glycogen and Seizures

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

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 rare genetic disorder involving glycogen metabolism disorder. It is inherited by autosomal recessive pattern presenting as a progressive myoclonus epilepsy and neurologic deterioration beginning in adolescence. It is characterized by Lafora bodies in tissues such as brain, skin, muscle, and liver.. We report a rare case of Lafora disease in a 16-year-old Albanian girl who presented at a tertiary health care center with generalized tonic-clonic seizures, eyelid twitches, hallucinations, headache, and cognitive dysfunction. She was initially treated for generalized epilepsy and received an antiepileptic drug. However, owing to resistance of seizures to this antiepileptic drug, a second drug was introduced. However, seizures continued despite compliance with therapy, and general neurological status began to deteriorate. The child began to have hallucinations and decline of cognitive function. She developed dysarthria and unsteady gait. When admitted to the hospital, blood tests and imaging examinations were planned. The blood tests were unremarkable. There was no relevant family history and no consanguinity. Electroencephalography showed multifocal discharges in both hemispheres, and brain magnetic resonance imaging revealed no abnormality. Axillary skin biopsy revealed inclusion bodies in apocrine glands. Consequently, the child was referred to an advanced center for genetic testing, which also confirmed diagnosis of Lafora disease with a positive mutation on NHLRC1 gene..  Even though rare as a condition, Lafora disease should be considered on differential diagnosis in progressive and drug-refractory epilepsy in adolescents, especially when followed by cognitive decline.

Topics: Adolescent; Anticonvulsants; Child; Female; Glycogen; Hallucinations; Humans; Lafora Disease; Seizures; Ubiquitin-Protein Ligases

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Blood Glucose; Carbohydrate Metabolism, Inborn Errors; Carbon; Consciousness; Deoxyglucose; Electroencephalography; Glucose Transport Proteins, Facilitative; Glycogen; Mice; Monosaccharide Transport Proteins; Seizures; Thalamus

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.

Topics: Animals; Biological Evolution; Cell Line; CRISPR-Cas Systems; Encephalitis; Female; Genes, Recessive; Glycogen; Humans; Inflammation; Male; Membrane Proteins; Mitochondrial Diseases; Pedigree; Seizures; Zebrafish

Topics: Animals; Cardiomyopathies; Disease Models, Animal; Dual-Specificity Phosphatases; Echocardiography; Glycogen; Humans; Lafora Disease; Mice; Mice, Knockout; Mutation; Myocytes, Cardiac; Protein Tyrosine Phosphatases, Non-Receptor; Seizures; Stroke Volume; Ubiquitin-Protein Ligases; Ventricular Dysfunction, Left; Ventricular Remodeling

To determine changes in glucose metabolism and the enzymes involved in the hippocampus ictally and postictally in the acute mouse flurothyl seizure model.. [U-. During seizures, total lactate levels increased 1.7-fold; however, [M + 3] enrichment of both lactate and alanine were reduced by 30% and 43%, respectively, along with a 28% decrease in phosphofructokinase activity. Postictally the %. Here, we show that the increase of lactate levels during flurothyl seizures is from a source other than [U-

Topics: Alanine; Amino Acids; Animals; Antioxidants; Blood Glucose; Citric Acid Cycle; Flurothyl; Gas Chromatography-Mass Spectrometry; Glycogen; Hippocampus; Lactic Acid; Lipid Peroxidation; Male; Mice; Mice, Inbred Strains; Phosphofructokinases; Phosphorylation; Pyruvate Dehydrogenase Complex; Seizures; Superoxide Dismutase

Ubiquitin ligases regulate quantities and activities of target proteins, often pleiotropically. The malin ubiquitin E3 ligase is reported to regulate autophagy, the misfolded protein response, microRNA silencing, Wnt signaling, neuronatin-mediated endoplasmic reticulum stress, and the laforin glycogen phosphatase. Malin deficiency causes Lafora disease, pathologically characterized by neurodegeneration and accumulations of malformed glycogen (Lafora bodies). We show that reducing glycogen production in malin-deficient mice by genetically removing PTG, a glycogen synthesis activator protein, nearly completely eliminates Lafora bodies and rescues the neurodegeneration, myoclonus, seizure susceptibility, and behavioral abnormality. Glycogen synthesis downregulation is a potential therapy for the fatal adolescence onset epilepsy Lafora disease.

Topics: Animals; Brain; Conditioning, Psychological; Down-Regulation; Fear; Glycogen; Glycogen Synthase; Intracellular Signaling Peptides and Proteins; Lafora Disease; Mice; Mice, Knockout; Myoclonus; Neuroprotective Agents; Plaque, Amyloid; Seizures; Ubiquitin-Protein Ligases

The experimental model of seizures which depends upon methionine sulfoximine (MSO) simulates the most striking form of human epilepsy. MSO generates epileptiform seizures in a large variety of animals, increases brain glycogen content and induces brain monoamines modifications. We selected two inbred lines of mice based upon their latency toward MSO-dependent seizures, named as MSO-Fast (sensitive), having short latency toward MSO, and MSO-Slow (resistant) with a long latency. We determined 13 monoamines and glycogen contents in brain cortices of the MSO-Fast and slow lines in order to determine the relationships with MSO-dependent seizures. The present data show that using these MSO-Fast and MSO-Slow inbred lines it could be demonstrated that: (1) in basal conditions the neurotransmitter 5-HT is significantly higher in MSO-Fast mice than in MSO-Slow ones; (2) MSO in both lines induced a significant increase in brain content of DOPAC (3,4-dihydroxyphenylacetic acid), HVA (homovanillic acid), MHPG (3-methoxy-4-hydroxyphenylglycol), and 5-HT (serotonin); a significant decrease in MSO-Slow mice in brain content of NME (normetepinephrine), and 5-HIAA (5-hydroxyindoleacetic acid) and the variation of other monoamines were not significant; (3) the brain glycogen content is significantly higher in MSO-Fast mice than in MSO-Slow ones, both in basal conditions and after MSO administration. From our data, we propose that brain glycogen content may constitute a defense against epileptic attack, as glycogen may be degraded down to glucose-6-phosphate that can be used to either postpone the epileptic attack or to provide neurons with energy when they needed it. Brain glycogen might therefore be considered as a molecule that can contribute to struggle seizures, at least in MSO-dependent seizure. The 5-HT content may constitute a defense against MSO-dependent epilepsy.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Biogenic Monoamines; Brain; Disease Models, Animal; Glycogen; Hydroxyindoleacetic Acid; Methionine Sulfoximine; Mice; Mice, Inbred Strains; Seizures; Serotonin; Thiophenes

Central nervous system space-occupying lesions with clear-cell features encompass a nosologically heterogeneous array, ranging from reactive histiocytic proliferations to neuroepithelial or meningothelial neoplasms of various grades and to metastases. In the face of such differential diagnostic breadth, recognizing cytoplasmic lucency as part of the morphological spectrum of some low grade gliomas will directly have an impact on patient care. We describe a prevailing clear-cell change in an epileptogenic left temporal pleomorphic xanthoastrocytoma surgically resected from a 36-year-old man. Mostly subarachnoid and focally calcified, the tumor was composed of fascicles of moderately atypical spindle cells with optically lucent cytoplasm that tended to intermingle with a desmoplastic mesh of reticulin fibers. Immunohistochemically, coexpression of S100 protein, vimentin, GFAP, and CD34 was noted. Conversely, neither punctate staining for EMA nor positivity for CD68 was seen. Mitotic activity was absent, and the MIB1 labeling index was 2-3% on average. Diastase-sensitive PAS-positive granula indicated clear-cell change to proceed from glycogen storage. Electron microscopy showed tumor cell cytoplasm to be largely obliterated by non-lysosomal-bound pools of glycogen, while hardly any fat vacuole was encountered. Neither ependymal-derived organelles nor annular lamellae suggesting oligodendroglial differentiation were detected. The latter differential diagnosis was further invalidated by lack of codeletion of chromosomal regions 1p36 and 19q13 on molecular genetic testing. By significantly interfering with pattern recognition as an implicit approach in histopathology, clear-cell change in pleomorphic xanthoastrocytoma is likely to suspend its status as a "classic", and to prompt more deductive differential diagnostic strategies to exclude look-alikes, especially clear-cell ependymoma and oligodendroglioma.

