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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine is an important inhibitory modulator of brain activity. In a previous ex vivo gene therapy approach, local release of adenosine by encapsulated fibroblasts implanted into the vicinity of an epileptic focus, was sufficient to provide transient protection from seizures (Huber, A., Padrun, V., Deglon, N., Aebischer, P., Mohler, H., Boison, D., 2001. Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. Proc. Natl. Acad. Sci. U. S. A. 98, 7611-7616). Long-term seizure suppression beyond 2 weeks was precluded by limited life expectancy of the encapsulated fibroblasts. To study the feasibility for long-term seizure suppression by adenosine releasing brain implants, in the present contribution, mouse C2C12 myoblasts were engineered to release adenosine by genetic inactivation of adenosine kinase. After encapsulation, the myoblasts were grafted into the lateral brain ventricles of epileptic rats kindled in the hippocampus. While seizure activity in animals with wild-type implants remained unaltered, 1 week after grafting all rats with adenosine-releasing implants (n = 25) displayed complete protection from convulsive seizures and a corresponding reduction of afterdischarges in EEG-recordings. The duration of seizure suppression was maintained for a period of 3 weeks in 50% of the animals ranging to a maximum of 8 weeks in one animal. During the course of these experiments, adenosine A1 receptors remained responsive to selective agonists and antagonists indicating a lack of desensitization of A1 receptors after local long-term exposure to adenosine. Furthermore, local release of adenosine did not affect locomotor activity, whereas systemic application of the A1 agonist 2-chloro-N6-cyclopentyladenosine caused strong sedation. Thus, the local release of adenosine by cellular implants provides a feasible option for a potential side-effect free approach for the long-term treatment of focal epilepsies.
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PMID:Seizure suppression and lack of adenosine A1 receptor desensitization after focal long-term delivery of adenosine by encapsulated myoblasts. 1637 62

Adenosine, acting at A1 receptors, exhibits anticonvulsant effects in experimental epilepsy--and inhibits progression to status epilepticus (SE). Seizures after traumatic brain injury (TBI) may contribute to pathophysiology. Thus, we hypothesized that endogenous adenosine, acting via A1 receptors, mediates antiepileptic benefit after experimental TBI. We subjected A1-receptor knockout (ko) mice, heterozygotes, and wild-type (wt) littermates (n=115) to controlled cortical impact (CCI). We used four outcome protocols in male mice: (1) observation for seizures, SE, and mortality in the initial 2 h, (2) assessment of seizure score (electroencephalogram (EEG)) in the initial 2 h, (3) assessment of mortality at 24 h across injury levels, and (4) serial assessment of arterial blood pressure, heart rate, blood gases, and hematocrit. Lastly, to assess the influence of gender on this observation, we observed female mice for seizures, SE, and mortality in the initial 2 h. Seizure activity was noted in 83% of male ko mice in the initial 2 h, but was seen in no heterozygotes and only 33% of wt (P<0.05). Seizures in wt were brief (1 to 2 secs). In contrast, SE involving lethal sustained (>1 h) tonic clonic activity was uniquely seen in ko mice after CCI (50% incidence in males), (P<0.05). Seizure score was twofold higher in ko mice after CCI versus either heterozygote or wt (P<0.05). An injury-intensity dose-response for 24 h mortality was seen in ko mice (P<0.05). Physiologic parameters were similar between genotypes. Seizures were seen in 100% of female ko mice after CCI versus 14% of heterozygotes and 25% wt (P<0.05) and SE was restricted to the ko mice (83% incidence). Our data suggest a critical endogenous anticonvulsant action of adenosine at A1 receptors early after experimental TBI.
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PMID:Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury. 1612 Nov 25

Adenosine kinase deficient (Adk-/-) embryonic stem cells (ESCs) encapsulated in synthetic polymers have previously been shown to provide therapeutic adenosine release and transient seizure suppression in epileptic rats. Here we explored the utility of biopolymer-substrates to promote long-term adenosine release from Adk-/- ESCs. Three different substrates were studied: (1) type I collagen (Col-1), (2) silk-fibroin (SF), and (3) poly(L-ornithine) (PO) coated tissue culture plastic. Adk-/- or wild type (wt) ESC-derived glial precursor cells were seeded on the substrates and cultured either in proliferation medium containing growth factors or in differentiation medium devoid of growth factors. In proliferation medium cell proliferation was higher and metabolic activity lower on Col-1 and PO substrates as compared to SF. Cells from both genotypes readily differentiated into astrocytes after growth factor removal on all substrates. Adk-/- cells cultured on biopolymers released significantly more adenosine than their wt counterparts at all developmental stages. Adenosine release was similar on SF and PO substrates and the amounts released from Adk-/- cells (>20 ng/ml) were considered to be of therapeutic relevance. Taken together, these results suggest that silk matrices are particularly suitable biomaterials for ESC encapsulation and for the design of adenosine releasing bioincubators for the treatment of epilepsy.
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PMID:The support of adenosine release from adenosine kinase deficient ES cells by silk substrates. 1670 37

