Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebrospinal fluid (CSF) from 6 cases of asymptomatic infantile spasms (IS) (mean age, 6.1 months) was collected before and after treatment with adrenocorticotropic hormone (ACTH). The concentration of CSF tryptophan (TRP) metabolites was analyzed using HPLC and compared to the metabolite concentration in CSF from 10 age-matched controls (mean age, 6.7 months). Levels of CSF serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and kynurenine (KYN) at pretreatment were significantly lower in IS patients compared to controls (p < 0.05). In contrast, the levels of CSF 3-hydroxykynurenine (3-OHKY) before ACTH treatment were significantly higher in IS patients than in controls (p < 0.05). After the treatment, significant increases in 5-HIAA and decreases in KYN and 3-OHKY levels (p < 0.05) were observed in CSF of infants whose seizures were eliminated by ACTH. These findings suggested that the presence of seizures in IS was associated with a significant decrease in serotonergic activity, or that the turnover in the direction of 3-OHKY was altered. The possibility that elimination of seizures by ACTH might be related to decreased production of kynurenine metabolites was discussed.
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PMID:[Changes in CSF tryptophan metabolite levels in infantile spasms]. 141 65

Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation. We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.
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PMID:Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. 142 88

Kynurenic acid (KYNA) was quantified in the extracellular spaces of the rat hippocampus using microdialysis and HPLC (fluorimetric detection) to study the possible role of this tryptophan metabolite in the modulation of the function of the N-methyl-D-aspartate (NMDA) receptor. Addition of probenecid (1 mM), which is an inhibitor of the organic acid transport system, to the Ringer's solution perfusing the dialysis probe increased the KYNA concentration in the dialysate from 10.4 +/- 0.9 to 48 +/- 6 nM. Addition of 2 mM aminooxyacetic acid, a nonspecific inhibitor of KYNA synthesis, reduced this concentration by 50%. These data suggest that KYNA is continuously synthesized in the rat hippocampus. Nicotinylalanine (NAL), 200-400 mg/kg i.p., an analogue of kynurenine that is able to direct the flow of tryptophan metabolites toward the synthesis of KYNA, significantly increased the KYNA concentration in the hippocampal dialysate and significantly potentiated the effect of tryptophan on the accumulation of KYNA in the brain and other organs. This increase resulted in pharmacological actions compatible with an antagonism of the NMDA receptors. In fact, NAL antagonized sound-induced seizures and prevented death in DBA/2 mice. Pretreatment of the mice with D-serine (100 micrograms intracerebroventricularly), a glycine agonist and a competitive antagonist of KYNA, completely prevented the anticonvulsive action of NAL. These data suggest that changes in the extracellular concentration of KYNA in the brain are associated with a modulation of NMDA receptor function.
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PMID:Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions. 143 95

1. Nicotinylalanine is an analogue of kynurenine which has been reported to inhibit the enzymes kynurenine hydroxylase and kynureninase. 2. In the present study rats were given a tryptophan load together with nicotinylalanine two hours before killing, and the brain, liver and kidneys analysed by HPLC for their kynurenic acid content. 3. Tryptophan alone produced a significant elevation of kynurenate but with the additional administration of nicotinylalanine, levels rose dramatically, including a 19-fold increase in brain. 4. In mice the same dose of nicotinylalanine reduced the incidence of seizures induced by leptazol or electroshock treatment. 5. Since kynurenic acid is an antagonist at excitatory amino acid receptors the results may herald a new approach to producing a pharmacological blockade of amino acid receptors in the brain.
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PMID:Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity. 163 38

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

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

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

The effect of central serotonergic stimulation on hippocampal and neocortical electrical activity and behavior was studied in freely moving rats by administering: (a) tranylcypromine followed by tryptophan, (b) fluoxetine followed by 5-hydroxytryptophan, or (c) p-chloroamphetamine alone. In all rats, scopolamine-resistant hippocampal rhythmical slow activity (RSA), thought to be dependent on brain serotonin, maintained its normal relation to behavior, occurring in close correlation with Type 1 behaviors (postural changes, turning of the head, walking). This RSA was generally absent during stereotyped behavior (head weaving, forepaw treading, hindlimb splaying and tremor). Scopolamine-resistant neocortical low-voltage fast activity (LVFA), also though to be dependent on brain serotonin, was present during Type 1 behaviors and also during stereotyped behavior. Most rats that developed a full stereotyped behavior syndrome had behavioral and electrocortical seizures which were associated with a reduction in the amplitude of hippocampal activity. These seizures were suppressed by methysergide or benserazide. Metergoline (and methysergide to a lesser extent) suppressed the stereotypic behaviors of the serotonin syndrome, resulting in a striking increase in the locomotion caused by central serotonergic stimulation. Such locomotion was accompanied by RSA and LVFA. It was concluded that increased serotonergic activity in the CNS causes an increase in motor activity and a correlated increase in scopolamine-resistant hippocampal RSA and scopolamine-resistant neocortical LVFA and suggested that metergoline blocks serotonin receptors mediating stereotyped behaviors, thereby permitting the expression of serotonin-mediated locomotion.
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PMID:The effects of serotonergic stimulation on hippocampal and neocortical slow waves and behavior. 193 39

Quinolinic acid (QUIN), an endogenous neuroactive metabolite of tryptophan, administered i.c.v. in doses of 45, 90, 180, and 270 nmol in rabbits, demonstrated an excitatory action on the sleep-wake cycle and behaviour. Doses of 90 and 180 nmol completely abolished the paradoxical sleep phase and induced a 5-fold decrease in the duration of deep slow wave sleep (dSWS) in the first hour of the experiment. Light slow wave sleep (1SWS) duration was not altered. Sniffing behaviour was markedly activated by 180 nmol of QUIN. A dose of 270 nmol completely blocked sleep, diminished the restoration of sleep, induced panic behaviour and, in some animals, induced generalized tonic seizures. Data suggest an excitatory action of QUIN on NMDA receptors involved in the regulation of the sleep-wake cycle in the rabbit.
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PMID:Effect of quinolinic acid on wakefulness and sleep in the rabbit. 214 74


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