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)

5.7-Dinitro-quinoxaline-2.3-dione (MNQX) displaced [3H]glycine binding to cortical membranes but had no effect n [3H]3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ([3H]CPP) binding. MNQX potently antagonized N-methyl-D-aspartate (NMDA)-evoked release of [3H]GABA from cultured cortical neurones, NMDA evoked spreading depression and NMDA depolarizations in the rat neo-cortex. All of these responses were reversed by addition of glycine to the perfusion media. These results suggested that MNQX is an antagonist at the strychnine-insensitive glycine receptor associated with the NMDA receptor/ionophore complex. Furthermore the compound was found to antagonise audiogenic seizures in DBA-2 mice indicating the potential of glycine antagonists of this type in anticonvulsant therapy.
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PMID:A potent antagonist of the strychnine insensitive glycine receptor has anticonvulsant properties. 256 Sep 79

1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors.
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PMID:Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants. 257 61

The effects of several 5-HT1A agonists and excitatory amino acid antagonists were compared to the standard benzodiazepines, diazepam and chlordiazepoxide (CDP) in two assays predictive of anxiolytic activity, the social interaction and elevated plus maze procedures. Indicative of anxiolytic effects the 5-HT1A agonists, buspirone, gepirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) all significantly increased social interaction time and open arm exploration time in the social interaction and elevated plus maze procedures, respectively. Likewise, anxiolytic activity in these assays were also produced by the competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphonovaleric acid (AP-5), 2-amino-7-phosphonoheptanoic acid (AP-7), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the non-competitive NMDA antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) while NMDA produced anxiogenic effects. Furthermore, the anxiolytic effects of these agents were of equal magnitude to the benzodiazepines. These two classes of compounds were differentiated in the yohimbine-induced seizure assay, with the NMDA antagonists dose dependently antagonizing seizures similar to the benzodiazepines while the 5-HT1A agonists were inactive. These results suggest that the 5-HT1A agonists and the NMDA antagonists may be potential non-classical anxiolytic agents with different mechanisms of action.
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PMID:Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. 257 84

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) was synthesized as a rigid analog of 2-amino-7-phosphonoheptanoate, a previously known antagonist at the N-methyl-D-aspartate (NMDA) preferring, or NMDA-type, of excitatory amino acid receptor. CPP was found to be a potent, selective and competitive antagonist of NMDA-type receptors. CPP antagonized with an IC50 of 8 muM [3H]ACh release which was evoked from rat striatal brain slices by NMDA (50 muM). In contrast, the release of [3H]ACh evoked by elevated KCI was not inhibited by CPP even at a concentration of 100 muM. The antagonism by CPP of NMDA-evoked [3H]ACh release was competitive, with a pA2 of 5.66 for CPP, compared with a pA2 value of 5.22 for 2-amino-7-phosphonoheptanoate. CPP affected neither the uptake of L-[3H]glutamate nor the inhibition by aconitine of L-[3H]glutamate uptake, suggesting a lack of membrane-stabilizing or local anesthetic effects, and also suggesting that CPP itself may not be taken up through the L-glutamate membrane transporter. Moreover, [3H] CPP was not accumulated by synaptosomes (P2 fraction) which avidly accumulate L-[3H]glutamate, supporting the concept that this NMDA-type receptor antagonist acts at an NMDA-type receptor on the external surface of the plasma membrane. CPP (10 muM) failed to interact with any of 21 other putative neurotransmitter receptors including alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding (quisqualate-type receptor) and [3H]kainate binding (kainate-type receptor). Audiogenic convulsions in DBA/2 mice were blocked by CPP (ED50 = 1.5 mg/kg i.p.) as were NMDA-induced seizures in CF-1 mice (ED50 = 1.9 mg/kg i.p.). In both strains, CPP impaired the traction reflex at higher doses (ED50 = 6.8 mg/kg and 6.1 mg/kg and 6.1 mg/kg i.p. for DBA/2 and CF-1, respectively). The traction reflex impairment by CPP may be due to muscle relaxant effects of the compound, an explanation supported by the finding that CPP reduced muscle tone as assessed by electromyogram measurement in animals whose muscle tone had been increased by opiate administration. Finally, cerebellar cyclic GMP levels, known to be sensitive to neurotransmission via NMDA-type receptors, were decreased by CPP (ED50 = 4.7 mg/kg i.p.) in mice. In conclusion, based upon the competitive antagonism by CPP of NMDA-evoked [3H] ACh release in vitro and the antagonism of NMDA-induced convulsions in vivo, the data presented are consistent with competitive antagonism of NMDA-type receptors.
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PMID:CPP, a selective N-methyl-D-aspartate (NMDA)-type receptor antagonist: characterization in vitro and in vivo. 288 14

