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 time course and severity of the excitotoxic syndrome induced in rats by s.c. injection of 10 mg/kg kainic acid (KA) was modified by pretreatment with MK801, a non-competitive inhibitor of the NMDA receptor, at doses of 0.1, 1 and 10 mg/kg. A dose-dependent increase in the severity of the KA-induced electrographic (EEG) manifestations of epilepsy was seen after MK801. This consisted of an earlier appearance and higher number of EEG seizures, longer time spent in seizures, and an earlier onset of status epilepticus. In contrast, behavioral seizures were increased only in the 0.1 mg/kg MK801 group, but abolished by higher doses. On the contrary, wet dog shakes were progressively reduced with increasing doses of MK801. Four of the 9 animals receiving KA-only group and 3 of the 10 animals in the 1 and 10 mg MK801 groups were sacrificed 5 days after KA. The brain of the KA-only rats presented diffuse gross and microscopic evidence of hemorrhagic necrosis and neuronal damage; the MK801 rats showed only minimal neuronal loss in the CA3 hippocampal sector. This study demonstrates that neuronal damage and epileptiform activity can be dissociated. Furthermore, it confirms the protective effect of MK801 against neuronal damage caused by multiple factors. Lastly, it emphasizes the need for EEG monitoring in order to accurately assess any epileptic/antiepileptic effect.
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PMID:Potentiation of kainic acid epileptogenicity and sparing from neuronal damage by an NMDA receptor antagonist. 254 57

The novel compound 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) was evaluated for activity in a variety of tests associated with receptors for excitatory amino acids. NPC 12626 failed to inhibit the specific binding of RS-[3H] amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid or [3H] kainic acid to brain membranes in vitro but displaced both agonist and antagonist binding to N-methyl-D-aspartic acid (NMDA) receptors. Like cis-(+/-)-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid, NPC 12626 competitively blocked NMDA-induced enhancement of [3H]-1-thienylcyclohexyl)piperidine binding. In the voltage-clamped frog oocyte expression system, NPC 12626 was a competitive inhibitor of NMDA-evoked inward current with a pA2 of 6.24. After both i.c.v. or i.p. administration, NPC 12626 was a potent anticonvulsant in the pentylenetetrazol, maximal electroshock and NMDA seizure models. Furthermore, low doses (25 mg/kg) of NPC 12626 given i.v. were effective in preventing damage to the CA1 region of hippocampus in the gerbil model of global ischemia. Unlike the noncompetitive NMDA antagonist, phencyclidine, but like cis-(+/-)-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid and pentobarbital, NPC 12626 only partially substituted for phencyclidine in a drug discrimination study. The results of the current study indicate that NPC 12626 is a novel, systemically active and competitive NMDA receptor antagonist.
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PMID:Pharmacological profile of NPC 12626, a novel, competitive N-methyl-D-aspartate receptor antagonist. 254 56

Guanine nucleotides were shown to alter N-methyl-d-aspartate (NMDA) receptor-effector coupling by competitive antagonism at the glutamate binding site, rather than via interaction with an intracellularly located GTP-binding protein. Thus, in contrast to known G-protein linked receptors, micromolar concentrations of guanine nucleotides and their analogs decreased both agonist [( 3H]glutamate) and antagonist [( 3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid binding to the NMDA receptor complex. The most potent compound, the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), was studied in detail. GDP beta S exhibited almost 200-fold selectivity for the glutamate recognition site vs. the strychnine-insensitive glycine binding site. IC50 values were 2.7 +/- 1.4 and 484 +/- 97 microM, respectively. GDP beta S also inhibited N-[1-(2-thienyl)cyclohexyl-3H]piperidine binding (IC50 was 28.0 +/- 3.7 microM) in an NMDA-reversible fashion. [3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid saturation binding studies revealed an increase in Kd from 263 +/- 49 (control) to 552 +/- 134 nM (8 microM GDP beta S) without any change in maximum binding (4.94 +/- 0.34 and 5.19 +/- 0.58 pmol/mg of protein, respectively). GDP beta S was also a competitive inhibitor of the following NMDA-stimulated responses: elevation of cyclic GMP in neonatal rat cerebellar slices, release of preloaded [3H]norepinephrine from superfused rat hippocampal slices and elevation of cytosolic calcium concentration in fura-2-loaded cultured rat forebrain neurons. IC50 values were 78.4, 53.4 and 1.6 microM, respectively. Finally, GDP beta S resembled known NMDA receptor antagonists in its ability to block NMDA receptor-induced seizures after i.c.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Guanine nucleotides are competitive inhibitors of N-methyl-D-aspartate at its receptor site both in vitro and in vivo. 254 57

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 high pressure neurological syndrome (HPNS) occurs when man or animals are exposed to hyperbaric pressure. Four non-competitive N-methyl-D-aspartate (NMDA) antagonists - MK-801, phencyclidine (PCP), SKF 10,047 and ketamine were tested in rats for effects on the HPNS. All drugs were injected i.p. prior to compression; ketamine was also infused i.v. Control rats received saline. Rats were exposed individually to increasing helium pressure (PO2 0.5 atmospheres absolute ATA). Three endpoints were used to assess HPNS: onset pressures for tremor, myoclonus and convulsions. Neither MK-801 (0.03 and 0.3 mg/kg) nor SKF 10,047 (50 mg/kg) had any effect on the onset pressures for tremor, myoclonus or convulsions, although the type of seizure was modified from the clonic/tonic seizure seen in controls to purely clonic. PCP (5 mg/kg) had no effect on the endpoints, but pressure enhanced the excitation and stereotypy seen at 1 ATA. Ketamine (100 mg/kg i.p.) did not affect tremor or myoclonus; ketamine infused i.v. at pressure only prevented tremor and myoclonus at 'anaesthetizing' concentrations. Our results show that these non-competitive NMDA antagonists had little effect on HPNS, in contrast to competitive NMDA antagonists, such as AP7, which are highly effective. Possible explanations for this lack of effect include (1) interactions with NMDA receptor channels are pressure dependent; (2) other actions of these antagonists override their effects on the NMDA receptor channel.
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PMID:The effects of non-competitive NMDA receptor antagonists on rats exposed to hyperbaric pressure. 254 78

A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.
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PMID:4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: synthesis, activity at N-methyl-D-aspartic acid receptors, and anticonvulsant activity. 254 46

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

MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of MK-801 in the lithium-pilocarpine model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block seizures induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the seizures. Administration of MK-801 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in status epilepticus and brain damage in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality.
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PMID:Anticonvulsant actions of MK-801 on the lithium-pilocarpine model of status epilepticus in rats. 255 70

Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-delta 6-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotype and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.
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PMID:Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. 255 19

Our recent studies on seizure-triggering mechanisms in the kindling model of epilepsy are reviewed. Electroencephalographic (EEG) events during kindling-inducing tetanic stimulation from the site of stimulation were recorded, with an emphasis on EEG suppression and rhythmic synchronous discharge. From electrophysiological and pharmacological analyses of these events, it is hypothesized that activation and subsequent collapse of GABA-A-mediated inhibition is an essential precondition in the initiation of kindled seizures. The excitatory role of NMDA receptors in kindling were also investigated by examining the effects of a noncompetitive antagonist of NMDA receptors (MK-801) on amygdala kindling and hippocampal long-term potentiation (LTP). The results indicate that activation of NMDA receptor complex combined with the collapse of GABA-A-mediated inhibition may be critical for kindling development.
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PMID:Seizure-triggering mechanisms in the kindling model of epilepsy: collapse of GABA-mediated inhibition and activation of NMDA receptors. 255 30


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