Adenosine is considered to be the brain's endogenous anticonvulsant as many studies have showed and it is responsible for seizure arrest and postictal refractoriness. Alterations in the adenosinergic system (adenosine and its receptors) have been referred by many previous studies indicating that deficiencies or modifications in the function of this purinergic system may contribute to epileptogenesis. Due to this emerging implication of adenosine in the managing of seizures, a new field of adenosine-based therapies has been introduced including adenosine itself, adenosine receptor agonists and antagonists and adenosine kinase inhibitors. The method with the least side effects (heart rate, blood pressure, temperature or even sedation) is being quested including intracerebral implantation of adenosine releasing cells or devices.
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PMID:Modulatory role of adenosine and its receptors in epilepsy: possible therapeutic approaches. 1684 57

Adenosine is a potent modulator of excitatory neurotransmission, especially in seizure-prone regions such as the hippocampal formation. In adult brain ambient levels of adenosine are controlled by adenosine kinase (ADK), the major adenosine-metabolizing enzyme, expressed most strongly in astrocytes. Since ontogeny of the adenosine system is largely unknown, we investigated ADK expression and cellular localization during postnatal development of the mouse brain, using immunofluorescence staining with cell-type specific markers. At early postnatal stages ADK immunoreactivity was prominent in neurons, notably in cerebral cortex and hippocampus. Thereafter, as seen best in hippocampus, ADK gradually disappeared from neurons and appeared in newly developed nestin- and glial fibrillary acidic protein (GFAP)-positive astrocytes. Furthermore, the region-specific downregulation of neuronal ADK coincided with the onset of myelination, as visualized by myelin basic protein staining. After postnatal day 14 (P14), the transition from neuronal to astrocytic ADK expression was complete, except in a subset of neurons that retained ADK until adulthood in specific regions, such as striatum. Moreover, neuronal progenitors in the adult dentate gyrus lacked ADK. Finally, recordings of excitatory field potentials in acute slice preparations revealed a reduced adenosinergic inhibition in P14 hippocampus compared with adult. These findings suggest distinct roles for adenosine in the developing and adult brain. First, ADK expression in young neurons may provide a salvage pathway to utilize adenosine in nucleic acid synthesis, thus supporting differentiation and plasticity and influencing myelination; and second, adult ADK expression in astrocytes may offer a mechanism to regulate adenosine levels as a function of metabolic needs and synaptic activity, thus contributing to the differential resistance of young and adult animals to seizures.
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PMID:Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme. 1685 34

Adenosine is an inhibitory modulator of brain activity with neuroprotective and anticonvulsant properties. Adenosine levels are regulated mainly by adenosine kinase (ADK), an enzyme that is responsible for the removal of adenosine via phosphorylation to AMP. Recent evidence indicates that expression of ADK undergoes rapid coordinated changes during brain development and following brain injury, such as after epileptic seizures and stroke. Thus, transient downregulation of ADK after acute brain injury protects the brain from seizures and cell death. Conversely, chronic overexpression of ADK causes seizures in epilepsy and promotes cell death in epilepsy and stroke. These findings have direct implications for the rational definition of ADK as a therapeutic target. In recent years, novel treatment strategies have been developed that make use of the intracerebral transplantation of cells that are ADK deficient and, thus, release adenosine. A new era of cell-based delivery of adenosine has begun, which holds great promise for novel therapies for epilepsy and stroke.
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PMID:Adenosine kinase, epilepsy and stroke: mechanisms and therapies. 1705 28

Adenosine is an endogenous anticonvulsant that exerts its effects through A1 receptors. As the piriform/amygdala is a critical circuit for limbic seizure propagation, in this study, the role of basolateral amygdala A1 receptors on piriform cortex (PC)-kindled seizures was investigated. Rats were kindled by daily electrical stimulation of PC. In fully kindled animals, bilateral intra-amygdala N6-cyclohexyladenosine (CHA; 10-500 micromol/L, a selective A1 receptor agonist) had no effect on kindled-seizure parameters. However, bilateral intra-amygdala 2% lidocaine (reversal neuronal inhibitor) reduced the kindled seizure severity. There was significant increase in stage 4 latency and decrease in stage 5 duration. Bilateral lesion of basolateral amygdala of kindled animals (by electrical DC current) reduced the kindled seizure severity more dramatically. Our results showed afterdischarge duration, stage 5 duration, and seizure duration were decreased and stage 4 latency increased significantly. In addition, daily intra-amygdala CHA had no significant effect on PC kindling acquisition. Therefore, it may be concluded that although the basolateral amygdala neuronal activity has a critical role in the propagation of epileptic seizures from PC, the amygdala A1 receptors have no role in this regard. On the other hand, amygdala A1 receptors have no anticonvulsant or antiepileptogenic effect on PC-kindled seizures.
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PMID:Amygdala adenosine A1 receptors have no anticonvulsant effect on piriform cortex-kindled seizures in rat. 1711 Oct 36

