, angiogenic and vasoactive effects, and has become an important therapeutic target for cancer, which has been translated into clinical trials. This study was designed to comprehensively assess adenosine metabolism in prostate and breast cancer cells. We identified cellular adenosine turnover as a complex cascade, comprising (1) the ectoenzymatic breakdown of ATP via sequential ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1, officially known as ENPP1), ecto-5'-nucleotidase (CD73, also known as NT5E), and adenosine deaminase reactions, and ATP re-synthesis through a counteracting adenylate kinase and members of the nucleoside diphosphate kinase (NDPK, also known as NME/NM23) family; (2) the uptake of nucleotide-derived adenosine via equilibrative nucleoside transporters; and (3) the intracellular adenosine phosphorylation into ATP by adenosine kinase and other nucleotide kinases. The exposure of cancer cells to 1% O for 24 h triggered an ∼2-fold upregulation of CD73, without affecting nucleoside transporters, adenosine kinase activity and cellular ATP content. The ability of adenosine to inhibit the tumor-initiating potential of breast cancer cells via a receptor-independent mechanism was confirmed using a xenograft mouse model. The existence of redundant pathways controlling extracellular and intracellular adenosine provides a sufficient justification for reexamination of the current concepts of cellular purine homeostasis and signaling in cancer.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.241463DOI Listing
May 2020

Adenosine Kinase Expression in the Frontal Cortex in Schizophrenia.

Schizophr Bull 2020 04;46(3):690-698

Department of Neuroscience, University of Toledo, Toledo, OH.

The adenosine hypothesis of schizophrenia posits that reduced availability of the neuromodulator adenosine contributes to dysregulation of dopamine and glutamate transmission and the symptoms associated with schizophrenia. It has been proposed that increased expression of the enzyme adenosine kinase (ADK) may drive hypofunction of the adenosine system. While animal models of ADK overexpression support such a role for altered ADK, the expression of ADK in schizophrenia has yet to be examined. In this study, we assayed ADK gene and protein expression in frontocortical tissue from schizophrenia subjects. In the dorsolateral prefrontal cortex (DLPFC), ADK-long and -short splice variant expression was not significantly altered in schizophrenia compared to controls. There was also no significant difference in ADK splice variant expression in the frontal cortex of rats treated chronically with haloperidol-decanoate, in a study to identify the effect of antipsychotics on ADK gene expression. ADK protein expression was not significantly altered in the DLPFC or anterior cingulate cortex (ACC). There was no significant effect of antipsychotic medication on ADK protein expression in the DLPFC or ACC. Overall, our results suggest that increased ADK expression does not contribute to hypofunction of the adenosine system in schizophrenia and that alternative mechanisms are involved in dysregulation of this system in schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbz086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147579PMC
April 2020

Effects of Preinjury and Postinjury Exposure to Caffeine in a Rat Model of Traumatic Brain Injury.

J Caffeine Adenosine Res 2020 Mar 4;10(1):12-24. Epub 2020 Mar 4.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey.

Lethal apnea is a significant cause of acute mortality following a severe traumatic brain injury (TBI). TBI is associated with a surge of adenosine, which also suppresses respiratory function in the brainstem. This study examined the acute and chronic effects of caffeine, an adenosine receptor antagonist, on acute mortality and morbidity after fluid percussion injury. We demonstrate that, regardless of preinjury caffeine exposure, an acute bolus of caffeine given immediately following the injury dosedependently prevented lethal apnea and has no detrimental effects on motor performance following sublethal injuries. Finally, we demonstrate that chronic caffeine treatment after injury, but not caffeine withdrawal, impairs recovery of motor function. Preexposure of the injured brain to caffeine does not have a major impact on acute and delayed outcome parameters; more importantly, a single acute dose of caffeine after the injury can prevent lethal apnea regardless of chronic caffeine preexposure.
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http://dx.doi.org/10.1089/caff.2019.0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071069PMC
March 2020

Adenosine kinase is critical for neointima formation after vascular injury by inducing aberrant DNA hypermethylation.