Topics: Adult; Antigens, CD34; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Diagnosis, Differential; Ependymoma; Glial Fibrillary Acidic Protein; Glycogen; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Microscopy, Electron; Oligodendroglioma; S100 Proteins; Seizures; Vimentin

Brain glycogen could be considered as an energy store for neuronal activity, with high relevance in epilepsies. We selected two lines of mice based upon their latency to methionine sulfoximine (MSO) dependent-seizures: MSO-Fast and MSO-Slow, and their neurochemical characterization was attempted in order to look for the mechanisms of epileptogeny. We determined the MSO effect on brain glycogen in the two selected lines and their eight parental strains, and on indolamines and catecholamines. The increase in brain glycogen content induced by MSO is significantly lower in MSO-Fast than in MSO-Slow. At the onset of seizures the degradation of accumulated glycogen was higher in MSO-Slow mice than in MSO-Fast ones. Moreover, a positive correlation was observed between the magnitude of latency toward MSO-induced seizures and brain glycogen content in the eight parental strains used for selection. A striking proportionality between the content of glycogen and 5-hydroxytryptamine (5-HT) was observed in cerebral cortices of both selected lines. However, the cortical 5-HT level is higher in MSO-Fast than in MSO-Slow, and it is significantly decreased at the onset of seizures in both lines. Brain glycogen content is implicated in the developed model of mice with different latency to MSO-dependent seizures: The higher the brain glycogen content, the longer the latency; and 5-HT is involved in the control of latency to seizures-induced by MSO in these two lines. Our model of MSO "sensitive" (MSO-Fast) and "resistant" (MSO-Slow) mice could lead to a better understanding of MSO mechanisms of epileptogenesis, and the relationship between epileptogenic and glycogenic MSO effects.

Topics: Analysis of Variance; Animals; Biogenic Monoamines; Brain; Glycogen; Methionine Sulfoximine; Mice; Seizures; Synaptic Transmission; Time Factors

We focused on over-dose insulin (250 IU/kg i.p.) induced gastric ulcers and then on other disturbances that were concomitantly induced in rats, seizures (eventually fatal), severely damaged neurons in cerebral cortex and hippocampus, hepatomegaly, fatty liver, increased AST, ALT and amylase serum values, breakdown of liver glycogen with profound hypoglycemia and calcification development. Calcium deposits were present in the blood vessel walls, hepatocytes surrounding blood vessels and sometimes even in parenchyma of the liver mainly as linear and only occasionally as granular accumulation. As an antidote after insulin, we applied the stable gastric pentadecapeptide BPC 157 (10 microg/kg) given (i) intraperitoneally or (ii) intragastrically immediately after insulin. Controls received simultaneously an equivolume of saline (5 ml/kg). Those rats that survived till the 180 minutes after over-dose application were further assessed. Interestingly, pentadecapeptide BPC 157, as an antiulcer peptide, may besides stomach ulcer consistently counteract all insulin disturbances and fatal outcome. BPC 157 rats showed no fatal outcome, they were mostly without hypoglycemic seizures with apparently higher blood glucose levels (glycogen was still present in hepatocytes), less liver pathology (i.e., normal liver weight, less fatty liver), decreased ALT, AST and amylase serum values, markedly less damaged neurons in brain and they only occasionally had small gastric lesions. BPC 157 rats exhibited mostly only dot-like calcium presentation. In conclusion, the success of BPC 157 therapy may indicate a likely role of BPC 157 in insulin controlling and BPC 157 may influence one or more causative process(es) after excessive insulin application.

Topics: Animals; Anti-Ulcer Agents; Antidotes; Brain; Calcinosis; Drug Overdose; Endothelium, Vascular; Glycogen; Hepatomegaly; Hypoglycemia; Hypoglycemic Agents; Insulin; Liver; Male; Neurons; Peptide Fragments; Proteins; Rats; Rats, Wistar; Seizures; Stomach Ulcer

The brain is heavily dependant on glucose for its function and survival. Hypoglycemia can have severe, irreversible consequences, including seizures, coma and death. However, the in vivo content of brain glycogen, the storage form of glucose, is meager and is a function of both neuronal activity and glucose concentration. In the intact in vitro hippocampus isolated from mice aged postnatal days 8-13, we have recently characterized a novel model of hypoglycemic seizures, wherein seizures were abolished by various neuroprotective strategies. We had hypothesized that these strategies might act, in part, by increasing cerebral glycogen content. In the present experiments, it was found that neither decreasing temperature nor increasing glucose concentrations (above 2 mM) significantly increased hippocampal glycogen content. Preparations of isolated frontal neocortex in vitro do not produce hypoglycemic seizures yet it was found they contained significantly lower glycogen content as compared to the isolated intact hippocampus. Further, the application of either TTX, or a cocktail containing APV, CNQX and gabazine, to block synaptic activity, did not increase, but paradoxically decreased, hippocampal glycogen content in the isolated intact hippocampus. Significant decreases in glycogen were noted when neuronal activity was increased via incubation with l-aspartate (500 muM) or low Mg(2+). Lastly, we examined the incidence of hypoglycemic seizures in hippocampi isolated from mice aged 15-19 and 22-24 days, and compared it to the incidence of hypoglycemic seizures of hippocampi isolated from mice aged 8-13 days described previously (Abdelmalik et al., 2007 Neurobiol Dis 26(3):646-660). It was noted that hypoglycemic seizures were generated less frequently, and had less impact on synaptic transmission in hippocmpi from PD 22-24 as compared to hippocampi from mice PD 15-19 or PD 8-13. However, hippocampi from 8- to 13-day-old mice had significantly more glycogen than the other two age groups. The present data suggest that none of the interventions which abolish hypoglycemic seizures increases glycogen content, and that low glycogen content, per se, may not predispose to the generation of hypoglycemic seizures.

Topics: Age Factors; Analysis of Variance; Anesthetics, Local; Animals; Animals, Newborn; Aspartic Acid; Cerebellum; Disease Models, Animal; Drug Combinations; Excitatory Amino Acid Antagonists; Glucose; Glycogen; Hippocampus; Hypoglycemia; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Seizures; Synaptic Transmission; Tetrodotoxin

The aim of the present study was to investigate the status of jejunal absorption and peripheral metabolism of glucose in Wistar Audiogenic Rats (WAR), a genetic model of epilepsy, after seizures induced by intensive sound exposure. The jejunal loop of rats was isolated and infused (0.5 mL min(-1)) with Tyrode solution containing twice the normal concentrations of glucose, sodium, and potassium. Samples were taken at 5 or 10-min intervals over a 40-min period. At the end of the experiment, samples of liver and gastrocnemius muscle were taken to measure the levels of glycogen, glucose-6-phosphate, fructose-6-phosphate and glucose transporter-4 (GLUT4). Hepatic glucose-6-phosphate increased in WAR submitted to audiogenic seizure (21.90 +/- 3.08) as compared to non-susceptible Wistar rats (8.12 +/- 0.87) and to WAR not submitted to audiogenic stimulation (5.17 +/- 0.97). In addition, an increase in hepatic fructose-6-phosphate, an intermediate metabolite of the glycolytic pathway, was observed in WAR submitted to audiogenic seizure (5.98 +/- 0.99) compared to non-susceptible Wistar rats (2.38 +/- 0.53). According to the present results, jejunal absorption of glucose was not changed by seizures. However, generalized tonic-clonic seizures produced by sound stimulation resulted in a decrease in muscle glycogen content. In addition, our results demonstrated that the concentration of GLUT4 in the gastrocnemius muscle of WAR was 1.6-fold higher than that observed in resistant rats and that the audiogenic stimulus led to decreased concentration of this receptor in the muscle of WAR animals.