A novel 4-substituted derivative of piperazine-2-carboxylic acid, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), with potent N-methyl-D-aspartate (NMDA) antagonist activity was evaluated as a muscle relaxant in genetically spastic rats. CPP, 0.02-0.1 mmol/kg, given intraperitoneally reduced the tonic activity in the electromyogram recorded from the gastrocnemius muscle of genetically spastic rats in a dose- and time-dependent manner. Muscle relaxation was also seen following intrathecal application of CPP, 0.0002-0.002 mumol, in genetically spastic rats. CPP, 0.1 mmol/kg, while not affecting Hoffman (H-) reflexes, depressed flexor reflexes in anesthetized rats following intravenous administration. In mice, CPP, 0.001 mumol, given intracerebroventricularly preferentially antagonized myoclonic seizures induced by NMDA and quinolinate, and had no effect on convulsions elicited by kainate, quisqualate and L-glutamate. These observations identify CPP as the most potent preferential NMDA antagonist so far tested with muscle relaxant and anticonvulsant activity resembling the profile of action of 2-amino-7-phosphonoheptanoate.
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PMID:Muscle relaxant and anticonvulsant activity of 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a novel N-methyl-D-aspartate antagonist, in rodents. 302 36

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a novel antagonist at the N-methyl-D-aspartate (NMDA)-preferring subtype of excitatory amino acid receptor, was evaluated in four rodent models of epilepsy, i.e. maximal electroshock seizures and pentylenetetrazol (PTZ)-induced seizures in mice, epileptic gerbils and amygdala-kindled rats. The effect of CPP after systemic (i.p.) injection was compared with that of the clinical antiepileptics, phenobarbital and diazepam, and in gerbils, in addition, with the effect of the NMDA antagonist 2-amino-5-phosphonopentanoate (AP5) and 2-amino-7-phosphonoheptanoate (AP7). CPP, 5 mg/kg i.p., increased the threshold for tonic electroshock seizures but this effect was associated with motor impairment in the chimney test whereas phenobarbital had comparable anticonvulsant potency without motor impairment. The threshold for clonic PTZ seizures was increased by CPP only at high doses (20 mg/kg) which induced ataxia and marked motor impairment in the chimney test, whereas both diazepam and phenobarbital were active in this test at doses which exerted no side-effects. CPP, 2-20 mg/kg i.p., could not reduce the severity or duration of focal and generalized clonic seizures or the duration of amygdalar afterdischarges in the amygdala-kindling model in rats but instead caused ataxia and reduced muscle tone at the higher doses examined. Diazepam and phenobarbital both had anticonvulsant efficacy in this model. CPP at doses of 5-10 mg/kg did not reduce seizure severity in gerbils in which generalized tonic-clonic seizures were induced by air-blast stimulation, but, as in mice and rats, it caused motor impairment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of CPP, a selective NMDA antagonist, in various rodent models of epilepsy. Comparison with other NMDA antagonists, and with diazepam and phenobarbital. 306 31

The effects of daily focal injections of excitatory amino acid antagonists into the prepyriform cortex on the development of electrically kindled seizures at this site were studied. The selective 'NMDA receptor' antagonists 2-amino-7-phosphonoheptanoic acid (AP7) and 3-[+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) significantly inhibited the development of the electrically evoked afterdischarge over a 10 day period and prevented the development of the motor seizure responses. The 'kainate and quisqualate receptor' antagonist gamma-D-glutamylaminomethyl sulphonic acid (GAMS) showed less potent but still significant inhibitory actions on these responses. When drug treatment ceased, kindling progressed in all animals at a rate similar to that of the control (buffer-treated) animals. These results suggest a critical role for NMDA receptors in the primary neuronal events initiating the epileptiform activity in this animal model of epilepsy.
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PMID:Inhibition of the development of electrical kindling of the prepyriform cortex by daily focal injections of excitatory amino acid antagonists. 320 34