Cardiovasc Res 2021 01;117(2):561-575

Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Aims: Adenosine receptors and extracellular adenosine have been demonstrated to modulate vascular smooth muscle cell (VSMC) proliferation and neointima formation. Adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels but is function in VSMC remains unclear. Here, we investigated the role of ADK in vascular injury-induced smooth muscle proliferation and delineated the mechanisms underlying its action.

Methods And Results: We found that ADK expression was higher in the neointima of injured vessels and in platelet-derived growth factor-treated VSMCs. Genetic and pharmacological inhibition of ADK was enough to attenuate arterial injury-induced neointima formation due to inhibition of VSMC proliferation. Mechanistically, using infinium methylation assays and bisulfite sequencing, we showed that ADK metabolized the intracellular adenosine and potentiated the transmethylation pathway, then induced the aberrant DNA hypermethylation. Pharmacological inhibition of aberrant DNA hypermethylation increased KLF4 expression and suppressed VSMC proliferation as well as the neointima formation. Importantly, in human femoral arteries, we observed increased ADK expression and DNA hypermethylation as well as decreased KLF4 expression in neointimal VSMCs of stenotic vessels suggesting that our findings in mice are relevant for human disease and may hold translational significance.

Conclusion: Our study unravels a novel mechanism by which ADK promotes VSMC proliferation via inducing aberrant DNA hypermethylation, thereby down-regulating KLF4 expression and promoting neointima formation. These findings advance the possibility of targeting ADK as an epigenetic modulator to combat vascular injury.
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http://dx.doi.org/10.1093/cvr/cvaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820850PMC
January 2021

Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression.

Epilepsy Curr 2020 Jan-Feb;20(1_suppl):14S-22S. Epub 2020 Jan 15.

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Area II of the 2014 Epilepsy Research Benchmarks aims to establish goals for preventing the development and progression of epilepsy. In this review, we will highlight key advances in Area II since the last summary of research progress and opportunities was published in 2016. We also highlight areas of investigation that began to develop before 2016 and in which additional progress has been made more recently.
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http://dx.doi.org/10.1177/1535759719895274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031802PMC
January 2020

Adenosine Metabolism: Emerging Concepts for Cancer Therapy.

Cancer Cell 2019 12;36(6):582-596

MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, 20520, Finland. Electronic address:

Adenosine is a key metabolic and immune-checkpoint regulator implicated in the tumor escape from the host immune system. Major gaps in knowledge that impede the development of effective adenosine-based therapeutics include: (1) lack of consideration of redundant pathways controlling ATP and adenosine levels; (2) lack of distinction between receptor-dependent and -independent effects of adenosine, and (3) focus on extracellular adenosine without consideration of intracellular metabolism and compartmentalization. In light of current clinical trials, we provide an overview of adenosine metabolism and point out the need for a more careful evaluation of the entire purinome in emerging cancer therapies.
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http://dx.doi.org/10.1016/j.ccell.2019.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224341PMC
December 2019

The Purinome and the preBötzinger Complex - A Ménage of Unexplored Mechanisms That May Modulate/Shape the Hypoxic Ventilatory Response.

Front Cell Neurosci 2019 21;13:365. Epub 2019 Aug 21.

Department of Physiology, Women and Children's Health Research Institute, Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Exploration of purinergic signaling in brainstem homeostatic control processes is challenging the traditional view that the biphasic hypoxic ventilatory response, which comprises a rapid initial increase in breathing followed by a slower secondary depression, reflects the interaction between peripheral chemoreceptor-mediated excitation and central inhibition. While controversial, accumulating evidence supports that in addition to peripheral excitation, interactions between central excitatory and inhibitory purinergic mechanisms shape this key homeostatic reflex. The objective of this review is to present our working model of how purinergic signaling modulates the glutamatergic inspiratory synapse in the preBötzinger Complex (key site of inspiratory rhythm generation) to shape the hypoxic ventilatory response. It is based on the perspective that has emerged from decades of analysis of glutamatergic synapses in the hippocampus, where the actions of extracellular ATP are determined by a complex signaling system, the purinome. The purinome involves not only the actions of ATP and adenosine at P2 and P1 receptors, respectively, but diverse families of enzymes and transporters that collectively determine the rate of ATP degradation, adenosine accumulation and adenosine clearance. We summarize current knowledge of the roles played by these different purinergic elements in the hypoxic ventilatory response, often drawing on examples from other brain regions, and look ahead to many unanswered questions and remaining challenges.
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http://dx.doi.org/10.3389/fncel.2019.00365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712068PMC
August 2019

Epigenetics and epilepsy prevention: The therapeutic potential of adenosine and metabolic therapies.

