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 organophosphate chemical nerve agent, soman, causes convulsions, neuropathology, and, ultimately, death. A major problem in treating soman intoxication is that peripherally acting pharmacological agents which prevent death do not prevent seizures. Although a primary cause of these symptoms is the excess of acetylcholine which follows acetylcholinesterase (AChE) inhibition, centrally acting muscarinic blockers, such as atropine, alleviate, but do not block, the convulsive actions of soman. Moreover, there is a relatively weak relationship between CNS reductions of AChE and the incidence of convulsions. There is evidence suggesting that soman intoxication stimulates the release of norepinephrine (NE) in the brain. Recent evidence has implicated NE in the induction and/or maintenance of seizures. Thus, in the present study the relations among soman-induced convulsions, AChE inhibition, and brain NE and other monoamine changes were examined. The time course of brain NE recovery was also determined. Rats were injected (im) with a single dose (78 micrograms/kg) of soman. At this dose 68% of the injected rats developed convulsions. Both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h following soman injection and NE levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. In all convulsive rats NE levels declined substantially. Forebrain NE levels were decreased by 50% at 1 h and 70% at 2 h following soman injection. Recovery of NE began at 8 h and was complete by 96 h following soman administration. Although nonconvulsive rats showed other signs of intoxication, NE levels in these rats were unchanged. Dopamine (DA) and serotonin (5-HT) levels were not significantly affected in either convulsive or nonconvulsive rats. However, 5-hydroxyindoleacetic acid, the major metabolite of 5-HT, and homovanillic acid and 3,4-dihydroxyphenylacetic acid, the two major metabolites of DA, were increased significantly in the forebrain of convulsive, but not nonconvulsive rats, indicating an increase in 5-HT and DA turnover. However, in contrast to the abrupt decline in NE, these increases in DA and 5-HT metabolites were slow and progressive. Taken together, the present results and other recent findings suggest that rapid, sustained NE release could play a role in the induction and/or maintenance of soman-induced convulsions, whereas increased release of 5-HT and DA may be a consequence of seizures. Further investigation of the role of NE in soman-induced convulsions may lead to improved treatment of soman intoxication and a better understanding of the role of NE in other forms of seizures, including human epilepsy.
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PMID:Brain norepinephrine reductions in soman-intoxicated rats: association with convulsions and AChE inhibition, time course, and relation to other monoamines. 142 25

An implanted stimulating device chronically stimulated the left cervical vagus nerve in epileptic patients. Cerebrospinal fluid concentrations of free and total gamma-aminobutyric acid, homovanillic acid, 5-hydroxyindoleacetic acid, aspartate, glutamate, asparagine, serine, glutamine, glycine, phosphoethanolamine, taurine, alanine, tyrosine, ethanolamine, valine, phenylalanine, isoleucine, vasoactive intestinal peptide, beta-endorphin, and somatostatin were measured before and after 2 months of chronic stimulation in six patients. Significant increases were seen in homovanillic acid and 5-hydroxyindoleacetic acid in three patients, and significant decreases in aspartate were seen in five patients. These changes were associated with a decrease in seizure frequency.
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PMID:Neurochemical effects of vagus nerve stimulation in humans. 150 37

Quinolinic acid (QUIN) is a neurotoxin and convulsant when injected directly into the brains of experimental animals and as such has been implicated in the etiology of human seizure disorders. In the present study, we quantified QUIN in cerebrospinal fluid (CSF) and in spiking (focus) and nonspiking (nonfocus) regions of surgically resected human temporal neocortex. L-tryptophan (L-TRP), the putative precursor of QUIN, was also measured in brain, along with CSF concentrations of L-TRP, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA). In brain tissue, no differences were found in the concentrations of QUIN and L-TRP between focus and nonfocus regions in 15 pairs of samples. No differences were found in CSF, L-TRP, 5-HIAA, or HVA concentrations between 11 neurologically normal controls and 15 interictal (no seizures for greater than 24 h) and 20 postictal (within 50 min of seizure) samples from epileptic patients. However, CSF QUIN concentrations were significantly lower (32%) in the epileptic patients as compared with controls, which may indicate a generalized disturbance in brain QUIN metabolism or perhaps a response to antiepileptic drugs.
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PMID:Quinolinic acid concentrations in brain and cerebrospinal fluid of patients with intractable complex partial seizures. 169 Jun 39

