Astrogliosis and adenosine kinase: a glial basis of epilepsy
2008; Future Medicine; Volume: 3; Issue: 3 Linguagem: Inglês
10.2217/14796708.3.3.221
ISSN1748-6971
Autores Tópico(s)Adenosine and Purinergic Signaling
ResumoFuture NeurologyVol. 3, No. 3 EditorialFree AccessAstrogliosis and adenosine kinase: a glial basis of epilepsyDetlev BoisonDetlev BoisonRS Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Ave, Portland, OR 97232, USA. Published Online:21 Apr 2008https://doi.org/10.2217/14796708.3.3.221AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Epilepsy has historically been described as a disease of neuronal dysfunction in the sense that excessive neuronal activity or insufficient neuronal inhibition is the cause for sudden brief episodes of altered or diminished consciousness, involuntary movements or convulsions. Consequently, pharmacotherapy of epilepsy has been guided by the concept that excessive neuronal firing is the cause of the disease. However, more than 30% of patients with epilepsy are refractory to current neuron-centered pharmacotherapy [1].This central dogma in epilepsy research claiming that epilepsy is merely caused by dysfunctional neurons has recently been challenged. Instead, new research data from several laboratories suggest that epilepsy is caused by non-neuronal, in particular glial, mechanisms, which are comprised of a self-reinforcing interplay between dysfunctional energy homeostasis, inflammation and astrocytic signaling. Thus, excessive neuronal firing in epilepsy appears to be downstream from pathologically altered neuron–glia interactions.An 'astrocytic basis of epilepsy' was first proposed by Maiken Nedergaard based on findings that seizures can be triggered by excessive astrocytic glutamate release [2]. In addition, a loss of astrocytic domain organization implicated in neurovascular coupling has been found in experimental models of epilepsy [3]. Astrocytes, formerly discredited as 'glue of the brain', are now recognized as key regulators of neuronal function and neurovascular coupling by a mechanism called gliotransmission [4,5]. Apart from mediating gliotransmission, astrocytes synthesize proinflammatory cytokines during seizures [6]. In astrocytes, cytokines affect extracellular glutamate levels by reducing glutamate reuptake and increasing its release. Such findings underline novel functional neuron–glia interactions mediated by cytokines that can play a role in the neuropathology associated with inflammatory reactions in epilepsy [6].Apart from being central in the mechanisms described above, astrocytes are key regulators of the brain's own anticonvulsant adenosine [7,8]. In the brain, adenosine exerts powerful anticonvulsant [9] and neuroprotective [10] effects, mediated largely by activation of pre- and post-synaptic adenosine A1 receptors that are coupled to inhibitory G-proteins [11,12]. While A1 receptors set the stage for adenosine-mediated global inhibition of neuronal networks and heterosynaptic depression, stimulatory synaptic A2A receptors play a highly localized role to potentiate synaptic transmission under conditions of high-frequency stimulation, thus maximizing salience between activated and nontetanized synapses [8]. The synaptic levels of adenosine are largely regulated by an astrocyte-based adenosine cycle [7], comprised of astrocytic vesicular release of ATP [5], extracellular degradation of ATP into adenosine via ectonucleotidases and reuptake into astrocytes via equilibrative nucleoside transporters [13], driven by intracellular phosphorylation of adenosine into AMP by adenosine kinase (ADK) [14]. Thus, reuptake of synaptic adenosine appears to be under the control of the astrocyte-specific enzyme ADK [14]. Owing to the existence of a highly active substrate cycle between adenosine and AMP involving ADK and 5´-nucleotidase, small changes in ADK activity can rapidly translate into major changes of ambient adenosine.A central role of ADK and astrocytes in determining the brain's susceptibility to seizures has recently been proposed in the ADK hypothesis of epileptogenesis [15]. As a homotypic acute and protective response of the brain to injury (e.g., status epilepticus, traumatic brain injury or stroke), adenosine levels rapidly rise [16–18], and this acute adenosine response has been directly correlated with rapid downregulation of ADK [18,19]. These experimental data are consistent with clinical data demonstrating that seizures in patients with epilepsy lead to rapid and significant increases in ambient adenosine. However, this