Topics: Acoustic Stimulation; Animals; Blotting, Western; Epilepsy, Reflex; Fructosephosphates; Glucose; Glucose Transporter Type 4; Glucose-6-Phosphate; Glycogen; Jejunum; Lactic Acid; Liver; Liver Glycogen; Male; Muscle, Skeletal; Rats; Rats, Wistar; Seizures

Severe hypoglycemia constitutes a medical emergency, involving seizures, coma and death. We hypothesized that seizures, during limited substrate availability, aggravate hypoglycemia-induced brain damage. Using immature isolated, intact hippocampi and frontal neocortical blocks subjected to low glucose perfusion, we characterized hypoglycemic (neuroglycopenic) seizures in vitro during transient hypoglycemia and their effects on synaptic transmission and glycogen content. Hippocampal hypoglycemic seizures were always followed by an irreversible reduction (>60% loss) in synaptic transmission and were occasionally accompanied by spreading depression-like events. Hypoglycemic seizures occurred more frequently with decreasing "hypoglycemic" extracellular glucose concentrations. In contrast, no hypoglycemic seizures were generated in the neocortex during transient hypoglycemia, and the reduction of synaptic transmission was reversible (<60% loss). Hypoglycemic seizures in the hippocampus were abolished by NMDA and non-NMDA antagonists. The anticonvulsant, midazolam, but neither phenytoin nor valproate, also abolished hypoglycemic seizures. Non-glycolytic, oxidative substrates attenuated, but did not abolish, hypoglycemic seizure activity and were unable to support synaptic transmission, even in the presence of the adenosine (A1) antagonist, DPCPX. Complete prevention of hypoglycemic seizures always led to the maintenance of synaptic transmission. A quantitative glycogen assay demonstrated that hypoglycemic seizures, in vitro, during hypoglycemia deplete hippocampal glycogen. These data suggest that suppressing seizures during hypoglycemia may decrease subsequent neuronal damage and dysfunction.

Topics: Action Potentials; Adenosine A1 Receptor Antagonists; Animals; Anticonvulsants; Cortical Spreading Depression; Disease Models, Animal; Excitatory Amino Acid Antagonists; Glucose; Glycogen; Hippocampus; Hypoglycemia; Male; Mice; Mice, Inbred C57BL; Midazolam; Nerve Degeneration; Neurons; Receptor, Adenosine A1; Seizures; Synaptic Transmission

The present study has examined the effect of free radical spin trap N-tert-butyl-alpha-phenylnitrone (PBN) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl-homocysteic acid (dl-HCA, 600 nmol/side). PBN was given i.p. in two doses (100 mg/kg each), 30 min prior and 30 min after dl-HCA infusion. PBN did not significantly influence the severity of seizures, evident both from the behavioral symptoms and EEG recordings. PBN normalized decreased ATP levels in the hippocampus, occurring during the acute phase of seizures ( approximately 45-50 min after infusion) and persisting until the end of the 24-h recovery period. PBN also led to normalization of decreased glucose levels and to a significant reduction of lactate accumulation in the cerebral cortex and hippocampus. The neuroprotective effect of PBN was evaluated after 24 h and 6 days of survival following dl-HCA-induced seizures (Nissl and Fluoro-Jade B staining). The administration of PBN resulted in a partial amelioration of severe damage observed in many brain regions following infusion of dl-HCA alone. The data suggest that increased free radical production is apparently occurring during seizures induced in immature rats by homocysteic acid. Free radical scavenger PBN had a clear-cut protective effect, evident as the improved recovery of brain energy status and as a partial, but significant, attenuation of neuronal degeneration associated with this model of seizures.

Topics: Adenosine Triphosphate; Animals; Brain; Cerebral Cortex; Disaccharides; Electroencephalography; Energy Metabolism; Free Radicals; Glucose; Glycogen; Hippocampus; Homocysteine; Injections, Intraperitoneal; Male; Neurons; Phosphocreatine; Rats; Rats, Wistar; Seizures; Spin Trapping

The present study has examined the anticonvulsant and neuroprotective effect of group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion. Comparable time intervals were used for sacrificing the pups which had received 2R,4R-APDC. Low doses of 2R,4R-APDC (0.05 nmol/side) provided a pronounced anticonvulsant effect which was abolished by pretreatment with a selective group II mGluR antagonist LY341495. Generalized clonic-tonic seizures were completely suppressed and cortical energy metabolite changes which normally accompany these seizures were either normalized (decrease of glucose and glycogen) or markedly reduced (an accumulation of lactate). EEG recordings support the marked anticonvulsant effect of 2R,4R-APDC, nevertheless, this was only partial. In spite of the absence of obvious motor phenomena, isolated spikes or even short periods of partial ictal activity could be observed. Isolated spikes could also be seen in some animals after application of 2R,4R-APDC alone, reflecting most likely subclinical proconvulsant activity of this agonist. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration, as revealed by Fluoro-Jade B staining, was observed in a number of brain regions following infusion of DL-HCA alone (seizure group), whereas 2R,4R-APDC pretreatment provided substantial neuroprotection. The present findings support the possibility that group II mGluRs are a promising target for a novel approach to treating epilepsy.

Topics: Amino Acids; Animals; Animals, Newborn; Anticonvulsants; Behavior, Animal; Brain; Brain Chemistry; Brain Injuries; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Excitatory Amino Acid Antagonists; Fluoresceins; Fluorescent Dyes; Functional Laterality; Glucose; Glycogen; Homocysteine; Lactic Acid; Male; Nerve Degeneration; Organic Chemicals; Proline; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Seizures; Time Factors; Xanthenes

We investigated the relationship between brain glycogen anabolism and methionine sulfoximine (MSO)-induced seizures in two inbred mouse strains that presented differential susceptibility to the convulsant. CBA/J was considered a MSO-high-reactive strain and C57BL/6J a MSO-low-reactive strain. Accordingly, the dose of MSO needed to induce seizures in CBA/J mice is lower than that in C57BL/6J mice, and CBA/J mice which had seizures, died during the first convulsion. In addition, the time--course of the MSO effect is faster in CBA/J mice than that in C57BL/6J mice. Analyses were performed in C57BL/6J and CBA/J mice after administration of 75 (subconvulsive dose) and 40 mg/kg of MSO (subconvulsive dose, not lethal dose), respectively. In the preconvulsive period, MSO induced an increase in the brain glycogen content of C57BL/6J mice only. Twenty-four hours after MSO administration, the brain glycogen content increased in both strains. The activity and expression of fructose-1,6-bisphosphatase, the last key enzyme of the gluconeogenic pathway, were increased in MSO-treated C57BL/6J mice as compared to control mice, at all experimental time points, whereas they were increased in CBA/J mice only 24 h after MSO administration. These latter results correspond to CBA/J mice that did not have seizures. Interestingly, the differences observed in vivo were consistent with results in primary cultured astrocytes from the two strains. This data suggests that the metabolism impairment, which was not a consequence of seizures, could be related to the difference in seizure susceptibility between the two strains, depending on their genetic background.

Topics: Animals; Astrocytes; Cells, Cultured; Convulsants; Dose-Response Relationship, Drug; Fructose-Bisphosphatase; Gluconeogenesis; Glycogen; Methionine Sulfoximine; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Osmolar Concentration; RNA, Messenger; Seizures; Species Specificity; Time Factors

The neuroendocrine-specific protein 7B2, which serves as a molecular escort for proPC2 in the secretory pathway, promotes the production of enzymatically active PC2 and may have non-PC2 related endocrine roles. Mice null for 7B2 exhibit a lethal phenotype with a complex Cushing's-like pathology, which develops from intermediate lobe ACTH hypersecretion as a consequences of interruption of PC2-mediated peptide processing as well as undefined consequences of the loss of 7B2. In this study we investigated the endocrine and metabolic alterations of 7B2 null mice from pathological and biochemical points of view. Our results show that 7B2 nulls exhibit a multisystem disorder that includes severe pathoanatomical and histopathologic alterations of vital organs, including the heart and spleen but most notably the liver, in which massive steatosis and necrosis are observed. Metabolic derangements in glucose metabolism result in glycogen and fat deposition in liver under conditions of chronic hypoglycemia. Liver failure is also likely to contribute to abnormalities in blood coagulation and blood chemistry, such as lactic acidosis. A hypoglycemic crisis coupled with respiratory distress and intensive internal thrombosis most likely results in rapid deterioration and death of the 7B2 null.