Adenosine exerts its anticonvulsants effect through different brain regions including piriform cortex. In this study, the effect of amygdala kindled seizures on adenosine A1 receptor-mediated neuromodulation in piriform cortex pyramidal neurons was tested at 24 h and 1 month after kindling. Animals were kindled by daily electrical stimulation of amygdala. Field potentials were recorded from layer II of piriform cortex pyramidal cells following stimulation of the lateral olfactory tract. Obtained results showed that N6-cyclohexyladenosine (CHA), a selective adenosine A1 receptor agonist (1, 10 and 100 microM; i.c.v.), reduced A1 slope and B1 amplitude of field potentials in both kindled and non-kindled (control) rats. However, its effects on kindled animals were more potent at 24 h, but not 1 month post-kindling. 8 cyclopenthyl-1,3-dimethylxanthine (CPT), a selective adenosine A1 receptor antagonist (50 microM, i.c.v.), had no significant effect on the field potential parameters. However, CPT (50 microM, i.c.v.) pretreatment eliminated effects of CHA (10 microM; i.c.v.) on the field potentials. These results indicate that activation of adenosine A1 receptors has an inhibitory effect on the field potentials of piriform cortex pyramidal neurons and the efficiency of adenosine A1 receptor neuromodulation in piriform cortex is increased at short-term (24 h) but return to normal at long-term (1 month) after kindling implementation.
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PMID:Changes in neuromodulatory effect of adenosine A1 receptors on piriform cortex field potentials in amygdala kindled rats. 1735 67

Despite recent medical advances pharmacoresistant epilepsy continues to be a major health problem. The knowledge of endogenous protective mechanisms of the brain may lead to the development of rational therapies tailored to a patient's needs. Adenosine has been identified as an endogenous neuromodulator with antiepileptic and neuroprotective properties. However, the therapeutic use of adenosine or its receptor agonists is largely precluded by strong peripheral and central side effects. Thus, local delivery of adenosine to a critical site of the brain may provide a solution for the therapeutic use of adenosine. The following rationale for the local augmentation of the adenosine system as a novel therapeutic principle in the treatment of epilepsy has been established: (1) Deficits in the adenosinergic system are associated with epileptogenesis and these deficits promote seizures. Thus, reconstitution of an inhibitory adenosinergic tone is a rational therapeutic approach. (2) The focal paracrine delivery of adenosine from encapsulated cells suppresses seizures in kindled rats without overt side effects. (3) The anticonvulsant activity of locally released adenosine is maintained in models of epilepsy which are resistant to major antiepileptic drugs. This review summarizes the rationale and recent approaches for adenosine-based cell therapies for pharmacoresistant epilepsies.
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PMID:Adenosine-based cell therapy approaches for pharmacoresistant epilepsies. 1742 16

Pentylenetetrazol (PTZ) is commonly used as a convulsant drug. The enhanced seizure susceptibility induced by kindling is probably attributable to plastic changes in the synaptic efficacy. Adenosine and guanosine act both as important neuromodulators and neuroprotectors with mostly inhibitory effects on neuronal activity. Adenosine and guanosine can be released per se or generated from released nucleotides (ATP, ADP, AMP, GTP, GDP, and GMP) that are metabolized and rapidly converted to adenosine and guanosine. The aim of this study was to evaluate nucleotide hydrolysis by ecto- and soluble nucleotidases (hippocampal slices and CSF, respectively) after PTZ-kindling (stages 3, 4, or 5 seizures) or saline treatment in rats. Additionally, the levels of purines in rat cerebrospinal fluid (CSF), as well as ecto-NTPDases (1, 2, 3, 5, 6 and 8) and ecto- 5'-nucleotidase expression were determined. Ecto-enzyme assays demonstrated that ATP, AMP, GDP, and GMP hydrolysis enhanced when compared with controls. In addition, there was an increase of ADP, GDP, and GMP hydrolysis by soluble nucleotidases in PTZ-kindling rats compared to control group. The HPLC analysis showed a marked increase in PTZ-kindled CSF concentrations of GTP, ADP, and uric acid, but GDP, AMP, and hypoxanthine concentrations were decreased. Such alterations indicate that the modulatory role of purines in CNS could be affected by PTZ-kindling. However, the physiological significance of these findings remains to be elucidated.
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PMID:Pentylenetetrazol kindling alters adenine and guanine nucleotide catabolism in rat hippocampal slices and cerebrospinal fluid. 1754 58


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