glycogen and Epilepsy

Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue often show low signals with

Topics: Electroencephalography; Epilepsy; Fluorodeoxyglucose F18; Glucose; Glycogen; Humans; Positron-Emission Tomography; Seizures

Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K(+) by astrocytes, thereby leading to increased extracellular K(+) and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K(+) homeostasis and increased susceptibility to seizures in epilepsy.

Topics: Animals; Astrocytes; Convulsants; Disease Susceptibility; Epilepsy; Gliosis; Glucans; Glutamate-Ammonia Ligase; Glutamates; Glutamine; Glycogen; Glycogen Synthase Kinase 3; Homeostasis; Humans; Membrane Potentials; Methionine Sulfoximine; Molecular Structure; Neurons; Potassium; Seizures; Sleep; Sleep Deprivation; Structure-Activity Relationship

Epilepsy is a heterogeneous family of neurological disorders that manifest as seizures, i.e. the hypersynchronous activity of large population of neurons. About 30% of epileptic patients do not respond to currently available antiepileptic drugs. Decades of intense research have elucidated the involvement of a number of possible signaling pathways, however, at present we do not have a fundamental understanding of epileptogenesis. In this paper, we review the literature on epilepsy under a wide-angle perspective, a mandatory choice that responds to the recurrent and unanswered question about what is epiphenomenal and what is causal to the disease. While focusing on the involvement of K+ and glutamate/GABA in determining neuronal hyperexcitability, emphasis is given to astrocytic contribution to epileptogenesis, and especially to loss-of-function of astrocytic glutamine synthetase following reactive astrogliosis, a hallmark of epileptic syndromes. We finally introduce the potential involvement of abnormal glycogen synthesis induced by excess glutamate in increasing susceptibility to seizures.

Topics: Animals; Astrocytes; Brain; Epilepsy; gamma-Aminobutyric Acid; Glutamic Acid; Glycogen; Humans; Models, Neurological; Neurons; Potassium

Seizures are the result of a sudden and temporary synchronization of neuronal activity, the reason for which is not clearly understood. Astrocytes participate in the control of neurotransmitter storage and neurotransmission efficacy. They provide fuel to neurons, which need a high level of energy to sustain normal and pathological neuronal activities, such as during epilepsy. Various genetic or induced animal models have been developed and used to study epileptogenic mechanisms. Methionine sulfoximine induces both seizures and the accumulation of brain glycogen, which might be considered as a putative energy store to neurons in various animals. Animals subjected to methionine sulfoximine develop seizures similar to the most striking form of human epilepsy, with a long pre-convulsive period of several hours, a long convulsive period during up to 48 hours and a post convulsive period during which they recover normal behavior. The accumulation of brain glycogen has been demonstrated in both the cortex and cerebellum as early as the pre-convulsive period, indicating that this accumulation is not a consequence of seizures. The accumulation results from an activation of gluconeogenesis specifically localized to astrocytes, both in vivo and in vitro. Both seizures and brain glycogen accumulation vary when using different inbred strains of mice. C57BL/6J is the most "resistant" strain to methionine sulfoximine, while CBA/J is the most "sensitive" one. The present review describes the data obtained on methionine sulfoximine dependent seizures and brain glycogen in the light of neurotransmission, highlighting the relevance of brain glycogen content in epilepsies.

Topics: Animals; Brain; Disease Models, Animal; Energy Metabolism; Epilepsy; Glycogen; Humans; Methionine Sulfoximine; Synaptic Transmission

Topics: Alkaline Phosphatase; Animals; Brain Edema; Cerebrovascular Disorders; Epilepsy; Glycogen; Guinea Pigs; Hematologic Diseases; Humans; Leukocytes; Neoplasms; Rabbits; Tuberculosis; Wounds and Injuries

Glucose is the main brain fuel in fed conditions, while astrocytic glycogen is used as supplemental fuel when the brain is stimulated. Brain glycogen levels are decreased shortly after induced seizures in rodents, but little is known about how glycogen levels are affected interictally in chronic models of epilepsy. Reduced glutamine synthetase activity has been suggested to lead to increased brain glycogen levels in humans with chronic epilepsy. Here, we used the mouse pilocarpine model of epilepsy to investigate whether brain glycogen levels are altered, both acutely and in the chronic stage of the model. One day after pilocarpine-induced convulsive status epilepticus (CSE), glycogen levels were higher in the hippocampal formation, cerebral cortex, and cerebellum. Opposite to expected, this was accompanied by elevated glutamine synthetase activity in the hippocampus but not the cortex. Increased interictal glycogen amounts were seen in the hippocampal formation and cerebral cortex in the chronic stage of the model (21 days post-CSE), suggesting long-lasting alterations in glycogen metabolism. Glycogen solubility in the cerebral cortex was unaltered in this epilepsy mouse model. Glycogen synthase kinase 3 beta (Gsk3b) mRNA levels were reduced in the hippocampal formations of mice in the chronic stage, which may underlie the elevated brain glycogen content in this model. This is the first report of elevated interictal glycogen levels in a chronic epilepsy model. Increased glycogen amounts in the brain may influence seizure susceptibility in this model, and this warrants further investigation.