1. Sodium di-n-propylacetate (DPA) treatment induced significant increases in brain contents of gamma-aminobutyric acid (GABA), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). Furthermore, the threshold for pentylenetetrazol (PTZ) clonic convulsions was also increased in response to DPA administration. 2. Pretreatment with inhibitors of monoamine synthesis alpha-methyl-p-tyrosine (AMPT) and p-chlorophenylalanine (PCPA) did not alter the anticonvulsant activity of DPA, but when given alone, both AMPT and PCPA caused significant decreases in brain monoamine contents and PTZ threshold seizures. 3. Experiments using probenecid suggest that the increases in 5-HIAA and HVA seen after DPA treatment could have resulted from inhibition of their active transport out of the brain. These data indicate that the anticonvulsant action of DPA is not dependent on changes in monoamine metabolism in the brain.
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PMID:Anticonvulsant activity of di-n-propylacetate and brain monoamine metabolism in the rat. 169 53

The aim of the present investigation was to look for the mechanisms causing disturbances in carbohydrate metabolism during the action of the epileptogenic agent methionine sulfoximine. The levels of glucose, glycogen, and indolamines were measured in seven different regions of rat brain. Methionine sulfoximine induced a decrease in serotonin level which was roughly dose-dependent. There were no obvious changes in tryptophan and 5-hydroxyindoleacetic levels in any area. Methionine sulfoximine induced the known increase in glucose and glycogen levels. The direct precursor of serotonin. 5-hydroxytryptophan, and benserazide (a decarboxylase inhibitor) were then injected into rats in association with methionine sulfoximine. In this case, methionine sulfoximine failed to induce seizures. Moreover, the serotonin level was unchanged and the carbohydrate content did not significantly increase. There was only a rise in 5-hydroxyindoleacetic acid level. This work shows a striking parallelism between serotonin decrease and glycogen increase.
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PMID:Possible involvement of indolamines in the glycogenic effect of the convulsant methionine sulfoximine in rat brain. 169 79

The effect of equal-dose regimens of amitriptyline and nortriptyline on the concentrations of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline increased to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs increased serotonin levels but decreased cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential increase in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an increase in dopamine turnover particularly in brain areas associated with motor function and posture which may account for tricyclic-antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition.
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PMID:Effects of a secondary and a tertiary amine tricyclic antidepressant on cerebral biogenic amines as a function of mouse strain: a comparative neurotoxicological evaluation. 171 94

Ten patients, suffering from drug-resistant complex partial seizures were treated for a period of up to 3 years with vigabatrin (Sabril). Vigabatrin is a novel antiepileptic agent, whose action is based on the inhibition of gamma-aminobutyric acid (GABA) aminotransferase, the enzyme responsible for the catabolism of the neurotransmitter GABA. Samples of lumbar cerebrospinal fluid were obtained from the patients prior to commencing vigabatrin therapy, and thereafter at 6 months, 1 year, 2 years, and up to 3 years following the initiation of vigabatrin treatment. The influence of vigabatrin on the cerebrospinal fluid concentrations of free and total GABA, homocarnosine, homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol, as well as of the drug itself, was assessed. All patients demonstrated a clinical response to vigabatrin, and the drug was well tolerated over the entire observation period. Mean (+/- SD) reduction of seizure frequency was 65% +/- 23% (range, 26% to 100%) when comparing the end of the treatment period to the previgabatrin baseline. The cerebrospinal fluid concentrations of both free and total GABA and of the dipeptide homocarnosine showed approximately 2- to 5-fold increases over baseline values, with free GABA and homocarnosine being the more sensitive variables. Cerebrospinal fluid concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol were not altered in a significant manner over the observation period. These findings support the concept that the effects of vigabatrin are restricted to an effect on GABA catabolism and do not extend to the neurotransmitters dopamine and norepinephrine. Clinical efficacy and elevation of GABA and homocarnosine concentration were sustained over the period of observation.
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PMID:Effect of long-term vigabatrin therapy on selected neurotransmitter concentrations in cerebrospinal fluid. 171 63