Topics: Adrenocorticotropic Hormone; Animals; Blood Glucose; Cause of Death; Corticosterone; Cushing Syndrome; Glucagon; Glucose; Glycogen; Hormones; Hypothermia; Lactic Acid; Liver; Magnesium; Metyrapone; Mice; Mice, Knockout; Multiple Organ Failure; Nerve Tissue Proteins; Neuroendocrine Secretory Protein 7B2; Pituitary Hormones; Radioimmunoassay; Seizures; Tissue Distribution

It is now well established that in epileptic patients, hypometabolic foci appear during interictal periods. The meaning and the mechanism of such an hypometabolism are as yet unclear. The aim of the present investigation was to look for a putative relationship between glucose metabolism in the brain and the genesis of seizures in mice using administration of the convulsant, methionine sulfoximine. Besides its epileptic action, methionine sulfoximine is a powerful glycogenic agent. We analyzed the epileptogenic and glycogenic effects of methionine sulfoximine in two inbred mouse strains with different susceptibility towards the convulsant. CBA/J mice displayed high response to methionine sulfoximine. The tonic convulsions appeared 5-6 h after MSO administration, without brain glycogen content variations during the preconvulsive period. These mice died of status epilepticus during the first seizure(s). Conversely, C57BL/6J mice displayed low response to MSO. The tonic and clonic seizures appeared 8 to 14 h after MSO administration with only 2% mortality. The seizures were preceded by an increase in brain glycogen content during the preconvulsive period. Moreover, during seizures, C57BL/6J mice were able to mobilize this accumulated brain glycogen, that returned to high value after seizures. The epileptic and glycogenic responses of the parental strains were also observed in mice of the F2 generation. The F2 mice that convulsed early (16%) did not utilize their small increase in brain glycogen content, and resembled CBA/J mice; while the F2 mice that seized tardily (24%) increased their brain glycogen content before convulsion, utilized it during convulsions, and resembled C57BL/6J mice. Sixty percent of the F2 mice presented an intermediate pattern in epileptogenic responses to the convulsant. These data suggest a possible genetic link between the two MSO effects, epileptiform seizures and increase in brain glycogen content. The increase in brain glycogen content and the capability of its mobilization during seizures could delay the seizure's onset and could be considered a "resistance factor" against the seizures.

Topics: Animals; Brain; Convulsants; Crosses, Genetic; Female; Genetic Predisposition to Disease; Glucose; Glycogen; Male; Methionine Sulfoximine; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Seizures

The causality of vascular and parenchymal damage to the central nervous system (CNS) was examined in rats with thiamine deficiency. Male Sprague-Dawley rats were divided into two groups; one was given a thiamine-deficient diet (TDD) and injected intraperitoneally with 10 micrograms/100 g bodyweight pyrithiamine (PT) in order to analyze morphometrically the topographical and sequential relationship between vascular and parenchymal changes and vasodilatation, and the other was given a TDD and 50 micrograms/100 g bodyweight PT in order to determine hemorrhagic sites using serial sections. Histological examination showed that spongiotic change occurred selectively in the inferior colliculus (100%) from day 19, and thereafter in the thalamus (95%), mammillary body (50%) and nuclei olivaris and vestibularis of the pons (25%), with or without hemorrhage. Simultaneously, glycogen accumulation was also observed in these regions at a frequency similar to that of hemorrhage. Ultrastructurally, however, hydropic swelling of astrocytic and neuronal processes without glycogen accumulation was observed as early as day 9 in the inferior colliculus, at which time an increase of glial fibrillary acidic protein-positive processes was also recognized. The superior colliculus was completely spared. From day 22 vasodilatation of the inferior colliculus occurred, concomitantly with bodyweight loss and neurological symptoms. Twenty-two examined hemorrhages, which occurred in the thalamus and inferior colliculus, were distributed along the arterioles or capillaries on the arterial side. In conclusion, the morphological CNS changes caused by thiamine deficiency with administration of low-dose PT in rats begin as hydropic swelling of neuronal and astrocytic processes, followed by hemorrhage and, thereafter, by vasodilation. The predilection for hemorrhage on the arterial side without parenchymal changes suggests that petechial hemorrhage is not simply secondary to parenchymal changes, but is due to hemodynamic change resulting from thiamine deficiency-induced vascular dysfunction.

Topics: Animals; Antimetabolites; Ataxia; Body Weight; Brain; Cerebral Hemorrhage; Glial Fibrillary Acidic Protein; Glycogen; Hypothermia; Immunohistochemistry; Inferior Colliculi; Male; Mammillary Bodies; Pyrithiamine; Rats; Rats, Sprague-Dawley; Seizures; Thalamus; Thiamine Deficiency; Vasodilation; Wernicke Encephalopathy

The primary objective of this study was to attempt to induce excessive intraglial acidosis during ischemia by subjecting rats to an initial insult which leads to post insult accumulation of glycogen, presumed to accumulate primarily in astrocytes. The initial insults were 15 min of transient forebrain ischemia, 30 min of hypoglycemic coma, and intraperitonial injection of methionine-sulphoximine (MSO). In the first two of these insults, glycogen content in neocortex increased to 6-7 mM kg(-1) after 6 h of recovery, and in MSO-treated animals even higher values were measured 24 h after administration ( 12 mM kg(-1)). In spite of this glycogen loading, the amount of lactate formed during a subsequent ischemic insult (of 5-30 min duration) did not exceed values usually obtained during complete ischemia in animals with normal glycogen contents (tissue lactate contents of 15 mM kg(-1)) This was because appreciable amounts of glycogen (3-7 mM kg(-1)) remained undegraded even after 30 min of ischemia. The undigested part largely reflected the extra amount of glycogen accumulated after the initial insults. It is discussed whether this part is unavailable to degradation by phosphorylase.

Topics: Acidosis; Animals; Astrocytes; Brain; Brain Ischemia; Coma; Energy Metabolism; Glycogen; Hypoglycemia; Ischemic Attack, Transient; Male; Methionine Sulfoximine; Phosphorylation; Rats; Rats, Wistar; Reperfusion Injury; Seizures

The present study was undertaken to explore how transient ischemia in rats alters cerebral metabolic capacity and how postischemic metabolism and blood flow are coupled during intense activation. After 6 h of recovery following transient forebrain ischemia 15 min in duration, bicuculline seizures were induced, and brains were frozen in situ after 0.5 or 5 min of seizure discharge. At these times, levels of labile tissue metabolites were measured, whereas the cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) were measured after 5 min of seizure activity. After 6 h of recovery, and before seizures, animals had a 40-50% reduction in CMRO2 and CBF. However, because CMRO2 rose three-fold and CBF fivefold during seizures, CMRO2 and CBF during seizures were similar in control and postischemic rats. Changes in labile metabolites due to the preceding ischemia encompassed an increased phosphocreatine/creatine ratio, as well as raised glucose and glycogen concentrations. Seizures gave rise to minimal metabolic perturbation, essentially comprising reduced glucose and glycogen contents and raised lactate concentrations. It is concluded that although transient ischemia leads to metabolic depression and a fall in CBF, the metabolic capacity of the tissue is retained, and drug-induced seizures lead to a coupled rise in metabolic rate and blood flow.