beneficial acute 'adenosine surge' might lead to changes in adenosine-receptor expression on neurons and astrocytes. Indeed, chronic epilepsy is characterized by downregulation of inhibitory A1 and upregulation of stimulatory A2A receptors [10] that, in part, regulate astrocyte proliferation [15]. Thus, the acute surge of adenosine could – by shifting the A1 versus A2A-receptor ratio on astrocytes – trigger astrogliosis, a hallmark of the pathology of the epileptic brain. The consequence of astrogliosis is upregulation of the astrocyte-based adenosine-removing enzyme ADK [14,19,20].A recent study from our laboratory has identified the enzyme ADK in astrocytes as a molecular link between astrogliosis and neuronal dysfunction in epilepsy [21]. The conclusions from this study are based on four different lines of evidence: • In a mouse model of CA3-selective epileptogenesis we demonstrate spatial and temporal colocalization of astrogliosis, upregulated ADK and spontaneous electrographic seizures (all restricted to CA3). In this model we find a highly localized area of astrocyte/ADK dysfunction; thus, normal components of the adenosine system within the rest of the brain prevent the spread of these focal seizures. This conclusion is consistent with our previous finding that activation of A1 receptors by ambient adenosine keeps an epileptic focus localized [22];• In a mouse model of transgenic overexpression of ADK in brain (Adk-tg) we demonstrate spontaneous CA3 seizures in the absence of astrogliosis, indicating that upregulation of ADK is sufficient to trigger seizures. In addition to increased seizure susceptibility [20], Adk-tg mice are characterized by increased susceptibility to stroke-induced neuronal cell loss [23] and by cognitive impairment [24], all features that are consistent with reduced levels of brain adenosine;• Conversely, in a mouse model of forebrain-selective reduction of ADK (fb-Adk-def) we demonstrate decreased susceptibility to acute seizures and seizure-induced cell death. In these animals, wild-type-like seizures and cell death can be restored when seizure induction is paired with an A1-receptor antagonist, indicating that elevated levels of brain adenosine protect these animals via activation of A1 receptors. Most importantly, fb-Adk-def mice subjected to an epileptogenesis-triggering acute brain injury (in the presence of the A1 antagonist) are resistant to the subsequent development of spontaneous seizures;• Infrahippocampal implants derived from mouse embryonic stem cells engineered to lack both alleles of the Adk gene and subjected to a neural differentiation paradigm, protect the hippocampus from generating spontaneous seizures, when cells are grafted after the acute epileptogenesis-triggering brain injury.These studies clearly demonstrate a critical role of astrocytes and ADK to link astrogliosis with neuronal dysfunction and ictogenesis. These experiments also suggest that reduced ADK has the potential to prevent epileptogenesis. This notion is supported by findings that ADK-deficient animals [21] or recipients of ADK-deficient grafted cells [21,25] do not develop spontaneous seizures. Likewise, these animals do not develop astrogliosis or upregulated ADK, two hallmarks of the epileptic brain. However, increased levels of adenosine (via reduced ADK or released from cells) could also mask epileptogenesis by suppressing ictogenesis. Future studies are needed to discriminate between the anti-ictogenic and the antiepileptogenic potential of adenosine.The identification of the role of astrocytes and ADK in regulating seizure susceptibility has important clinical implications. First, focal overexpression of ADK in human brain – for example, to be diagnosed by suitable PET ligands – would be a diagnostic marker to localize epileptogenic brain areas and to predict seizure generation. Second, upregulated ADK implies (focal) adenosine deficiency and provides a neurochemical rationale for (focal) adenosine augmentation therapies (AATs). Focal AATs have been tested in various approaches that provided a local source of adenosine by polymeric devices or ADK-deficient cells implanted into the vicinity of an epileptogenic brain region [9]. Local adenosine-releasing brain implants in rats and mice suppress induced kindled seizures, but also spontaneous seizures by a paracrine mode of action [26]. In contrast with systemic AATs (e.g., systemic application of A1-receptor agonists or ADK inhibitors), focal AATs are not associated with overt cardiovascular side effects or sedation [27]. AATs are