Guanidinoethanesulfonic acid (GES) is known to induce convulsive seizures when administered intracisternally to rabbits and cats. The effects of GES on behavior, electroencephalographic recording and brain monoamine levels were examined in mice. When GES (900 nmol) was intraventricularly injected into mice, focal clonic movements of the face, vibrissae and ears together with twitching of the limbs were observed 0.5-1 min after the injection. Hypersensitivity was observed up to 7 min after the injection, after which the mice behaved normally. GES also induced sporadic spike discharges on electrocorticogram. The levels of 5-hydroxytryptamine (5-HT) of the GES-injected mice were lower than those of the saline-injected mice in the hippocampus, diencephalon, pons-medulla oblongata and cerebellum 5 min after the injection. No changes in the norepinephrine or dopamine levels were found after the GES injection. The level of 5-hydroxyindoleacetic acid increased in the striatum and cerebellum 5 min after the GES injection. These results suggest that GES-induced convulsive activities enhance the serotonergic neuroactivity in order to suppress the convulsions.
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PMID:Effect of guanidinoethanesulfonic acid on brain monoamines in the mouse. 172 53

Cerebrospinal fluid from 8 patients with infantile spasms (mean age: 6.1 months) was collected before treatment. The concentration of cerebrospinal fluid tryptophan metabolites was analyzed using high-performance liquid chromatography and compared to metabolite concentrations in cerebrospinal fluid from 20 age-matched controls (mean age: 5.8 months). The levels of cerebrospinal fluid serotonin, 5-hydroxyindoleacetic acid, and kynurenine were significantly lower in infantile spasm patients compared to controls (P less than .05). In contrast, the levels of cerebrospinal fluid 3-hydroxykynurenine were significantly higher in infantile spasm patients than in controls (P less than .05). There were no significant differences in the levels of cerebrospinal fluid tryptophan and 5-hydroxytryptophan. Although the study population was small, these findings suggest that the presence of seizures in infantile spasms is associated with a decrease in serotonergic metabolites which, in turn, may indicate a decrease in serotonergic activity, altered clearance of these metabolites, or altered turnover in the direction of 3-hydroxykynurenine. The perturbance caused by increased 3-hydroxykynurenine and decreased kynurenine in the homeostatic balance between these 2 tryptophan metabolites could further contribute to the pathogenesis of infantile spasms.
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PMID:Studies on CSF tryptophan metabolism in infantile spasms. 172 1

Cerebrospinal fluid (CSF) from 7 patients with infantile spasms (mean age: 6.7 months) was collected before and after treatment with adrenocorticotropic hormone (ACTH). The concentration of neurotransmitter metabolites was analyzed using high-performance liquid chromatography and compared to the metabolite concentration in the CSF from 7 age-matched controls (mean age: 6.1 months). Pretreatment levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid, 3-methoxy-4-hydroxyphenyl glycol (MHPG), and kynurenine were significantly lower in infantile spasm patients compared to controls. Following treatment, marked increases in 5-HIAA and decreases in kynurenine levels were observed in the CSF of the 5 infants whose seizures were eliminated or reduced by ACTH. In the 2 nonresponders 5-HIAA levels decreased. The level of MHPG was reduced slightly in 5 infants, including the 2 nonresponders, and was increased in 2 responders. CSF homovanillic acid levels increased in 4 infantile spasm infants and decreased in 3 following ACTH. These data demonstrate that the presence of seizures in infantile spasms is associated with a significant decrease in serotonergic activity and that elimination of seizures by ACTH is accompanied by increased serotonin turnover. The simultaneous increase of 5-HIAA and decrease of kynurenine, an alternate metabolite of tryptophan, suggests an underlying disturbance of tryptophan metabolism in infantile spasms. The possibility that elimination of seizures by ACTH may be related to decreased production of certain kynurenine metabolites, particularly quinolinic acid, is discussed.
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PMID:Changes in CSF neurotransmitters in infantile spasms. 172 2


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