Topics: Animals; Bicuculline; Cerebrovascular Circulation; Creatine; Energy Metabolism; Glucose; Glycogen; Ischemic Attack, Transient; Kinetics; Male; Oxygen; Phosphocreatine; Prosencephalon; Rats; Rats, Wistar; Seizures

Seizures were induced in 7-day-old rats by intraperitoneal injection of DL-homocysteine thiolactone. Phosphocreatine (PCr), ATP, glucose, glycogen and lactate were determined in the cerebral cortex during various intervals after injection, corresponding to the early, as well as long periods of seizure activity. The unchanged levels of ATP, a very mild PCr decline and a pronounced accumulation of lactate (in the face of modest changes in brain glucose and glycogen) were observed. These results suggest that the immature rat brain is able to compensate energy expenditure associated with seizure activity by increased energy production, mainly due to increased anaerobic glycolysis. It remains to be determined whether a similar conclusion is also valid for other brain regions, e.g. subcortical structures.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Cerebral Cortex; Energy Metabolism; Glucose; Glycogen; Homocysteine; Lactates; Lactic Acid; Male; Phosphocreatine; Rats; Rats, Wistar; Seizures

Seizures were induced in 7-day-old rats by intraperitoneal injection of DL-homocysteine thiolactone. Phosphocreatine (PCr), ATP, glucose, glycogen and lactate were determined in the cerebral cortex during various intervals after injection, corresponding to the early, as well as long periods of seizure activity. The unchanged levels of ATP, a very mild PCr decline and a pronounced accumulation of lactate (in the face of modest changes in brain glucose and glycogen) were observed. These results suggest that the immature rat brain is able to compensate energy expenditure associated with seizure activity by increased energy production, mainly due to increased anaerobic glycolysis. It remains to be determined whether a similar conclusion is also valid for other brain regions, e.g. subcortical structures.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Cerebral Cortex; Energy Metabolism; Glucose; Glycogen; Homocysteine; Lactates; Male; Phosphocreatine; Rats; Rats, Wistar; Seizures

Diazinon, in acute doses (40 mg/kg, i.p.) in rats produced tremors and convulsions with lactic acidosis which was accompanied by depletion of glycogen and activation of glycogen phosphorylase activity in triceps and diaphragm muscles, 2 h after its administration. Prevention of convulsions with phenobarbitone administered immediately before diazinon, resulted in neither the development of lactic acidosis nor mobilization of muscle glycogen or activation of glycogen phosphorylase. Lactic acidosis was due to depletion of glycogen through enhanced activity of glycogen phosphorylase in muscles on account of tremors and convulsions induced by diazinon in rats.

Topics: Acidosis, Lactic; Acute Disease; Animals; Diazinon; Female; Glycogen; Insecticides; Lactates; Lactic Acid; Muscles; Phosphorylases; Rats; Rats, Inbred Strains; Seizures

The time courses of changes in liver, blood, and brain cortical glucose and glycogen levels were measured in 21-day-old DBA/2J mice after an IP injection of 10 g/kg glucose. Other mice were injected with glucose and tested for susceptibility to audiogenic seizures (AGS). Susceptibility to AGS fell from maximal levels to complete protection by 4 h, remained low through 6 h, then began to return to control levels by 8 h. Liver, blood, and brain glucose levels all rose to a peak soon after the injection, then fell linearly and returned to control levels by 6-8 h. Changes in brain glycogen levels reflected changes in AGS susceptibility.

Topics: Acoustic Stimulation; Animals; Blood Glucose; Brain; Cerebral Cortex; Glucose; Glycogen; Liver; Liver Glycogen; Mice; Mice, Inbred DBA; Seizures; Time Factors

The time courses of changes in levels of beta-hydroxybutyrate (BOHB), glucose (GLC), and glycogen (GLY) were measured hourly for 7 h after i.p. 2 g/kg ethanol (ETOH) in samples of liver, blood, and brain in 21 day old C57BL/6J mice. After acute ETOH, brain GLC remained at 2.1 mmol/kg for 2 h, fell to a low of 1.5 mmol/kg at 5 h, then rose slightly. Blood GLC remained near 8 mmol/kg until 3 h, then fell. Liver GLC fell steadily from 10.2 to 7.2 mmol/kg at 7 h. Brain GLY rose from 1.7 to 2.9 mmol/kg at 3 h, then fell steadily. Blood GLY increased from 2.7 to 4.6 mmol/kg at 2 h, then fell to 1.7 mmol/kg. Liver GLY decreased from 70 to 30 mmol/kg. BOHB changes were similar in all samples. BOHB in brain fell from 0.12 to 0.08 mmol/kg at 2 to 3 h; then rose steadily to 0.27 mmol/kg at 7 h. Blood and liver BOHB fell from 0.40 to 0.25 mmol/kg, then rose to 1.0 mmol/kg. In a previous study, susceptibility to audiogenic seizures after 2 g/kg ETOH was completely suppressed for up to 1 h, then susceptibility increased to a maximum at 5 1/2 h, when a period of potentiation was observed. In this study, brain GLY levels were increased during the period of protection, and brain GLC levels were decreased during the period of potentiation. Together, these data may lend support to an hypothesis of an indirect effect of ETOH on the brain, leading to changes in susceptibility to audiogenic seizures via changes in metabolite availability.

Topics: 3-Hydroxybutyric Acid; Animals; Blood Glucose; Brain; Ethanol; Glycogen; Hydroxybutyrates; Liver; Liver Glycogen; Mice; Mice, Inbred C57BL; Seizures

Norepinephrine (NE) depletion of the cerebral cortex after lesion of the ipsilateral locus ceruleus (LC) causes abnormalities of cerebral oxidative metabolism when the cortex is stimulated to increased energy demand (Harik, S. I., J. C. LaManna, A. I. Light, and M. Rosenthal (1979) Science 206: 69-71; LaManna, J. C., S. I. Harik, A. I. Light, and M. Rosenthal (1981) Brain Res. 204: 87-101). These abnormalities were exhibited as decreased mitochondrial reducing equivalent flow. One possible cause of this would be the decreased availability of oxidative metabolic substrates in the NE-depleted cortex. We therefore investigated the effect of unilateral LC lesion and the resultant depletion of ipsilateral endogenous NE on glycogen and other energy metabolites in the cerebral cortex of rats under three conditions: (1) at "rest," (2) when energy demand is inncreased markedly by seizures, and (3) during total cerebral ischemia. We report no differences in cerebral metabolites between NE-depleted and control hemispheres at "rest." In seizures and ischemia, however, the increase in the level of adenosine 3':5'-monophosphate (cyclic AMP) and the breakdown of glycogen were impaired considerably in the NE-depleted cortex. The data suggest that depletion of central NE impairs cerebral glycogenolysis in response to increased energy demands and ischemia. Such impairment may be mediated via a cyclic AMP-related mechanism.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cyclic AMP; Electroencephalography; Energy Metabolism; Glycogen; Male; Norepinephrine; Oxidation-Reduction; Rats; Rats, Inbred Strains; Seizures

The effects of lithium on several brain energy metabolites were investigated in rats. Lithium was administered by three alternative routes: 1) in food, 2) via IP injection, or 3) intracisternally via the suboccipital route. Lithium given in food induced permanent changes, mainly in glycolytic processes and in glycogen content. Lithium injected IP induced, in addition, several changes which depended on the increase in brain lithium concentration following injection of lithium. These changes in brain metabolites disappeared as brain lithium concentration stabilized. Intracisternal injection of lithium produced brain lithium concentrations between 1 and 2 mmoles/kg wet wt., with a mean of about 1.6 mmoles/kg wet wt. Lithium concentrations below about 1.6 mmoles/kg wet wt. induced changes in brain metabolites which were similar to the changes seen after IP injection of lithium. Lithium concentrations above about 1.6 mmoles/kg wet wt. induced changes in several brain metabolites which were at variance with the changes induced by lower lithium concentrations. These changes were in many respects similar to changes in brain metabolites seen in rats exposed to convulsive treatment. It is hypothesized that such metabolic changes during lithium treatment, in discrete areas of the brain with higher concentration of lithium, e.g., hypothalamus, might be related to the prophylactic effect of lithium treatment in man.

Topics: Animals; Brain; Female; Glucose; Glycogen; Injections, Intraperitoneal; Lithium; Rats; Seizures

Audiogenic seizure-prone mice (DBA/2J) were exposed to a broad band noise source. A reproducible response consisting of wild run, clonus, and tonic stages resulted in all mice. Layers 1 and pyramidal from the parietal cortex and the molecular and Purkinje cell-rich layers from the cerebellar vermis were separately analyzed for glucose, glycogen, ATP, and phosphocreatine. Results showed a biphasic cerebellar response, with decreases in high energy phosphates occurring during the wild run and tonic stage. In the cortex, similar changes occurred in the pyramidal cell layer, but the decreases were not as pronounced as those in the cerebellum. Cells from layer 1 of the parietal cortex were not affected as much as those of the pyramidal layer, suggesting a differential effect between neuronal and nonneuronal cell populations. The greater response of the cerebellum could indicate an attempt to reduce the severity of both the wild run and the tonic extension seizure.

