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

Food restriction can extend life span in rodents and was recently reported to increase the resistance of neurons in the brain to excitotoxic and metabolic insults. In principle, administration to ad libitum fed rodents of an agent that reduces glucose availability to cells should mimick certain aspects of food restriction. We now report that administration of 2-deoxy-D-glucose (2DG), a non-metabolizable analog of glucose, to adult rats results in a highly significant reduction in seizure-induced spatial memory deficits and hippocampal neuron loss. Pretreatment of rat hippocampal cell cultures with 2DG decreases the vulnerability of neurons to excitotoxic (glutamate) and oxidative (Fe2+) insults. The protective action of 2DG is associated with decreased levels of cellular oxidative stress and enhanced calcium homeostasis. 2DG treatment increased levels of the stress-responsive proteins GRP78 and HSP70 in hippocampal neurons, without affecting levels of Bcl-2 or GRP75, suggesting that mild reductions in glucose availability can increase neuronal resistance to oxidative and metabolic insults by a mechanism involving induction of stress proteins. Our findings establish cell culture and in vivo models of "chemical food restriction" which may prove useful in elucidating mechanisms of neuroprotection and in developing preventive approaches for neurodegenerative disorders that involve oxidative stress and excitotoxicity.
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PMID:2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: evidence for the involvement of stress proteins. 1039 35

Status epilepticus remains a life-threatening condition associated with a high mortality. In order to understand the pathophysiological mechanisms underlying sustained seizures, the identification of structures involved in seizure activity allowing to define epileptic networks may be important. Thus, local cerebral metabolic rate for glucose (LCMR(glc)) was measured in a rat model of self-sustaining status epilepticus (SSSE) induced by a brief intermittent perforant path stimulation of 30 min, using the quantitative [(14)C]2-deoxyglucose autoradiographic technique. SSSE induced a generalized bilateral increase in LCMR(glcs) affecting 27 of the 42 structures studied. Largest metabolic increases (>250%) were recorded in the hippocampus, amygdala, entorhinal and piriform cortices, and lateral septum. Marked metabolic activation was also seen in basal ganglia areas such as the substantia nigra, globus pallidus and accumbens nucleus. LCMR(glcs) in brainstem, some midbrain structures, and in the neocortex were not affected by SSSE. In conclusion, a brief stimulation of the hippocampus induced a reproducible limbic SSSE in 100% of the rats, characterized by the metabolic activation of limbic and extralimbic structures, known to be involved in this type of seizures. Therefore, this new model allowing the development of a well-defined SSSE, appears to be particularly suitable for further studies on the mechanisms involved in status epilepticus.
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PMID:Self-sustaining status epilepticus after a brief electrical stimulation of the perforant path: a 2-deoxyglucose study. 1044 23

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.
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PMID:Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie. 1064 90

A six-year-old, spayed female, cocker spaniel was presented for hypoglycemic seizures. Hypoglycemia with concomitant hyperinsulinemia suggested an insulin-secreting tumor. Pancreatic masses were resected, and insulinoma was diagnosed. Six weeks later, the dog presented in hyperinsulinemic-hypoglycemic crisis (HHC). The dog was initially stabilized with intravenous dextrose boluses and infusions, but seizure activity recurred and persisted. A glucagon constant-rate infusion (GCRI) was initiated, and neurological signs quickly resolved. Dextrose was withdrawn over 24 hours, and euglycemia was maintained by GCRI alone. Despite aggressive medical management including the use of prednisone, diazoxide, bovine somatotropin, and streptozocin, the dog presented on two subsequent occasions in HHC and both times was rapidly stabilized with GCRI alone. In this dog, GCRI was a fast, safe, and effective method of achieving and maintaining euglycemia despite intractable hyperinsulinism. The clinical use of GCRI merits further investigation for management of HHC in veterinary species.
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PMID:Glucagon constant-rate infusion: a novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. 1066 3