CPP has a potent anticonvulsant effect against sound-induced seizures in audiogenic DBA/2 mice. Pretreatment with CPP (0.01-10 nmol i.c.v., 45 min) protects against successive phases of sound-induced seizures in a dose-dependent fashion (ED50, tonic phase, 0.023 nmol; clonic phase, 0.039 nmol; wild running, 0.17 nmol). Systemic administration of CPP (0.001-0.1 mmol/kg i.p., 45 min) produces a similar protection (ED50, tonic phase, 0.0012 mmol/kg; clonic phase, 0.0026 mmol/kg; wild running, 0.021 mmol/kg). Following the administration of a fully anticonvulsant dose of CPP (0.1 mmol/kg i.p., 45 min) to adult DBA/2 mice regional brain glucose (cerebellum and striatum) levels are elevated and lactate (striatum and hippocampus) levels decrease. The CPP-induced changes in alanine, serine and glycine paralleled those of lactate. Aspartate levels are significantly decreased by CPP in the striatum (-21%) and the hippocampus (-23%).
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PMID:Anticonvulsant action and biochemical effects in DBA/2 mice of CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate), a novel N-methyl-D-aspartate antagonist. 330 90

Neurologically critically ill patients, more often than others, are unable to communicate and, for a crucial period of time, have the vital functions of their brains hidden in the "black box" of the cranial vault behind a curtain of ambiguity and immobility. Customarily--and naively--we have relied upon beside clinical observations to pierce these barriers. Recent insights lead us to conclude that these "neurochecks" no longer suffice. This article has surveyed four major monitoring systems relied upon by neurointensivists to evaluate the pathophysiology of their patients. Of these, ICPM has the longest clinical track record. It provides a quantitative measure of the brain's capacity to withstand ICP and helps us monitor interventions to reduce it. To utilize this information intelligently requires an understanding of the principles of ICC, CPP, ICP wave morphology, and the hardware available. NICU-CEEG is a more recent introduction but, in principle, it transfers from the laboratory and operating suite to the ICU bedside, established correlations among electrophysiology, CBF, and CM. Digital EEG has allowed us to overcome significant logistical barriers and made NICU-CEEG a practical ICU tool. Early but impressive data suggest that NICU-CEEG has a significant clinical impact in patients with ACI, uncontrolled seizures, or coma. It also has revealed that NICU patients have a surprisingly high incidence of NCS, which may adversely affect their outcome. TCD has contributed greatly to diagnosis and management of SAH vasospasm. It also can be applied with benefit to patients with increased ICP, and has promising value in patients with ACI. It may prove beneficial in monitoring unstable cerebral embolization. Several bedside methods for monitoring CBF are available, but they require refinement to become true monitoring systems. These methods have revealed clinically important insights in patients with head trauma, SAH vasospasm, and ACI. Methods for directly monitoring CM and CMRo2 are improving our understanding of the brain's responses to injury, and becoming increasingly relevant to bedside management. SjvO2 can detect cerebral ischemia caused by overzealous hyperventilation and accelerated ICP. ICO holds promise as a noninvasive transcranial method for assessing Scvo2. We soon may see a scalp array of such detectors, similar to an EEG "montage," that allows us to assess multiregional Scvo2. To be useful, a clinical method should raise questions for further investigation. If the neurophysiologic monitoring systems described here provide us with some answers and lead us to ask useful new questions, they will prove their benefit to our patients.
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PMID:Neurophysiologic monitoring in the neuroscience intensive care unit. 747 20

Physical dependence on ethanol can result in seizure susceptibility during ethanol withdrawal. In rats, generalized tonic-clonic seizures are precipitated by auditory stimulation during the ethanol withdrawal syndrome. Excitant amino acids (EAAs) are implicated as neurotransmitters in the inferior colliculus and the brain stem reticular formation, which play important roles in the neuronal network for genetic models of audiogenic seizures (AGSs). Ethanol blocks the actions of EAAs in various brain regions, including the inferior colliculus. In this study, dependence was produced by intragastric administration of ethanol for 4 days. During ethanol withdrawal, AGSs were blocked by systemic administration of competitive or noncompetitive NMDA antagonists 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or dizocilpine (MK-801). Focal microinjections of NMDA or non-NMDA antagonists into the inferior colliculus or the pontine reticular formation also inhibited AGSs. MK-801 was the most potent anticonvulsant systemically. When injected into the inferior colliculus, CPP had a more potent anticonvulsant effect than either MK-801 or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. The inferior colliculus was more sensitive than the pontine reticular formation to the anticonvulsant effects of both competitive NMDA and non-NMDA antagonists. The results of the present support the idea that continued ethanol administration may lead to development of supersensitivity to the action of EAAs in inferior colliculus and pontine reticular formation neurons. This may be a critical mechanism subserving AGS susceptibility during ethanol withdrawal.
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PMID:Seizures during ethanol withdrawal are blocked by focal microinjection of excitant amino acid antagonists into the inferior colliculus and pontine reticular formation. 769 44


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