Topics: Acoustic Stimulation; Adenosine Triphosphate; Animals; Cerebellum; Cerebral Cortex; Clonazepam; Energy Metabolism; Female; Glucose; Glycogen; Mice; Mice, Inbred DBA; Phosphocreatine; Seizures; Valproic Acid

Isoniazid is a useful chemical convulsant in that metabolic events associated with the preseizure state can be easily examined. In the present study, net levels of glucose, glycogen, ATP, and phosphocreatine were measured using enzymatic techniques in control mice, and in those injected with isoniazid. Results from this study showed a differential effect of isoniazid on cells from the cerebral cortex and the cerebellum. In the preseizure stage, the high energy phosphates ATP and phosphocreatine were decreased in layer 1 and the pyramidal cell layer of the cerebral parietal cortex, but were unchanged in the cerebellum. At the onset of seizures, metabolites were decreased not only in cortical layers, but in the molecular layer and Purkinje cell rich layer of the cerebellum as well. The somewhat delayed response of the cerebellum emphasizes the differential nature of metabolism in various brain regions. Such a delay in cerebellar energy response to perturbation may be conducive to the seizure state. In another series of mice, either sodium valproate or clonazepam was administered prior to isoniazid, and metabolite studies repeated. Results showed that at a time when each anticonvulsant acted to eliminate overt seizure activity, the reduction in ATP and phosphocreatine was not as great as it was in seizing mice treated with isoniazid alone.

Topics: Adenosine Triphosphate; Animals; Cerebellar Cortex; Cerebral Cortex; Clonazepam; Energy Metabolism; Female; Glucose; Glycogen; Isoniazid; Mice; Phosphocreatine; Seizures; Valproic Acid

Pentylenetetrazole was administered to Swiss-Albino mice, producing clonic-tonic seizures. Other groups were pretreated with one of the three anticonvulsants: phenytoin, clonazepam, or sodium valproate. Mice were sacrificed during the preseizure (1 minute) stage and at the onset of clonic-tonic seizures (2 minutes). Glucose, glycogen, ATP, and phosphocreatine were measured in layers of the parietal cortex and cerebellar vermis. Cortical metabolites were unchanged, or increased slightly, suggesting decreased utilization. In both cerebellar layers, glucose and glycogen were significantly decreased, and phosphocreatine was decreased in the molecular layer. These results indicate a regionally selective effect for pentylenetetrazole on cerebral energy metabolites. Pretreatment with anti-convulsants reduced the severity of the seizure, and eliminated the effect of pentylenetetrazole on glucose and glycogen.

Topics: Adenosine Triphosphate; Animals; Behavior, Animal; Blood Glucose; Cerebellum; Energy Metabolism; gamma-Aminobutyric Acid; Glycogen; Muridae; Parietal Lobe; Pentylenetetrazole; Phosphocreatine; Purkinje Cells; Seizures

Valproate (n-dipropylacetate), the most recent major anticonvulsant drug, is unique in that it is a short-chained branched fatty acid with no cyclic components. It is proposed that its anticonvulsant action may be due to its stimulation of the beta-oxidation pathway, with a concomitant whole-body system shift toward metabolic acidosis. The circulating ketone bodies may then be utilized by brain, allowing an increased brain energy reserve and a greater tolerance to a transient stimulation which would have, without Valproate, triggered an epileptic seizure.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Brain; Fatty Acids; gamma-Aminobutyric Acid; Glycogen; Ketone Bodies; Kinetics; Mice; Models, Biological; Seizures; Valproic Acid

Topics: Animals; Astrocytes; Cell Differentiation; Cerebellum; Cerebral Cortex; Cobalt; Glycogen; Rats; Seizures

Topics: Acoustic Stimulation; Adenosine Triphosphate; Aging; Animals; Brain; Glucose; Glycogen; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Phosphocreatine; Seizures; Species Specificity

A study was made to test the influence of rapid variations in glutamic acid decarboxylase (GAD) activity on the susceptibility of rats to hyperbaric oxygen (HBO). GAD was inhibited by the convulsant drug unsymmetrical dimethylhydrazine (UDMH) and reactivated by pyridoxine (PYR) after onset of convulsive activity. There was a relatively long induction period after UDMH injection until the onset of convulsions and the predictable interictal periods between successive periodic convulsions made it possible to study the impact of variations in GAD activity on survival rates, suspectibility to HBO and brain glycogen levels in a time sequence after UDMH administration. The experiments showed that UDMH interferes with aerobic metabolism in brain in such a way that profound alterations in resistance to acute oxygen poisoning resulted. An accumulation of substrate proximal to the enzyme block is assumed to develop during UDMH poisoning. The protective effect against HBO toxicity that was achieved after reactivation of GAD by PYR injection, as well as the rapid re-establishment of glycogen levels, is believed to speak in favour of this hypothesis.

Topics: Animals; Brain; Carboxy-Lyases; Glutamate Decarboxylase; Glycogen; Hyperbaric Oxygenation; Kinetics; Male; Oxygen; Pyridoxine; Rats; Rats, Inbred Strains; Seizures

The effect of mammalian insulin was studied in a freshwater fish, Clarias batrachus, at both high and low ambient temperatures. The hormone produced a significant but delayed, yet recoverable, lowering of blood glucose, a concurrent decrease in liver glycogen, and an increase in the glycogen content of muscles. The decrease in brain glycogen occurred during advanced hypoglycemia. Hypoglycemic seizures developed intermittently in most of the fishes whose plasma glucose and brain glycogen levels had been considerably depleted. Necrobiotic changes in the pancreatic islets, including degranulation and atrophy, and necrosis of B cells, were seen in the treated fish. In some cases damage to A cells and the acinar tissue was also observed. With the restitution of normal glucose and glycogen values, the islet cells also seemed to have recuperated. Changes in glycemia, glycogen, and the islets were more pronounced in the fishes held at 24 degrees C than in those at 10 degrees C, indicating that the ambient temperature plays an important role in blood glucose homeostasis as well as insulin.

Topics: Animals; Blood Glucose; Brain Chemistry; Fishes; Glucose; Glycogen; Insulin; Islets of Langerhans; Liver Glycogen; Muscles; Seizures

Topics: Adenosine Triphosphate; Animals; Brain; Cyclic AMP; Cyclic GMP; Electroshock; gamma-Aminobutyric Acid; Glucose; Glycogen; Kinetics; Lactates; Male; Mice; Phenytoin; Phosphocreatine; Purkinje Cells; Seizures

Sustained, generalized seizure activity was induced in anaesthetized (70% N2O), paralyzed and artifically ventilated rats by i.p. DL-homocysteine thiolactone in a dose of 11 mmol/kg. Epileptic discharges in the EEG were accompanied by marked perturbation of tissue metabolites. There was a fall in phosphocreatine concentration to 40% of control but only moderate changes in adenine nucleotides, a marked rise in lactate concentration, and a pronounced increase in the lactate/pyruvate ratio. Excessive amounts of dihydroxyacetone phosphate (and glyceraldehyde phosphate) accumulated, indicating that depletion of NAD+ occurred. There was marked accumulation of ammonia, glutamine and alanine, and reduction in glutamate and aspartate concentrations. Administration of a subconvulsive dose of homocysteine (7.5 mmol/kg) gave rise to changes in ammonia and amino acids, qualitatively similar to those occurring during seizures. It is concluded that although changes in the metabolites of the energy reserve were mainly caused by the induced seizures, those affecting amino acid concentrations were significantly influenced by accumulation of ammonia, secondary to metabolism of injected homocysteine. Cerebral blood flow (CBF) and oxygen utilization (CMRO2) were measured during sustained seizures. CMRO2 rose to 150% of control, with a corresponding increase in CBF.