Topics: Animals; Brain; Disease Models, Animal; Epilepsy; Glutamate-Ammonia Ligase; Glycogen; Mice; Pilocarpine; Seizures; Status Epilepticus

Lafora disease is a fatal neurodegenerative condition characterized by the accumulation of abnormal glycogen inclusions known as Lafora bodies. It is an autosomal recessive disorder caused by mutations in either the laforin or malin gene. To study whether glycogen is primarily responsible for the neurodegeneration in Lafora disease, we generated malin knockout mice with impaired (totally or partially) glycogen synthesis. These animals did not show the increase in markers of neurodegeneration, the impairments in electrophysiological properties of hippocampal synapses, nor the susceptibility to kainate-induced epilepsy seen in the malin knockout model. Interestingly, the autophagy impairment that has been described in malin knockout animals was also rescued in this double knockout model. Conversely, two other mouse models in which glycogen is over-accumulated in the brain independently of the lack of malin showed impairment in autophagy. Our findings reveal that glycogen accumulation accounts for the neurodegeneration and functional consequences seen in the malin knockout model, as well as the impaired autophagy. These results identify the regulation of glycogen synthesis as a key target for the treatment of Lafora disease.

Topics: Animals; Autophagy; Biomarkers; Disease Models, Animal; Dual-Specificity Phosphatases; Electrical Synapses; Epilepsy; Glycogen; Glycogen Synthase; Hippocampus; Humans; Inclusion Bodies; Kainic Acid; Lafora Disease; Mice; Mice, Knockout; Mutation; Protein Tyrosine Phosphatases, Non-Receptor; Ubiquitin-Protein Ligases

Abnormalities of carbohydrate metabolism and monoamine neurotransmitters have been widely implicated in the pathoetiology of human epilepsy, and glucose hypometabolism and/or tryptophan utilization can be used to localize epileptic foci in the human brain. To investigate the neurochemical changes that underlie seizure susceptibility we studied four strains of mice that respond differently to the convulsant methionine sulfoximine (MSO). Seizures in CBA/J strain were induced by MSO at a dosage half that necessary to provoke seizures in C57BL/6J, BALB/c, or Swiss mice. We report that brain glycogen content in response to MSO administration was markedly increased in all four strains of mice. Of the monoamine neurotransmitters studied, the most prominent change was in brain serotonin (5-hydroxytryptamine, 5-HT) levels that showed a significant reduction following MSO administration. MSO also lowered the concentration of the 5-HT precursor tryptophan. Notably, inhibition of the fall in 5-HT levels by coadministration of 5-hydroxytryptophan delayed the onset of MSO-induced seizures. These results indicate that increased glycogen content and decreased brain levels of 5-HT and tryptophan are hallmarks of MSO action in mice, and suggest that defective serotonergic neurotransmission could trigger glycogen increase and seizure genesis.

Topics: Animals; Convulsants; Epilepsy; Glycogen; Male; Methionine Sulfoximine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Serotonin; Synaptic Transmission

Topics: Abdominal Pain; Adult; Diabetes Mellitus, Type 1; Diagnosis, Differential; Epilepsy; Female; Glycated Hemoglobin; Glycogen; Humans; Hypoglycemic Agents; Insulin; Liver; Liver Diseases; Liver Function Tests; Ultrasonography

During intense cerebral activation approximately half of the glucose plus lactate taken up by the human brain is not oxidized and could replenish glycogen deposits, but the human brain glycogen concentration is unknown. In patients with temporal lobe epilepsy, undergoing curative surgery, brain biopsies were obtained from pathologic hippocampus (n=19) and from apparently 'normal' cortical grey and white matter. We determined the in vivo brain glycogen level and the activity of glycogen phosphorylase and synthase. Regional differences in glycogen concentration were examined similarly in healthy pigs (n=5). In the patients, the glycogen concentration in 'normal' grey and white matter was 5 to 6 mmol/L, but much higher in the hippocampus, 13.1+/-4.3 mmol/L (mean+/-s.d.; P<0.001); the activities of glycogen phosphorylase and synthase displayed the same pattern. In normal hippocampus from pigs, glycogen was similarly higher than in grey and white matter. Consequently, in human grey and white matter and, particularly, in the hippocampus of patients with temporal lope epilepsy, glycogen constitutes a large, active energy reserve, which may be of importance for energy provision during sustained synaptic activity as epileptic seizures.

