Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The involvement of nitric oxide (NO) in kainic acid (KA)-induced excitotoxicity was studied in rat brain. With the onset of KA (15 mg kg(-1), s.c.)-induced seizures (convulsions) 30 min after injection, increases in NO, as measured by the formation of citrulline, were seen in cortex (302%), amygdala (171%) and hippocampus (203%). The highest increases were determined 90 min after onset of seizures (120 min after KA injection) with 633%, 314% and 365%, respectively. These changes in NO preceded significant decreases in ATP and phosphocreatine (PCr) ranging from 44 to 53% for ATP and from 40 to 52% for PCr in the respective brain areas. With the exception of the cortex, normal citrulline values were restored within 24 h. Pretreatment with the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg kg(-1), i.p.) or the antioxidant vitamin E (Vit-E, 100 mg kg(-1) per day for 3 days) prevented the increase in citrulline and significantly attenuated the loss in ATP and PCr without affecting seizure activity. It is concluded that seizures induced by KA produced a marked increase in the free radical NO, causing oxidative stress and leading to depletion of energy stores. The prevention of the increase in NO and preservation of ATP and PCr levels by PBN and Vit-E suggests the involvement of NO and other related free radicals, such as peroxynitrite (ONOO(-)). The lack of effect of PBN and Vit-E on seizure activity, suggests that NO is not involved in mechanisms regulating KA seizure generation and propagation. PBN and Vit-E or similar compounds may be important protective agents against status epilepticus-induced neuronal degeneration.
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PMID:Involvement of nitric oxide in kainic acid-induced excitotoxicity in rat brain. 1244 75

Guanidinoacetate methyltransferase deficiency, which so far has been exclusively detected in children, was diagnosed in a 26-year-old man. The full-blown spectrum of clinical symptoms already had been present since infancy without progression of symptoms during adolescence. Cranial magnetic resonance imaging showed normal findings. Ophthalmological examination showed no retinal changes. Besides creatine deficiency in the brain, a distinct lack of phosphocreatine in skeletal muscle was proved by (31)P magnetic resonance spectroscopy. Creatine substitution combined with a guanidinoacetate-lowering diet introduced first at the age of 26 years was shown to be effective by an impressive improvement of epileptic seizures, mental capabilities, and general behavior and by normalization of the (31)P spectrum in the skeletal muscle.
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PMID:Lack of creatine in muscle and brain in an adult with GAMT deficiency. 1255 93

Whereas ATP consumption increases with neural activity and is buffered by phosphocreatine (PCr), it is not known whether PCr synthesis by ubiquitous mitochondrial creatine kinase (uMtCK) supports energy metabolism in all neurons. To explore the possibility that uMtCK expression in neurons is modulated by activity and during development, we used immunocytochemistry to detect uMtCK-containing mitochondria. In the adult brain, subsets of neurons including layer Va pyramidal cells, most thalamic nuclei, cerebellar Purkinje cells, olfactory mitral cells and hippocampal interneurons strongly express uMtCK. uMtCK is transiently expressed by a larger group of neurons at birth. Neurons in all cortical layers express uMtCK at birth (P0), but uMtCK is restricted to layer Va by P12. uMtCK is detected in cerebellar Purkinje cells at birth, but localization to dendrites is only observed after P5 and is maximal on P14. Hippocampal CA1 and CA3 pyramidal neurons contain uMtCK-positive mitochondria at birth, but this pattern becomes progressively restricted to interneurons. Seizures induced uMtCK expression in cortical layers II-III and CA1 pyramidal neurons. In the cortex, but not in CA1, blockade of seizures prevented the induction of uMtCK. These findings support the concept that uMtCK expression in neurons is (1) developmentally regulated in post-natal life, (2) constitutively restricted in the adult brain, and (3) regulated by activity in the cortex and hippocampus. This implies that mitochondrial synthesis of PCr is restricted to those neurons that express uMtCK and may contribute to protect these cells during periods of increased energy demands.
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PMID:Restricted neuronal expression of ubiquitous mitochondrial creatine kinase: changing patterns in development and with increased activity. 1270 12

Since the first description of a creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected creatine deficiency syndromes--the creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed. GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CrT1 defect is a X-linked disorder. All patients reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech. The common feature of all creatine deficiency syndromes is the severe depletion of creatine/phosphocreatine in the brain. Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids. Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency. Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiency, whereas in CrT1 defect it is not able to replenish creatine in the brain. Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome. The lack of the creatine/phosphocreatine signal in the patient's brain by means of in vivo proton magnetic resonance spectroscopy is the common finding and the diagnostic clue in all three diseases. In AGAT deficiency guanidinoacetic acid is decreased, whereas creatine in blood was found to be normal. On the other hand the CrT1 defect is characterized by an increased concentration of creatine in blood and urine whereas guanidinoacetic acid concentration is normal. The increasing number of patients detected very recently suffering from a creatine deficiency syndrome and the unfavorable outcome highlights the need of further attempts in early recognition of affected individuals and in optimizing its treatment. The study of creatine deficiency syndromes and their comparative consideration contributes to the better understanding of the pathophysiological role of creatine and other guanidino compounds in man.
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PMID:Creatine deficiency syndromes. 1270 24