Topics: Amino Acids; Ammonia; Animals; Blood Glucose; Brain; Cerebrovascular Circulation; Citric Acid Cycle; Creatine; Electroencephalography; Energy Metabolism; Evoked Potentials; Glycogen; Homocysteine; Lactates; Male; Organophosphorus Compounds; Oxygen Consumption; Pyruvates; Rats; Seizures

High pressure oxygen (HBO) and 1,1-dimethylhydrazine (UDMH) both cause grand mal seizures, brain glycogen degradation, and inhibition of glutamic acid decarboxylase (GAD). Brain glycogen degradation is a sudden process that is perhaps initiated by convulsions in the case of UDMH-poisoning, but a gradual decrease in glycogen is detectable before the onset of hyperbaric oxygen toxicity symptoms. UDMH injection causes consecutive convulsions that follow a predictable sequence. (Time to convulsions is referred to as the induction period, and time between convulsions as the interictal period.) After a single injection of UDMH, there is a gradual decrease in resistance to HBO during the induction period, measured as time to convulsions breathing 100% oxygen at 6 ATA; in the first interictal period, this time is only 4 1/2 min in comparison with a control value of 26 min for untreated rats. Administration of pyridoxine, a B6-vitamin, 2 h after UDMH injection in the first interictal period, resulted in an immediate tenfold increase in resistance to oxygen toxicity, from 4 1/2 to 48 min. Pyridoxine may reverse the inhibitary effect of UDMH on GAD, and there is perhaps an accumulation of substrate, which is made available when GAD inhibition is diminishing. Simultaneous injection of pyridoxine and UDMH causes no convulsions, no change in brain glycogen levels, and an unchanged or increased resistance to HBO, measured two and three hours after injection.

Topics: Animals; Brain; Convulsants; Dimethylhydrazines; Glycogen; Hyperbaric Oxygenation; Male; Methylhydrazines; Pyridoxine; Rats; Seizures

Implantation of cobalt powder in the cerebral cortex of rat determines an epileptogenic focus where two types of reactive astrocytes are observed. The first type is mostly represented in the subcortical white matter but it does exist in the cortex around the implant. Phosphorylase and branching enzyme are both very active in these cells which are filled with glycogen. The second type is limited to the cortex and phosphorylase activity leads to an unbranched polysaccharid. These cells correspond to the "activated astrocytes" described by the authors in a previous paper and observed round irritative lesions which, in the cerebral cortex, produce epileptogenic foci.

Topics: 1,4-alpha-Glucan Branching Enzyme; Animals; Astrocytes; Cerebral Cortex; Cobalt; Glucosyltransferases; Glycogen; Histocytochemistry; Male; Phosphorylases; Rats; Seizures

Topics: Animals; Brain; Glycogen; Phosphoglucomutase; Phosphorylases; Rats; Seizures; Strychnine

Topics: Animals; Brain; Dose-Response Relationship, Drug; Glycogen; Male; Methionine Sulfoximine; Metyrapone; Mice; Seizures

Topics: 3-Mercaptopropionic Acid; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cerebral Cortex; Energy Metabolism; Glucose; Glycogen; Homocysteine; Lactates; Male; Mice; Phenobarbital; Phosphocreatine; Seizures; Sulfhydryl Compounds

The biological activity of human insulin, prepared by total chemical synthesis, was compared in various tests in vivo and in vitro with that of natural human or pork insulin. The potencies of the synthetic and natural hormone, as determined by the mouse convulsion assay, by hypoglycaemic effect and diaphragm glycogen increase in fasted rats in vivo, or by stimulation of 14C-glucose metabolism in fat cells and binding to anti-insulin serum in vitro, did not differ significantly. It is concluded that this synthetic human insulin is biologically equivalent to the natural hormone.

Topics: Adipose Tissue; Animals; Biological Assay; Blood Glucose; Diaphragm; Fasting; Glycogen; Glycolysis; Humans; Insulin; Male; Mice; Rats; Seizures

Topics: Animals; Blood Glucose; Body Temperature; Brain; Carboxy-Lyases; Glucose; Glutamate Decarboxylase; Glycine; Glycogen; Isoniazid; Male; Methionine Sulfoximine; Mice; Pyridoxine; Seizures; Time Factors

Topics: Adenine Nucleotides; Animals; Blood Pressure; Brain; Creatine Kinase; Electroencephalography; Electroshock; Energy Metabolism; Flurothyl; Glucose; Glycogen; Hydrogen-Ion Concentration; L-Lactate Dehydrogenase; Lactates; Male; Mice; NAD; Oxidation-Reduction; Pentylenetetrazole; Phosphocreatine; Rats; Seizures

Topics: Animals; Cerebral Cortex; Female; Glycine; Glycogen; Homocysteine; Mice; Mice, Inbred Strains; Phenobarbital; Phosphorylases; Pregnancy; Seizures; Spectrometry, Fluorescence

A major concern in the use of neural prostheses is whether electrical stimualtion can cause irreversible damage to neurons. The Neural Damage Model was devised to study the problem and to provide guidlines. The cerebral cortex of cats was stimulated continuously for 36 hours with balanced, biphasic waveforms. The charge per phase, charge density and current density were varied in 16 separate tests. Of these stimulus parameters the charge per phase was more closely correlatable with neuronal damage than charge density and current density. Furthermore, the findings in this study suggest that current flow is more important than electrochemical reactions in causing neural damage. Correlation between blood-brain barrier (BBB) breakdown and neuronal damage was valid only in the group of animals sacrificed immediately following stimulation. The BBB is restored within one month following electrical injury. Convulsive seizures occurred in all but one of the animals during electrical stimulation. A technique for localizing the electrode sites at autopsy and in the microscopic sections is described.

Topics: Animals; Astrocytes; Blood-Brain Barrier; Brain Injuries; Cats; Cerebral Cortex; Disease Models, Animal; Electric Stimulation; Glycogen; Neurons; Seizures

Topics: Animals; Brain; Brain Edema; Brain Neoplasms; Central Nervous System; Dogs; Glycogen; Guinea Pigs; Haplorhini; Hibernation; Humans; Hypoglycemia; Hypoxia; Ischemia; Mice; Microscopy, Electron; Neuroglia; Neurons; Physical Exertion; Rabbits; Radiation Effects; Rats; Seizures; Shock; Starvation

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Glucose; Cerebral Cortex; Electrochemistry; Energy Metabolism; Glucose; Glycogen; Homocysteine; Humans; Lactates; Lactones; Mice; Phosphocreatine; Seizures

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Blood Proteins; Electric Stimulation; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Histocytochemistry; Humans; Lactates; Lipid Metabolism; Male; Muscles; Muscular Diseases; Pyruvates; Seizures; Syndrome

Topics: Animals; Brain Chemistry; Cerebral Cortex; Enzyme Activation; Fluorometry; Glucose; Glycogen; In Vitro Techniques; Male; Methionine; Methionine Sulfoximine; Mice; Mice, Inbred Strains; Phosphorylases; Seizures; Time Factors

Topics: Animals; Blood Glucose; Electroshock; Female; Glycogen; Pentylenetetrazole; Rats; Seizures

Topics: Amino Acids; Brain Chemistry; Brain Diseases; Cerebellum; Cerebral Cortex; Cerebrosides; Cholesterol; Electroencephalography; Glycogen; Growth Disorders; Hair; Humans; Infant; Male; Nerve Degeneration; Pedigree; Phenobarbital; Phenytoin; Phospholipids; Plasmalogens; Seizures; Ubiquinone; Vitamin E

Topics: Adenosine Triphosphate; Animals; Brain; Brain Chemistry; Carbon Isotopes; Chickens; Chromatography; Galactose; Glucose; Glutamates; Glycogen; Lipid Metabolism; Phosphates; Phosphoric Monoester Hydrolases; Phosphorus Isotopes; Seizures

Topics: Adipose Tissue; Amides; Ammonium Chloride; Animals; Blood Glucose; Butyrates; Carbon Isotopes; Diabetes Mellitus, Experimental; Diaphragm; Glucose; Glucose Tolerance Test; Glycogen; Guanidines; Insulin; Insulin Antibodies; Insulin Secretion; Islets of Langerhans; Liver; Liver Glycogen; Metabolism; Mice; Muscles; Ornithine; Phenformin; Rabbits; Radioimmunoassay; Rats; Seizures; Starvation; Stimulation, Chemical; Urea