Neuropharmacology 2020 05 13;167:107741. Epub 2019 Aug 13.

Depts. of Neurosciences and Pediatrics, University of California San Diego, Rady Children's Hospital, San Diego, CA, 92117, USA.

Prevention of epilepsy and its progression remains the most urgent need for epilepsy research and therapy development. Novel conceptual advances are required to meaningfully address this fundamental challenge. Maladaptive epigenetic changes, which include methylation of DNA and acetylation of histones - among other mechanisms, are now well recognized to play a functional role in the development of epilepsy and its progression. The methylation hypothesis of epileptogenesis suggests that changes in DNA methylation are implicated in the progression of the disease. In this context, global DNA hypermethylation is particularly associated with chronic epilepsy. Likewise, acetylation changes of histones have been linked to epilepsy development. Clinical as well as experimental evidence demonstrate that epilepsy and its progression can be prevented by metabolic and biochemical manipulations that target previously unrecognized epigenetic functions contributing to epilepsy development and maintenance of the epileptic state. This review will discuss epigenetic mechanisms implicated in epilepsy development as well as metabolic and biochemical interactions thought to drive epileptogenesis. Therefore, metabolic and biochemical mechanisms are identified as novel targets for epilepsy prevention. We will specifically discuss adenosine biochemistry as a novel therapeutic strategy to reconstruct the DNA methylome as antiepileptogenic strategy as well as metabolic mediators, such as beta-hydroxybutyrate, which affect histone acetylation. Finally, metabolic dietary interventions (such as the ketogenic diet) which have the unique potential to prevent epileptogenesis through recently identified epigenetic mechanisms will be reviewed. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220211PMC
May 2020

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis.

Brain Pathol 2020 03 22;30(2):246-260. Epub 2019 Aug 22.

Department of Brian Institute, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Epilepsy Research, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China.

Rasmussen encephalitis (RE) is a severe pediatric inflammatory brain disease characterized by unilateral inflammation and atrophy of the cerebral cortex, drug-resistant focal epilepsy and progressive neurological and cognitive deterioration. The etiology and pathogenesis of RE remain unclear. Our previous results demonstrated that the adenosine A1 receptor (A1R) and the major adenosine-removing enzyme adenosine kinase play an important role in the etiology of RE. Because the downstream pathways of inhibitory A1R signaling are modulated by stimulatory A2AR signaling, which by itself controls neuro-inflammation, glial activation and glial glutamate homeostasis through interaction with glutamate transporter GLT-1, we hypothesized that maladaptive changes in adenosine A2A receptor (A2AR) expression are associated with RE. We used immunohistochemistry and Western blot analysis to examine the expression of A2ARs, glutamate transporter-I (GLT-1) and the apoptotic marker Bcl-2 in surgically resected cortical specimens from RE patients (n = 18) in comparison with control cortical tissue. In lesions of the RE specimen we found upregulation of A2ARs, downregulation of GLT-1 and increased apoptosis of both neurons and astroglia. Double staining revealed colocalization of A2ARs and Bcl-2 in RE lesions. These results suggest that maladaptive changes in A2AR expression are associated with a decrease in GLT-I expression as a possible precipitator for apoptotic cell loss in RE. Because A2AR antagonists are already under clinical evaluation for Parkinson's disease, the A2AR might likewise be a tractable target for the treatment of RE.
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http://dx.doi.org/10.1111/bpa.12770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018059PMC
March 2020

Adenosine Kinase Deficiency Increases Susceptibility to a Carcinogen.

J Caffeine Adenosine Res 2019 Mar 14;9(1):4-11. Epub 2019 Mar 14.

Department of Neurobiology, Legacy Research Institute, Portland, Oregon.