Previous studies using the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) and the antioxidant vitamin E established the involvement of free radicals in kainic acid (KA)-induced neurotoxicity. In the present study, we examined the effects of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) to establish a possible role of nitric oxide (NO) in the neurotoxicity caused by KA-induced status epilepticus (SE). A single injection of KA (15 mg/kg, s.c.) induced seizures within 40-45 min, progressing to full seizure activity lasting about 3 h. Following microwave (head-focused) irradiation, perchloric acid extracts of rat brain regions (cortex, amygdala, and hippocampus) were analyzed for citrulline (determinant of NO) and high-energy phosphates (HEP) and their metabolites using high-performance liquid chromatograph (HPLC). KA-induced seizures produced a maximum increase in NO (3- to 6-fold) and a decrease in HEP (ATP 45-51% and phosphocreatine 45-58%) 2 h after KA injection in brain regions tested. 7-NI (50 mg/kg, i.p.) when given alone, reduced citrulline/NO levels (10-24%), while repeat administration of 7-NI (60 min apart) reduced NO levels by 32-49%. Neither application of 7-NI produced changes in HEP levels or toxicity. Pretreatment with 7-NI 30 min before KA injection, delayed the onset of seizures by 15-20 min, and significantly prevented an increase in NO and a decrease in HEP. Repeat administration of 7-NI, i.e. 30 min before and 30 min after KA injection, further increased protection by the delayed onset of seizures, attenuating the increase in NO and the decrease in HEP. Neurotoxicity of seizures involves activation of nNOS and of energy consumption in affected neurons. This increased energy consumption, coupled with decreased energy production caused by NO-induced mitochondrial dysfunction, may be a contributing factor to neuronal injury in KA toxicity.
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PMID:Prevention of kainic acid seizures-induced changes in levels of nitric oxide and high-energy phosphates by 7-nitroindazole in rat brain regions. 1288 40

The aim of this study was to evaluate the usefulness of proton and phosphorus (1H and 31P) magnetic resonance spectroscopy (MRS) for temporal lobe epilepsy (TLE) patients, and to evaluate neural damage and metabolite dysfunction in the TLE patient brain. We performed 1H and 31P MRS of medial temporal lobes (MTL) in the same TLE patients (n = 14) with a relatively wide range of severity from almost seizure-free to intractable, and calculated the ratio of N-acetylasparate to choline-containing compounds and creatine + phosphocreatine (NAA/Cho + Cr) in 1H MRS and inorganic phosphate to all main peaks (%Pi) in 31P MRS. There was no significant correlation between NAA/(Cho + Cr) and %Pi in each side (ipsilateral, r = -0.20; contralateral, r =-0.19). The values of NAA/(Cho + Cr) showed a significant difference between ipsilateral and contralateral MTLs to the focus of TLE patients (P < 0.01, paired t-test). Although %Pi also had a tendency to show the laterality of TLE, there was no significance. Ipsilateral (r = -0.90, P < 0.0001) and contralateral (r = -0.70, P < 0.005) NAA/(Cho + Cr) decreases and contralateral %Pi increase (r = 0.81, P < 0.001) had significant correlation with seizure frequency. 1H MRS provides more important information concerning neuronal dysfunction in MTL of TLE patients than 31P MRS.
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PMID:Neural damage due to temporal lobe epilepsy: dual-nuclei (proton and phosphorus) magnetic resonance spectroscopy study. 1467 57

We examined energy metabolism and amino acid content in the hippocampus of amygdaloid-kindled rats using (1)H NMR spectroscopy. Three weeks after the last stage 5 seizure, kindled rats were killed by microwave irradiation. The hippocampus was dissected out and subjected to MeOH/CHCl(3) extraction. All (1)H spectra were analyzed to quantify absolute concentrations using a non-linear least squares method, combined with a prior knowledge of chemical shifts. Saturation effects were compensated for by the T1 measurement of each component. Levels of energy metabolism-related compounds, phosphocreatine, creatine, glucose and succinate were the same in both kindled rats and sham controls. Lactate concentration had a tendency to increase, although this was not statistically significant. When compared with sham controls, levels of aspartate, glutamate, glycine and glutamine, as well as GABA and inositol, were increased in the ipsilateral but not the contralateral hippocampus. In contrast, levels of taurine, alanine and threonine were unchanged. Finally, N-acetylaspartylglutamate content was elevated, whereas N-acetyl-l-aspartate content was unaltered in the ipsilateral hippocampus of kindled animals. Our results suggest that amygdala kindling may affects amino acid metabolism, but not energy metabolism.
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PMID:In vitro 1H NMR spectroscopy shows an increase in N-acetylaspartylglutamate and glutamine content in the hippocampus of amygdaloid-kindled rats. 1574 51