Topics: Adult; Animals; Brain Chemistry; Energy Metabolism; Epilepsy; Glycogen; Glycogen Phosphorylase; Glycogen Synthase; Hippocampus; Humans; Middle Aged; Swine

This work shows that the convulsant methionine sulfoximine induces an increase in glucose and glycogen levels and a parallel decrease in norepinephrine and dopamine levels in rat brain. Among the epileptogenic agents, methionine sulfoximine is known to have a glycogenic property in the central nervous system. The aim of this work is to look for the neurochemical mechanism underlying this property. For this, catecholamines, glucose, and glycogen were measured at the same time in different areas of the brain in rats submitted to methionine sulfoximine. The convulsant induced an increase in glucose and glycogen levels as previously described and a decrease in dopamine and norepinephrine levels in all the areas of the rat brain. These changes were roughly dose dependent. When L-dihydroxyphenylalanine and benserazide (a decarboxylase inhibitor) were administered with methionine sulfoximine, the latter failed to induce seizures in rat up to 8 h after dosing. Moreover, the glucose and glycogen amounts did not increase. In all these experiments, there was an obvious evidence of parallelism between seizures, increase in carbohydrate levels, and decrease in catecholamine levels. These results allow to conclude that the glycogenic property of methionine sulfoximine in the central nervous system probably results from its ability to decrease norepinephrine and dopamine levels. Because the effect of the convulsant on the catecholamine levels persisted for long, it is normal that glucose and glycogen levels increased during preconvulsive, convulsive and postconvulsive period. Methionine sulfoximine is probably glycogenic in rat brain because it decreases catecholamine levels for a long time.

Topics: Animals; Benserazide; Brain; Carbohydrate Metabolism; Catecholamines; Dopamine; Dose-Response Relationship, Drug; Epilepsy; Glucose; Glycogen; Levodopa; Male; Methionine Sulfoximine; Norepinephrine; Rats; Rats, Inbred Strains

K+, at concentrations reached in the extracellular space during neuronal activity (5-10 mM), promotes a time- and concentration-dependent hydrolysis of [3H]glycogen newly synthesized by mouse cerebral cortical slices. In the present study, the glycogenolytic action of K+ was examined in the neocortex of the quaking mouse, a spontaneously epileptic mutant characterized by deficient myelination of the CNS. The potency and efficacy of K+ in eliciting glycogen hydrolysis was greatly enhanced in cerebral cortical slices prepared from homozygous quaking mice (qk/qk) older than 7 weeks of age, indicating a supersensitive response to a metabolic action of the ion. A detailed ontogenic analysis showed an evolution of the supersensitive response to K+ which is reminiscent of the previously described increase in the number of alpha 2-adrenoreceptors in the brainstem of this mutant. In contrast to the altered response to K+, the glycogenolytic action of noradrenaline and vasoactive intestinal peptide reported earlier was equally expressed in qk/qk and in their unaffected littermates.

Topics: Aging; Animals; Cerebral Cortex; Epilepsy; Glycogen; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Potassium

The glycogenolytic action of norepinephrine (NE) was examined in the tottering mouse, a spontaneously epileptic mutant which presents a noradrenergic hyperinnervation of various CNS areas, including the cerebral cortex. The potency and efficacy of NE in promoting glycogenolysis were markedly decreased in cerebral cortical slices prepared from homozygous tottering (tg/tg) when compared to control C57BL/6j (+/+) mice, indicating a sub-sensitive response to a cellular action of NE. The metabolic nature of this adaptive change suggests that an impaired capacity of NE in mobilizing energy substrates may be related to the expression of the epileptic symptomatology in this mutant.

Topics: Animals; Cerebral Cortex; Epilepsy; Glycogen; In Vitro Techniques; Isoproterenol; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Norepinephrine

The effects of the convulsant methionine sulfoximine (MSO) on the glucose pathway have been investigated in mouse and rat brain. The key gluconeogenic enzyme fructose-1,6-biphosphatase (FBPase) (EC 3.1.3.11) was immunostained by rat anti-FBPase antibody. The rat cortex slices were very lightly stained, almost unstained in controls. After MSO injection, there was a marked staining only in astrocytes (perikarya, processes, and end feet). The activity of this enzyme also increased. MSO induced an increase of 63% in the stability at heating (47 degrees C) and of 36% in the stability at proteolysis (trypsin, 10 micrograms/ml) of FBPase. The convulsant had no effect on the concentrations of the metabolites related to the FBPase-phosphofructokinase step, i.e., fructose-1,6-biphosphate, glyceraldehyde-3-phosphate, and dihydroxyacetone phosphate, before, during, or after the convulsions. These results show that the cellular site of glucose pathway impairment induced by MSO in rodent brain is presumably the astroglial cells and that one mechanism of glycogenesis could be the reinforcement of the molecules of FBPase, which enhances gluconeogenesis. A hypothetical diagram of glucose metabolism under the effect of MSO has been proposed.