Carbohydrate-deficient glycoprotein syndrome (CDGS) is a newly delineated group of inherited multisystemic disorders associated with abnormal glycosylation of a number of serum glycoproteins. Several types have been described on the basis of clinical presentation and biochemical changes of the glycosylation of serum transferrin and attributed to different enzymatic defects; their clinical presentations are fully different and a clinical heterogeneity is observed within a same type of CDGS. Patients with CDGS type la usually present with neurologic (hypotonia, strabismus and cerebellar hypoplasia) and cutaneous (inverted nipples, abnormal distribution of adipose tissue) abnormalities, together with multivisceral involvement (digestive, hepatic, cardiac, renal). However, neurologic and cutaneous symptoms may be absent, so that CDGS must be looked for in case of unexplained organ failure such as isolated liver insufficiency, cardiomyopathy, pericarditis, tubulopathy, nephrotic syndrome, vascular accident or retinitis pigmentosa. Patients with CDGS type Ib present with liver disease, enteropathy and hypoglycemia without neurologic involvement. These patients are successfully treated with oral mannose administration emphasizing the importance of making the diagnosis. Patients with CDGS type Ic present with mild psychomotor retardation and seizures. Patients with CDGS type II have psychomotor retardation association with severe gastrointestinal disorder, dysmorphic features and abnormal electroretinogram. Other types (III, IV) are less clearly defined and the clinical presentation includes convulsive encephalopathy. Biological abnormalities such as mild hepatic cytolysis, hematologic and hormonal abnormalities are consistently observed in CDGS type I, as well as renal hyperechogeneity, leading one to look for this syndrome when they are associated. Until now, only four enzymatic deficiencies have been identified (types Ia, Ib, Ic, II).
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PMID:[Carbohydrate-deficient blood glycoprotein syndrome]. 1070 Oct 64

We have synthesized D-glucose or D-galactose esters of 7-chlorokynurenic acid (7ClKynA) as prodrugs to facilitate the transport of 7ClKynA across the blood-brain barrier. Intraperitoneal (i.p.) administration of either 7ClKynA-D-glucopyranos-6'-ylester (7ClKynA/Glu6) or 7ClKynA-D-glucopyranos-3'-yl ester (7ClKynA/Glu3) was protective against seizures induced by N-methyl-D-aspartate (NMDA) in mice, with the former drug showing the highest anticonvulsive activity. Systemic injection of equal amounts of 7ClKynA-D-galactopyranos-6'-yl ester (7ClKynA/Gal6) or free 7ClKynA did not protect against NMDA seizures. Microdialysis in freely moving rats showed the presence of significant amounts of 7ClKynA/Glu6, as well as of 7ClKynA or KynA, in cortical perfusates after i.p. injections of 7ClKynA/Glu6. In contrast, only small amounts of 7ClKynA or KynA were detected after i.p. injection of unconjugated 7ClKynA. Prodrug metabolism has also been examined in mouse cortical cultures containing both neurons and astrocytes. 7ClKynA/Glu6 and 7ClKynA/Gal6 were rapidly metabolized into 7ClKynA and KynA, whereas 7ClKynA/Glu3 was metabolized with a slower kinetics. As a result of its conversion into 7ClKynA and KynA, 7ClKynA/Glu6 protected cortical neurons against NMDA toxicity. We conclude that sugar conjugates of 7ClKynA (and perhaps of other excitatory amino acid receptor antagonists) are prodrugs of potential interest in the experimental therapy of epilepsy and acute or chronic neurodegenerative disorders.
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PMID:Systemically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents. 1072 34

Status epilepticus (SE) is a potentially life-threatening condition that requires prompt and aggressive treatment. Prolonged status seizures are associated with significant physiological sequelae and neurological deficits. Although systemic events such as hyperthermia and anoxia contribute to neuronal damage, SE in and of itself can induce cell death. In general, the sooner it is brought under control, the more favourable is the prognosis. Benzodiazepines, as a group, are the most frequently used anticonvulsants in the management of status seizures. Midazolam, a water-soluble benzodiazepine, is a potent anticonvulsant that offers many advantages over typical benzodiazepines. Because of its stability in aqueous media, midazolam dissolves in common diluents such as normal saline or dextrose water. Consequently, midazolam both intravenously (i.v.) and intramuscularly (i.m.) is well tolerated locally and is associated with less venoirritation than benzodiazepines or antiepileptics that require organic solvents. The water solubility of midazolam also allows rapid and reliable absorption of the drug from the i.m. injection site. Because it is rapidly metabolised and its metabolites are pharmacologically inactive, midazolam has a short duration of action. Most patients regain full conscious state and can be evaluated soon after the cessation of treatment. Midazolam by continuous i.v. infusion and by the i.m. route has been successfully used in the treatment of SE. Although some respiratory and haemodynamic side-effects have been associated with midazolam, no clinically significant side-effects were observed with its use for the indication of SE. It is suggested that midazolam is a safe and rapidly effective treatment option in the management of SE in the critical care setting.
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PMID:Treatment of status epilepticus with midazolam in the critical care setting. 1075 Feb 57