particularly promising, since A1-receptor activation or ADK inhibition is effective in suppressing spontaneous seizures in mice that are refractory to conventional antiepileptic drugs [19,28].Stem cell-based AATs may have advantages compared with cell therapies using non-engineered cells, since functional integration of graft-derived cells into neural circuitry is not a prerequisite for therapeutic success, as long as these cells provide a paracrine source of adenosine. Alternatively, RNAi directed against ADK might be developed as a therapeutic tool to 'knockdown' upregulated ADK in the epileptic brain. Finally, the identification of astrocytes as the culprit in epilepsy should lead to the development of novel non-neuronal therapies for epilepsy. These should include anti-inflammatory therapies, therapies aimed at preventing astrogliosis or therapies aimed at modulating energy homeostasis. Thus, recent evidence suggests that ketogenic diet-induced changes in energy metabolism increase levels of ATP and adenosine, purines that are critically involved in neuron–glia interactions, neuromodulation and synaptic plasticity and that play dual and sometimes reciprocal roles in regulating cellular energy states and neuronal activity [29].In conclusion, the identification of astrocytes and ADK as upstream regulators of neuronal dysfunction in epilepsy holds great promise for the development of future non-neuronal therapies for epilepsy. Targeting the upstream regulators of neuronal dysfunction would, for the first time, enable us to integrate anticonvulsive therapeutic strategies with antiepileptogenic, neuroprotective and disease-modifying approaches. Only a comprehensive treatment approach taking into consideration the mechanisms of epileptogenesis and disease progression is likely to improve treatment options for patients suffering from intractable epilepsy and – finally – to cure epilepsy.Financial & competing interests disclosureThe work of the author is supported by the NIH through grant R01NS058780 from the National Institute of Neurological Disorders and Stroke, by the Epilepsy Research Foundation through the generous support of the Arlene & Arnold Goldstein Family Foundation, by the CURE Foundation in partnership with the Department of Defense and by the Good Samaritan Hospital Foundation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.Bibliography1 Vajda FJE: Pharmacotherapy of epilepsy: new armamentarium, new issues. J. Clin. Neurosci.14,813–823 (2007).Crossref, Medline, CAS, Google Scholar2 Tian GF, Azmi H, Takano T et al.: An astrocytic basis of epilepsy. Nat. Med.11,973–981 (2005).•• Demonstrates that astrocyte dysfunction can be a direct cause of seizures via excessive glutamate release.Crossref, Medline, CAS, Google Scholar3 Iadecola C, Nedergaard M: Glial regulation of the cerebral microvasculature. Nat. 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(2008) (In Press).• Reviews evidence that the ketogenic diet modulates ATP and adenosine levels in the brain.Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByKetogenic Diet, Inflammation, and Epilepsy19 May 2021Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis26 November 2020 | Frontiers in Neurology, Vol. 11Role of Adenosine in Epilepsy and SeizuresJournal of Caffeine and Adenosine Research, Vol. 10, No. 2Influence of Adenosine on Synaptic ExcitabilityPurinergic mechanisms in neuroinflammation: An update from molecules to behaviorNeuropharmacology, Vol. 104Antiepileptic effects of silk-polymer based adenosine release in kindled ratsExperimental Neurology, Vol. 219, No. 1Adenosine augmentation therapies (AATs) for epilepsy: Prospect of cell and gene therapiesEpilepsy Research, Vol. 85, No. 2-3Uncoupling of astrogliosis from epileptogenesis in adenosine kinase (ADK) transgenic mice13 August 2009 | Neuron Glia Biology, Vol. 4, No. 2 Vol. 3, No. 3 Follow us on social media for the latest updates Metrics Downloaded 537 times History Published online 21 April 2008 Published in print May 2008 Information© Future Medicine LtdFinancial & competing interests disclosureThe work of the author is supported by the NIH through grant R01NS058780 from the National Institute of Neurological Disorders and Stroke, by the Epilepsy Research Foundation through the generous support of the Arlene & Arnold Goldstein Family Foundation, by the CURE Foundation in partnership with the Department of Defense and by the Good Samaritan Hospital Foundation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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