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)

N-methyl-D-aspartate (NMDA) receptors are known to play an important role in learning and memory and to be involved in neuron cell death accompanying cerebral ischemia, seizures, and Alzheimer's disease. The NMDA receptor complex has been considered to consist of an L-glutamate recognition site, a strychnine-insensitive glycine modulatory site, and a voltage-dependent cation channel. In the present study, effects of age on an L-glutamate recognition site and a glycine site were examined in rat brain by quantitative in vitro autoradiography with [3H]-CPP and [3H]-glycine. Both [3H]-glycine and [3H]-CPP binding sites were most abundant in the hippocampus and cerebral cortex, and they showed a similar distribution pattern throughout the brain. [3H]-glycine binding sites were severely decreased in the telencephalic regions, including the hippocampus and cerebral cortex, in aged brain. Conversely, [3H]-CPP binding sites were well preserved in these brain areas. In the mid-brain regions and cerebellum, neither [3H]-glycine nor [3H]-CPP binding sites changed in the aged brain. Our results indicate that within the NMDA receptor complex, glycine receptors are primarily affected in the aging process.
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PMID:Influence of age on NMDA receptor complex in rat brain studied by in vitro autoradiography. 214 8

Experimental febrile seizures can be evoked in epileptic chicks by elevation of their body temperature. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(+/- )2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), DL-2-amino-7-phosphosphonoheptanoic acid (APH), DL-2-amino-5-phosphonovaleric acid (APV), D-alpha-aminoadipic acid (AAA), and DL-alpha, epsilon-diaminopimelic acid (DAP)] and the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5, 10-imine maleate (MK-801) produced dose-dependent increases in latency to the onset of seizures. Of the drugs tested, MK-801 had the highest potency followed in order by CPP = APH greater than APV much greater than AAA greater than DAP. There was a high correlation (r = 0.995) between the dose capable of doubling seizure latency and the affinity of the competitive NMDA antagonists for the NMDA receptor as determined by in vitro binding assays. These data suggest that NMDA receptor mediated mechanisms may be involved in the production of seizures in response to hyperthermia.
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PMID:Attenuation of febrile seizures in epileptic chicks by N-methyl-D-aspartate receptor antagonists. 215 87

The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the gamma-aminobutyric acidA (GABAA) antagonist bicuculline (BIC) were tested in mice. 3-[+/-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists. gamma-D-Glutamylaminomethylsulphonate (gamma-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v. administration with a CD50 of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (ED50 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), gamma-D-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABAA agonist, blocked BMI-induced seizures with an ED50 of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CD50 of 2.2 mg/kg (range 1.9-2.5) for clonus and CD50 of 2.4 mg/kg (range 2.2-2.7) for tonus.2+ the pathogenesis of seizures triggered by bicuculline in mice.
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PMID:Excitatory amino acid antagonists protect mice against seizures induced by bicuculline. 216 7

Status epilepticus (SE) evolves through several stages when untreated. The later stages of SE are less responsive to standard anticonvulsants and may require general anesthesia to suppress seizures. Antagonists acting at the N-methyl-D-aspartate (NMDA) subclass of glutamate (excitatory) receptors have been demonstrated to exert antiepileptic activity in some seizure models. We report experiments performed to determine if NMDA receptor antagonists are effective in stopping seizures in the late stages of SE. A model of limbic SE induced by 90 min of 'continuous' electrical stimulation of the hippocampus in rats was employed. Three NMDA receptor antagonists, one 'competitive' (CPP) and two 'non-competitive' (ketamine and MK-801), were compared to 3 standard antiepileptic drugs (diazepam, phenobarbital, and phenytoin) for their ability to suppress seizures at a physiologically defined stage of SE. All NMDA receptor antagonists, diazepam and phenobarbital were effective in suppressing behavioral and electrographic seizures for varying periods of time. Phenytoin had no effect on SE. Ketamine and MK-801 induced a paradoxical enhancement of electrographic seizures that preceded SE suppression. We believe that NMDA-receptor antagonists offer a novel approach for treating the late stages of SE.
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PMID:NMDA receptor antagonists and limbic status epilepticus: a comparison with standard anticonvulsants. 216 58

D-(-)4-(3-phosphonopropyl)piperazine-2-carboxylic acid (D-CPP) and its unsaturated analogue (D(-)(E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (D-CPPene) have been administered to DBA/2 mice (intracerebroventricularly, i.c.v., intraperitoneally, i.p., and orally, p.o.) and to photosensitive baboons, Papio papio (intravenously, i.v., and orally), and their effects on reflexly induced epileptic responses assessed. In DBA/2 mice the clonic phase of the seizure response to sound is suppressed by D-CPP with an ED50 of 5.5 micrograms/mouse, i.c.v.; 0.69 mg (2.75 mumol)/kg i.p. and 16.6 mg (65.8 mumol)/kg p.o. compared with, for D-CPPene, 2.2 micrograms/mouse i.c.v., 0.41 mg (1.54 mumol)/kg i.p. and 10.8 mg (40.2 mumol)/kg, p.o. In Papio papio myoclonic responses to stroboscopic stimulation are suppressed 24 and 48 h after D-CPP 32 mg (127 mumol)/kg p.o. Administration of D-CPPene 8-16 mg (30-60 mumol)/kg i.v. produces protection against myoclonic responses after 1-2 h, lasting for 48 h. Oral administration of D-CPPene 32-64 mg (119-239 mumol)/kg produces protection beginning after 4 h and sustained for 48 h. Measurements of plasma D-CPPene concentration show rapid clearance after i.v. injection and a low plasma concentration 1.5-5 h after oral administration. The prolonged anticonvulsant action of D-CPP and D-CPPene following oral administration suggests that these compounds merit evaluation as antiepileptic therapy in man.
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PMID:Anticonvulsant activity of the NMDA antagonists, D(-)4-(3-phosphonopropyl) piperazine-2-carboxylic acid (D-CPP) and D(-)(E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (D-CPPene) in a rodent and a primate model of reflex epilepsy. 229 44