Topics: Animals; Brain; Epilepsy; Fructose-Bisphosphatase; Gluconeogenesis; Glycogen; Histocytochemistry; Hot Temperature; Immunologic Techniques; Male; Methionine Sulfoximine; Mice; Rats; Rats, Inbred Strains; Trypsin

Topics: Animals; Anticonvulsants; Brain; Brain Chemistry; Dioxolanes; Energy Metabolism; Epilepsy; Female; Glucose; Glucosephosphate Dehydrogenase; Glycogen; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains

Tissues from the cerebral cortex, liver and myocardium of a patient with Lafora disease were obtained at autopsy and were studied biochemically. 1. Glucose content in the myocardium and liver was almost nil while that in the controls was 0.66 mg/g wet weight in the former and 8.80 mg/g wet weight in the latter. Glycogen content in the cerebral cortex and myocardium was about 10 and 3 times more than in controls. 2. Polyglucosan extracted from the cerebral cortex, liver and myocardium had a longer exterior glucose chain than that in the liver of the control but a normal, alpha or beta 1,4-glucosidic linkage was observed. 3. The activities of glucose-6-phosphatase and amylo-1,6-glucosidase in the cerebral cortex, liver and myocardium were well preserved. The activities of acid maltase in the three organs mentioned above and of neutral maltase in the myocardium were elevated twice and one and half times more than the control. Phosphorylase levels in the myocardium were extremely small, while in the cerebral cortex and liver normal activities were observed. In light of these findings, glycogen metabolism in Lafora disease is discussed.

Topics: Adult; Cerebral Cortex; Chromatography, Gas; Epilepsy; Glucose; Glucose-6-Phosphatase; Glucosidases; Glycogen; Humans; Liver; Male; Maltose; Myocardium; Myoclonus; Organ Specificity; Spectrophotometry; Spectrophotometry, Ultraviolet

Topics: Adolescent; Adult; Carbohydrate Metabolism, Inborn Errors; Carbohydrates; Epilepsy; Female; Glycogen; Histocytochemistry; Humans; Inclusion Bodies; Male; Myocardium; Myoclonus; Phosphorylases

Topics: Adult; Amylases; Biopsy; Cytoplasmic Granules; Diagnosis, Differential; Epilepsy; Glycogen; Humans; Inflammation; Male; Microscopy, Electron; Muscles; Myoclonus; NADH, NADPH Oxidoreductases; Staining and Labeling; Tetrazolium Salts

Topics: Acid Phosphatase; Adult; Autopsy; Biopsy; Chromatography, Paper; Colorimetry; Epilepsy; Female; Glucosidases; Glycogen; Histocytochemistry; Humans; Maltose; Molecular Weight; Muscles; Myoclonus; Myofibrils; Phosphorylases; Polysaccharides; Staining and Labeling

Topics: Adolescent; Adult; DNA; Epilepsy; Female; Glycogen; Humans; Male; Middle Aged; Phosphoric Monoester Hydrolases; RNA

Topics: Animals; Brain Chemistry; Chromatography, Thin Layer; Epilepsy; Glycogen; Humans; Liver Glycogen; Myoclonus; Spectrum Analysis; Swine

Topics: Adult; Biopsy; Cerebral Cortex; Chromatography, Thin Layer; Cytoplasmic Granules; Electroencephalography; Epilepsy; Gangliosides; Glycogen; Humans; Lipids; Liver; Male; Monosaccharides; Muscles; Myoclonus; Polysaccharides

Topics: Adolescent; Adult; Cerebral Cortex; Chromatography, Thin Layer; Epilepsy; Female; Glucose; Glycogen; Histocytochemistry; Humans; Male; Spectrum Analysis; Staining and Labeling

Topics: Adolescent; Brain Diseases; Carbohydrate Metabolism; Child; Epilepsy; Epilepsy, Absence; Glycogen; Hexosamines; Humans; Metabolic Diseases; Myoclonic Epilepsies, Progressive; Neurochemistry; Pathology