Topics: Adenosine Triphosphate; Animals; Brain Stem; Central Nervous System; Cerebellum; Cerebral Cortex; Electroshock; Glucose; Glycogen; Lactates; Male; Mice; Phenobarbital; Phosphocreatine; Seizures; Spinal Cord; Thalamus

Topics: Adenosine Triphosphate; Animals; Brain Stem; Central Nervous System; Cerebellum; Cerebral Cortex; Citric Acid Cycle; Glucose; Glycogen; Glycolysis; Hexosephosphates; Ketoglutaric Acids; Lactates; Malates; Male; Mice; Phosphocreatine; Seizures; Spinal Cord; Thalamus

Topics: Adenosine Triphosphate; Anesthetics; Brain; Brain Edema; Cerebral Cortex; Cerebrovascular Circulation; Cerebrovascular Disorders; Coma; Consciousness; Diabetic Coma; Glucose; Glycogen; Hepatic Encephalopathy; Humans; Hypoglycemia; Lactates; Oxygen Consumption; Seizures; Sleep

Topics: Adenosine Triphosphate; Animals; Brain; Brain Chemistry; Fluorometry; Freezing; Glucose; Glycogen; Hypoxia; Ischemia; Lactates; Male; Mice; Phosphocreatine; Seizures; Time Factors

Topics: Adenosine Triphosphate; Alanine; Amino Acids; Aminobutyrates; Ammonia; Animals; Aspartic Acid; Brain; Carbon Isotopes; Cats; Central Nervous System; Chromatography, Paper; Citrates; Colorimetry; Female; Fluorine; Glucose; Glutamates; Glutamine; Glycogen; Kidney; Liver; Lysine; Nerve Tissue Proteins; Poisoning; Rats; Seizures; Spectrophotometry; Spinal Cord

1. The effect of the method of killing on the concentration of glycogen in mouse brain was determined. The cerebral glycogen content of mice killed by immersion in liquid nitrogen did not differe significantly from that of animals decapitated and the heads immediately frozen. A delay before freezing led to the rapid loss of brain glycogen, with a 17% fall at 10 s and an 82% loss after 5 min.2. Hyperglycaemia, induced by the administration of D-glucose, resulted in an 8.3% loss of brain glycogen after 120 min. Insulin hypoglycaemia produced a 10.7% fall in glycogen at 60 min followed by an 11.2% increase at 120 min.3. Exposure to either high (32 degrees C) or low (10 degrees C) ambient temperatures caused a depletion of brain glycogen.4. A circadian rhythm of brain glycogen concentration was found, with a nadir which was coincident with the peak of locomotor activity and body temperature.5. Drugs from several pharmacological classes were studied for their in vivo effect on the concentration of glycogen in mouse brain.6. Brain glycogen was increased by all the depressant drugs tested, and by some drugs which had little effect on behaviour (diphenhydramine, phenytoin and propranolol), or which caused excitation (caffeine and nialamide).7. Glycogen was depleted only by amphetamine-like compounds or by bemegride-induced convulsions.8. The results are discussed with particular reference to the possible relation between catecholamines and glycogen metabolism in the brain.

Topics: Amphetamine; Animals; Bemegride; Body Temperature; Brain Chemistry; Caffeine; Catecholamines; Circadian Rhythm; Diphenhydramine; Glucose; Glycogen; Hyperglycemia; Insulin; Male; Mice; Motor Activity; Nialamide; Phenytoin; Propranolol; Seizures; Temperature

Topics: Adenine Nucleotides; Adenosine Triphosphate; Amino Acids; Aminobutyrates; Animals; Brain; Centrifugation; Citrates; Fluorometry; Freezing; Glucose; Glutamates; Glycogen; Lactates; Male; Metabolism; Pentylenetetrazole; Phosphates; Phosphocreatine; Pyruvates; Rats; Seizures; Spectrophotometry; Spectrum Analysis

Topics: Acetylcholinesterase; Adenosine Triphosphate; Amino Acids; Aminobutyrates; Animals; Brain; Chromatography, Paper; Disease Models, Animal; Glucose; Glycogen; Lactates; Oxygen Consumption; Phosphates; Phosphocreatine; Plant Extracts; Propionates; Rats; Seizures; Toxins, Biological

Topics: Aminobutyrates; Ammonia; Animals; Blood Glucose; Brain Chemistry; Citrates; Citric Acid Cycle; Fluoroacetates; Glucose; Glycogen; Heart; Hypnotics and Sedatives; Lactates; Male; Myocardium; Norepinephrine; Rats; Seizures; Sodium

Topics: Adenosine Triphosphate; Animals; Brain; Glucose; Glycogen; Lactates; Methionine; Methionine Sulfoximine; Mice; Phosphocreatine; Seizures

Topics: Adipose Tissue; Animals; Biological Assay; Carbon Isotopes; Cattle; Chickens; Diaphragm; Glucose; Glycogen; In Vitro Techniques; Insulin; Lipids; Mice; Seizures; Stimulation, Chemical

Topics: Animals; Antigen-Antibody Reactions; Blood Glucose; Cattle; Chickens; Fishes; Glycogen; Guinea Pigs; Immune Sera; Insulin; Insulin Antibodies; Mice; Neutralization Tests; Pancreas; Passive Cutaneous Anaphylaxis; Rodentia; Seizures; Species Specificity

Topics: Adenosine Triphosphate; Ammonia; Animals; Brain; Cerebellum; Cerebral Cortex; Glucose; Glutamates; Glycogen; Lactates; Male; Methionine Sulfoximine; Methods; Phosphocreatine; Rats; Seizures; Time Factors

Topics: Adrenal Medulla; Alkaloids; Animals; Brain; Brain Chemistry; Catatonia; Female; Glucose; Glucose Oxidase; Glycogen; Humans; Hyperglycemia; Lactates; Muscles; Rats; Seizures; Sound

Topics: Animals; Centrifugation; Cerebral Cortex; Chlorpromazine; Electric Stimulation; Electroshock; Freezing; Glucose; Glycogen; Hypoxia; Insulin; Lactates; Male; Mice; Pentylenetetrazole; Phenobarbital; Phosphocreatine; Secobarbital; Seizures; Stress, Physiological

Topics: Adenine Nucleotides; Animals; Aspartic Acid; Brain; Brain Chemistry; Central Nervous System Stimulants; Citrates; Glutamates; Glycogen; Glycolysis; Hexokinase; Hexosephosphates; In Vitro Techniques; Lactates; Mice; Phosphocreatine; Phosphofructokinase-1; Seizures

Topics: Adolescent; Blood Chemical Analysis; Electromyography; Glycogen; Glycogen Storage Disease Type V; Histocytochemistry; Humans; Muscles; Muscular Diseases; Myoglobinuria; Necrosis; Pathology; Phosphotransferases; Physical Exertion; Regeneration; Rhabdomyolysis; Seizures

Topics: Brain; Brain Chemistry; Dimethylhydrazines; Glycogen; Hydrazines; Pharmacology; Phenobarbital; Phosphotransferases; Pyridoxine; Rats; Research; Seizures; Toxicology

Topics: Acidosis; Carbohydrate Metabolism; Child; Diet; Glycogen; Humans; Hypoglycemia; Ketones; Metyrapone; Mineralocorticoid Receptor Antagonists; Pituitary-Adrenal Function Tests; Seizures; Thyroid Function Tests; Urine

Topics: Adrenal Glands; Blood; Blood Chemical Analysis; Body Weight; Brain; Brain Chemistry; Carbohydrate Metabolism; Chemical Phenomena; Chemistry; Chlorides; Cold Temperature; Electroshock; Glucose; Glycogen; Hyperglycemia; Hyperplasia; Hypertrophy; Liver; Muscles; Neurochemistry; Physiology; Potassium; Rats; Research; Seizures; Sodium; Thymus Gland; Water

Topics: Animals; Diet; Disease Susceptibility; Glycogen; Mice; Proteins; Seizures

Topics: Brain; Convulsants; Glycogen; Humans; Nerve Tissue; Seizures

Topics: Brain; Glucose; Glycogen; Lactates; Lactic Acid; Neurochemistry; Phosphates; Seizures