CPP (3-(2-carboxypiperazine-4-yl)-1-phosphonate), and its unsaturated analogue, CPPene (3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid), have potent anticonvulsant activity against sound-induced clonic seizures in DBA/2 mice. Following i.p. administration the protection is maximal at 1-2 h, and the ED50 values (mumol/kg) are: D(-)-CPPene, 1.54; D(-)-CPP, 2.75; D,L( +/- )-CPP, 4.36. Following oral administration the protection is maximal at 3-4 h and the ED50 (mumol/kg) values are: D(-)-CPPene, 40.19; D(-)-CPP, 65.80; D,L( +/- )-CPP, 108.1.
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PMID:Potent oral anticonvulsant action of CPP and CPPene in DBA/2 mice. 233 32

Modification of central serotonergic transmission resulted in alterations of pilocarpine convulsive activity in male Wistar rats. Seizure activity was increased after pizotifen injection and the latency period to onset of convulsions was shortened in animals pretreated with mianserine and quipazine. Stimulation of 5-HT1A receptors with 8-hydroxy-di-N,N-propylaminotetralin (8-OH-DPAT) and blockade of 5-HT1B receptors with cyanopindolol resulted in seizure protection. Intracerebroventricular injections of 5,6-dihydroxytryptamine (5,6-DHT) did not change the protective effect of cyanopindolol. Other agents specifically affecting serotonergic receptors, the agonists 1-(3-chlorophenyl)piperazine (mCPP) and 5-methoxytryptamine (5-MT) and the antagonists spiperone, metergoline, methysergide, cyproheptadine and metoclopramide, did not influence pilocarpine-induced seizures. In conclusion, the present study suggests that the inhibition of pilocarpine-induced seizures may be mediated by stimulation of 5-HT1A and by blockade of 5-HT1B receptors, located probably on the cholinergic terminals.
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PMID:The role of the central serotonergic system in pilocarpine-induced seizures: receptor mechanisms. 253 36

The N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(+/-)2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP), +/- 2-amino-7-phosphonoheptanoic acid (2AP7), +/- 2-amino-5-phosphonovaleric acid (2AP5), D-alpha-aminoadipic acid (alpha AA), and +/- alpha, epsilon-diaminopimelic acid (DAP)] were tested for anticonvulsant activity in epileptic chickens. There was a high correlation between anticonvulsant potencies (ED50) and the affinity for the NMDA receptor measured by displacement of L-[3H]glutamate from synaptosomal membranes. The high seizure susceptibility is not due to abnormalities in the NMDA receptor as comparison of KD, Bmax and Ki values in synaptosomal preparations from epileptic and non-epileptic chickens indicated no differences in NMDA receptor binding receptor characteristics.
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PMID:The relationship between anticonvulsant activity and receptor affinity of N-methyl-D-aspartate antagonists in epileptic fowl. 254 14

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. 255 Feb 53

To test the hypothesis that the motor hyperactivity associated with intra-accumbens injections of N-methyl-d-aspartate (NMDA) results from stimulation (direct or indirect) of nucleus accumbens dopaminergic mechanisms, the behavioral effects of intra-accumbens and intraventricular NMDA were compared to those of the prototypic dopaminergic releasing agent, amphetamine, and the competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP). Drugs were injected into the right lateral ventricle, or bilaterally into the nucleus accumbens of rats. Locomotor activity was monitored electronically and by direct observation for 40 min prior to, and 1 hour after, drug treatment. Intra-accumbens injections of NMDA (0.4, 1.2 and 2.0 micrograms/side) produced dose-related increases in distance traveled, but had no significant effect on movement time or vertical movements. The NMDA-induced increase in distance traveled was temporally correlated with convulsive wild running, but not with exploratory behavior, suggesting that this increase may have been secondary to seizure-like activity. Intra-accumbens injections of amphetamine (10, 20 and 40 micrograms) or CPP (0.1 microgram) produced dose-related increases in all three measures. By the intraventricular route, the effects of NMDA were similar to those of intra-accumbens administration, whereas intraventricularly administered d-amphetamine had no effect. The behavioral effects of intra-accumbens NMDA cannot be explained by an NMDA receptor-mediated facilitation of dopaminergic neurotransmission; rather, this type of facilitation may be associated with competitive NMDA receptor antagonism.
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PMID:Hyperactivity induced by N-methyl-d-aspartate injections into nucleus accumbens: lack of evidence for mediation by dopaminergic neurons. 256 Feb 12


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