Neuropsychiatric systemic lupus erythematosus (SLE) is frequently associated with deficits in brain glucose metabolism, even if morphological imaging by magnetic resonance imaging (MRI) shows no abnormalities. In these patients it is unclear whether or not the changes of brain metabolism measured by F-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) may progress to lesions of cerebral structure. We describe a 20-year-old woman with SLE who presented with depression, headache and impairment of memory. Initially, a cranial MRI was negative, but FDG-PET revealed significant hypometabolism in the frontal and parieto-temporo-occipital regions on both sides as well as hypermetabolism in the nuclei caudati. Within two months the patient developed an acute confusional state, seizures, visual disturbances and cranial MRI became positive showing hyperintensities at the basal ganglia and the temporo-occipital regions. Focal cerebral symptoms responded to treatment with high dose corticosteroids and brain lesions in MRI disappeared. However, a second FDG-PET showed persistent hypometabolism at frontal regions in accordance with the persistence of subclinical depression. To our knowledge, this is the first SLE case report showing that functional brain lesions visualized by FDG-PET may be a risk factor for subsequent structural brain damage seen in MRI. Thus, FDG-PET may help to verify cerebral involvement of SLE earlier than MRI.
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PMID:Alterations of cerebral glucose metabolism indicate progress to severe morphological brain lesions in neuropsychiatric systemic lupus erythematosus. 1087 34

7-Chlorokynurenic acid 1 is a potent glycine-N-methyl-D-aspartate (NMDA) receptor antagonist, but it shows weak activity after systemic administration. In order to overcome the Blood-brain barrier (BBB), we synthetized three new esters 2-4 of 1 obtained by chemical conjugation with essential nutrients such as glucose and galactose, that are actively transported across the BBB. These compounds were assayed to evaluate their in vitro chemical and enzymatic hydrolysis. In addition the prodrugs 2-4 were tested for their ability to protect mice against NMDA-induced seizures after systemic administration. All the prodrugs 2-4 appeared moderately stable in pH 7.4 buffered solution and were susceptible to in vitro enzymatic hydrolysis. Intraperitoneal administration of either esters 2 or 4 was highly protective against seizures induced by NMDA in mice, with the latter prodrug showing the highest anticonvulsive activity. In addition, ester 4 undergoes a time-dependent extracellular hydrolysis into 1 when applied to mixed cultures of mouse cortical cells, a model that reproduces in vitro the cellular milieu encountered by the prodrugs once they penetrate the brain parenchyma.
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PMID:Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. 1091 29

Brain extraction of (18)F-labeled 2-fluoro-2-deoxy-D-glucose (FDG) was significantly higher in pentylene tetrazole (PTZ)-treated rats (32 +/- 4%) than controls (25 +/- 4%). The FDG permeability-surface area product (PS) was also significantly higher with PTZ treatment (0.36 +/- 0.05 ml. min(-1). g(-1)) than in controls (0.20 +/- 0.06 ml. min(-1). g(-1)). Cerebral blood flow rates were also elevated by 50% in seizures. The internal carotid artery perfusion technique indicated mean [(14)C]glucose clearance (and extraction) was increased with PTZ treatment, and seizures increased the PS by 37 +/- 16% (P < 0.05) in cortical regions. Because kinetic analyses suggested the glucose transporter half-saturation constant (K(m)) was unchanged by PTZ, we derived estimates of 1) treated and 2) control maximal transporter velocities (V(max)) and 3) a single K(m). In cortex, the glucose transporter V(max) was 42 +/- 11% higher (P < 0.05) in PTZ-treated animals (2.46 +/- 0.34 micromol. min(-1). g(-1)) than in control animals (1.74 +/- 0.26 micromol. min(-1). g(-1)), and the K(m) = 9.5 +/- 1.6 mM. Blood-brain barrier (BBB) V(max) was 31 +/- 10% greater (P < 0.05) in PTZ-treated (2.36 +/- 0. 30 micromol. min(-1). g(-1)) than control subcortex (1.80 +/- 0.25 micromol. min(-1). g(-1)). We conclude acute upregulation of BBB glucose transport occurs within 3 min of an initial seizure. Transporter V(max) and BBB glucose permeability increase by 30-40%.
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PMID:Acute upregulation of blood-brain barrier glucose transporter activity in seizures. 1099 2


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