Methylmalonic acidemias are metabolic disorders caused by a severe deficiency of methylmalonyl CoA mutase activity, which are characterized by neurological dysfunction, including convulsions. It has been reported that methylmalonic acid (MMA) accumulation inhibits succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase activity and respiratory chain complexes in vitro, leading to decreased CO2 production, O2 consumption and increased lactate production. Acute intrastriatal administration of MMA also induces convulsions and reactive species production. Though creatine has been reported to decrease MMA-induced convulsions and lactate production, it is not known whether it also protects against MMA-induced oxidative damage. In the present study we investigated the effects of creatine (1.2-12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) on the convulsions, striatal content of thiobarbituric acid reactive substances (TBARS) and on protein carbonylation induced by MMA. Moreover, we investigated the effect of creatine (12 mg/kg, i.p.) on the MMA-induced striatal creatine and phosphocreatine depletion. Low doses of creatine (1.2 and 3.6 mg/kg) protected against MMA-induced oxidative damage, but did not protect against MMA-induced convulsions. A high dose of creatine (12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) protected against MMA-induced seizures (evidenced by electrographic recording), protein carbonylation and TBARS production ex vivo. Furthermore, acute creatine administration increased the striatal creatine and phosphocreatine content and protected against MMA-induced creatine and phosphocreatine depletion. Our results suggest that an increase of the striatal high-energy phosphates elicited by creatine protects not only against MMA-induced convulsions, but also against MMA-induced oxidative damage. Therefore, since NMDA antagonists are limited value in the clinics, the present results indicate that creatine may be useful as an adjuvant therapy for methylmalonic acidemic patients.
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PMID:Effectiveness of creatine monohydrate on seizures and oxidative damage induced by methylmalonate. 1646 66

Carbamate insecticides mediate their neurotoxicity by acetylcholinesterase (AChE) inactivation. Male Sprague-Dawley rats acutely intoxicated with the carbamate insecticide carbofuran (1.5 mg/kg, sc) developed hypercholinergic signs within 5-7 min of exposure, with maximal severity characterized by seizures within 30-60 min, lasting for about 2 h. At the time of peak severity, compared with controls, AChE was maximally inhibited (by 82-90%), radical oxygen species (ROS) markers (F(2)-isoprostanes, F(2)-IsoPs; and F(4)-neuroprostanes, F(4)-NeuroPs) were elevated 2- to 3-fold, and the radical nitrogen species (RNS) marker citrulline was elevated 4- to 8-fold in discrete brain regions (cortex, amygdala, and hippocampus). In addition, levels of high-energy phosphates (HEPs) were significantly reduced (ATP, by 43-56%; and phosphocreatine, by 37-48%). Values of total adenine nucleotides and total creatine compounds declined markedly (by 41-56% and 35-45%, respectively), while energy charge potential remained unchanged. Quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant decreases in dendritic lengths (by 64%) and spine density (by 60%). Pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (18 mg/kg, sc), in combination with atropine sulfate (16 mg/kg, sc), significantly attenuated carbofuran-induced changes in AChE activity and levels of F(2)-IsoPs and F(4)-NeuroPs, declines in HEPs, as well as the alterations in morphology of hippocampal neurons. MEM and ATS pretreatment also protected rats from carbofuran-induced hypercholinergic behavioral activity, including seizures. These findings support the involvement of ROS and RNS in seizure-induced neuronal injury and suggest that memantine by preventing carbofuran-induced neuronal hyperactivity blocks pathways associated with oxidative damage in neurons.
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PMID:Neuronal oxidative injury and dendritic damage induced by carbofuran: protection by memantine. 1718 16

The efficacy of the ketogenic diet (KD) develops gradually over a period of 1-3 weeks, suggesting that adaptive changes in gene expression are involved in its anticonvulsant effects. Previously, microarrays were employed to define patterns of gene expression in the hippocampus of rats maintained on either a KD or a control diet for 3 weeks. The density of mitochondria in hippocampal tissue was assessed by electron microscopy. Levels of selected energy metabolites, enzyme activities, and the effect of low glucose on synaptic transmission were also investigated in hippocampal tissue taken from either KD- or control-fed animals. We found a coordinated up-regulation of transcripts encoding energy metabolism enzymes and a dramatic 46% increase in the density of mitochondria observed in neuronal processes. These changes were accompanied by an increased phosphocreatine (PCr):creatine (Cr) energy-store ratio. Consistent with heightened energy reserves, hippocampal synaptic transmission in KD-fed animals was maintained approximately 50% longer compared to controls after exposure to a mild metabolic stressor. Taken together, several lines of evidence indicate that the KD enhances energy production in the brain. As a consequence, brain tissue appears to become more resistant to metabolic stress. It is proposed...that the observed KD-induced enhancements in energy metabolism help to compensate for the metabolic deficits exhibited (interictally) within epileptic foci and transient failures of gamma-aminobutyric acid (GABA) ergic inhibition, which would otherwise favor the initiation and propagation of seizure activity.
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PMID:Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. 1904 99


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