Adenosine kinase (ADK) is a key regulator of hepatic metabolism. Its deficiency in the liver causes hepatic steatosis and methylation defects. In this study, we investigated whether reduced ADK expression affects the susceptibility of the liver to a carcinogen. We investigated ADK expression in samples from 11 liver cancer patients. We used transgenic Adk-tg mice with reduced hepatic ADK to study their susceptibility to a carcinogen. We exposed 45 Adk-tg and 21 wild-type (WT) mice to the carcinogen diethylnitrosamine (DEN) and the tumor promoter phenobarbital (PB) and examined the survival and body weight. Seven of 11 patients with liver cancer had reduced ADK expression. A Kaplan-Meier survival curve showed a significantly increased mortality rate of DEN/PB-exposed Adk-tg mice compared with WT mice. Reduced hepatic ADK increases the susceptibility to the acute toxic effects of a carcinogen. Low hepatic ADK might be a risk factor and biomarker for cancer development.
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http://dx.doi.org/10.1089/caff.2018.0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444920PMC
March 2019

Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice.

Epilepsia 2019 04 27;60(4):615-625. Epub 2019 Feb 27.

RS Dow Neurobiology Laboratories, Portland, Oregon.

Objective: Over one-third of all patients with epilepsy are refractory to treatment and there is an urgent need to develop new drugs that can prevent the development and progression of epilepsy. Epileptogenesis is characterized by distinct histopathologic and biochemical changes, which include astrogliosis and increased expression of the adenosine-metabolizing enzyme adenosine kinase (ADK; EC 2.7.1.20). Increased expression of ADK contributes to epileptogenesis and is therefore a target for therapeutic intervention. We tested the prediction that the transient use of an ADK inhibitor administered during the latent phase of epileptogenesis can mitigate the development of epilepsy.

Methods: We used the intrahippocampal kainic acid (KA) mouse model of temporal lobe epilepsy, which is characterized by ipsilateral hippocampal sclerosis with granule cell dispersion and the development of recurrent hippocampal paroxysmal discharges (HPDs). KA-injected mice were treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 1.6 mg/kg, b.i.d., i.p.) during the latent phase of epileptogenesis from day 3-8 after injury; the period when gradual increases in hippocampal ADK expression begin to manifest. HPDs were assessed at 6 and 9 weeks after KA administration followed by epilepsy histopathology including assessment of granule cell dispersion, astrogliosis, and ADK expression.

Results: 5-ITU significantly reduced the percent time in seizures by at least 80% in 56% of mice at 6 weeks post-KA. This reduction in seizure activity was maintained in 40% of 5-ITU-treated mice at 9 weeks. 5-ITU also suppressed granule cell dispersion and prevented maladaptive ADK increases in these protected mice.

Significance: Our results show that the transient use of a small-molecule ADK inhibitor, given during the early stages of epileptogenesis, has antiepileptogenic disease-modifying properties, which provides the rationale for further investigation into the development of a novel class of antiepileptogenic ADK inhibitors with increased efficacy for epilepsy prevention.
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http://dx.doi.org/10.1111/epi.14674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713278PMC
April 2019

The role of adenosine in epilepsy.

Brain Res Bull 2019 09 20;151:46-54. Epub 2018 Nov 20.

Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR, USA. Electronic address:

Adenosine is a well-characterized endogenous anticonvulsant and seizure terminator of the brain. Through a combination of adenosine receptor-dependent and -independent mechanisms, adenosine affects seizure generation (ictogenesis), as well as the development of epilepsy and its progression (epileptogenesis). Maladaptive changes in adenosine metabolism, in particular increased expression of the astroglial enzyme adenosine kinase (ADK), play a major role in epileptogenesis. Increased expression of ADK has dual roles in both reducing the inhibitory tone of adenosine in the brain, which consequently reduces the threshold for seizure generation, and also driving an increased flux of methyl-groups through the transmethylation pathway, thereby increasing global DNA methylation. Through these mechanisms, adenosine is uniquely positioned to link metabolism with epigenetic outcome. Therapeutic adenosine augmentation therefore not only holds promise for the suppression of seizures in epilepsy, but moreover the prevention of epilepsy and its progression overall. This review will focus on adenosine-related mechanisms implicated in ictogenesis and epileptogenesis and will discuss therapeutic opportunities and challenges.
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http://dx.doi.org/10.1016/j.brainresbull.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527499PMC
September 2019
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