Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 role of metabotropic excitatory amino acid receptors in seizures and brain injury was examined using the selective metabotropic agonist 1S,3R-ACPD [(1S,3R)-1-aminocyclopentane-1-3-dicarboxylic acid] in 7-d-old neonatal rats. Systemic administration of 1S,3R-ACPD produced dose-dependent convulsions (ED50 = 16 mg/kg, i.p.) that were stereoselective for the active metabotropic ACPD isomer, since 1R,3S-ACPD was less potent (ED50 = 93 mg/kg, i.p.). 1S,3R-ACPD-induced seizures were antagonized by systemic administration of dantrolene, an inhibitor of intracellular calcium mobilization, but not by the ionotropic glutamate antagonists MK-801 or GYKI-52466. As indexed by hemispheric brain weight differences 5 d postinjection, unilateral intrastriatal injection of 1S,3R-ACPD (0.1-2.0 mumol/microliters), but not 1R,3S-ACPD, produced dose-dependent brain injury (maximal effect of 3.4 +/- 0.5% damage). 1S,3R-ACPD brain injury occurred in the absence of prominent behavioral convulsions. Histologic and ultrastructural examination of 1S,3R-ACPD-injected rat brains revealed swelling and degeneration of select neurons at 4 hr postinjection, but little evidence of injured neurons 5 d later. 1S,3R-ACPD-mediated brain injury was not attenuated by systemic administration of the NMDA antagonist MK-801 or the AMPA antagonist GYKI-52466. However, cointrastriatal injection of dantrolene reduced the severity of 1S,3R-ACPD injury by 88 +/- 7%. These studies indicate that seizures and neuronal injury can be elicited by the selective activation of metabotropic glutamate receptors in perinatal rats, and these effects of 1S,3R-ACPD involve the mobilization of intracellular calcium stores.
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PMID:Seizures and brain injury in neonatal rats induced by 1S,3R-ACPD, a metabotropic glutamate receptor agonist. 841 Jan 97

alpha-Amino-3-hydroxy-5-methyl-isoxazole-4-propionate/kainate (AMPA/kainate) receptor antagonists (at subthreshold doses against electroconvulsions), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466 at maximally 5 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX at maximally 20 mg/kg) enhanced the protective effects of NMDA receptor antagonists, MK-801 (dizocilpine) or 2-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene), against electroconvulsions. Similarly, MK-801 or D-CPP-ene reduced the ED50 values of both NBQX and GYKI 52466 against maximal electroshock. The adverse effects of D-CPP-ene, evaluated in the chimney and rotorod tests, were potentiated by both GYKI 52466 (2.5 mg/kg) and NBQX (10 mg/kg). Also, D-CPP-ene (0.1 mg/kg) worsened the motor performance of mice pretreated with GYKI 52466 in the rotorod test. Neither MK-801 (0.025 mg/kg) nor D-CPP-ene (0.1 mg/kg) affected the NBQX-induced impairment of motor coordination. Similarly, GYKI 52466 (2.5 mg/kg) or NBQX (10 mg/kg) did not influence the performance of mice treated with MK-801 (0.2 mg/kg). It may be concluded that the blockade of more than one subtype of glutamate receptors leads to a more pronounced anticonvulsive effect when compared with the effect of blockade of an individual receptor subtype. In some cases more efficient seizure protection was not associated with increased adverse effects.
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PMID:Influence of combined treatment with NMDA and non-NMDA receptor antagonists on electroconvulsions in mice. 852 17

5-Chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) has analgesic properties in animal models of tonic pain. To investigate the mechanisms underlying this effect we used electrical recording techniques to characterize the in vitro pharmacology of ACEA-1011 at mammalian glutamate receptors. Two preparations were used: Xenopus oocytes expressing rat brain receptors and cultured rat cortical neurons. Results showed that ACEA-1011 is a competitive antagonist at NMDA receptor glycine sites. Apparent antagonist affinities (Kb values) were 0.4 to 0.8 microM in oocytes and approximately 0.6 microM in neurons. IC50 values for ACEA-1011 against four binary subunit combinations of cloned rat NMDA receptors (NR1A/NR2A, 2B, 2C or 2D) ranged from 0.4 to 8 microM (1 microM glycine). The 20-fold variation in sensitivity was due to a combination of subunit-dependent differences in glycine and antagonist affinities; EC50 values for glycine ranged between 0.08 to 0.8 microM and Kb values for ACEA-1011 between 0.2 to 0.8 microM. In addition, ACEA-1011 inhibited AMPA-preferring non-NMDA receptors by competitive antagonism at glutamate binding sites. Kb values were 4 to 9 microM in oocytes and 9 to 10 microM in neurons. The ED50 for ACEA-1011 in a mouse maximum electroshock-induced seizure model was approximately 12 mg/kg i.v.. Our results indicate that ACEA-1011 is a systemically active broad selectivity ionotropic glutamate receptor antagonist.
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PMID:Pharmacology of 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione: a novel systemically active ionotropic glutamate receptor antagonist. 853 Oct 83

Autoantibodies to GluR3, an AMPA glutamate receptor subtype, may be a cause of chronic unilateral encephalitis (Rasmussen's syndrome). We report a woman with chronic left hemisphere encephalitis whose partial seizures, aphasia, and motor weakness are highly responsive to intermittent steroids and cyclophosphamide. Her serum and CSF were negative for antibodies to GluR3 by both immunoblot and immunocytochemical analysis of cells transfected with GluR3 cDNA, indicating that separate immune-mediated processes may be involved in some cases of chronic encephalitis.
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PMID:Chronic steroid-responsive encephalitis without autoantibodies to glutamate receptor GluR3. 855 86

We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [3H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2,3-b]pyrazinedione derivatives 4, 7-1-, 13, 15 and 16 showed some differences in comparison with those of the corresponding substituted quinoxalinediones, including 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione (1) (YM90K). The X-ray study exhibited that conformation of the 7-nitro group of 1.HCl was nearly coplanar with the quinoxaline ring, whereas the 6-imidazol-1-yl group was rotated with respect to the aromatic ring. From the glycine site on NMDA receptor binding study, it is indicated that bulkiness of 6-substituents on pyridopyrazinediones may be responsible for the selectivity against the glycine site. Among the series of azaquinoxalinediones, 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3-b]pyrazinedione (8c) exhibited a combination of the best affinity to AMPA receptors with a Ki value of 0.14 microM and selectivity against the glycine site (no affinity at 10 microM). In vivo, 8c also protected against sound-induced seizure in DBA/2 mice (minimum effective dose, 10 mg/kg ip).
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PMID:Novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonists: synthesis and structure-activity relationships of 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3-b]pyrazinedione and related compounds. 863 40

The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.
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PMID:Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. 870 33

There is a great body of evidence, that excitatory amino acid antagonists, apart from their anticonvulsive properties per se, potentiate the protective activity of conventional antiepileptics against maximal electroshock-induced seizures in mice. It is worth stressing, that combinations of valproate with either CGP 37849 (a competitive NMDA antagonist) or dizocilpine (MK-801, a non-competitive NMDA antagonist), providing a 50% protection against maximal electroshock, resulted in no adverse effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). On the other hand, valproate administered alone at its ED50, to protect against maximal electroshock, produced profound adverse effects. However, some NMDA antagonists (D-CPP-ene, memantine, procyclidine or trihexyphenidyl) did enhance the protection offered by common antiepileptics but these combined treatments were associated with considerable side-effects on motor coordination and long-term memory. Interestingly, ifenprodil (an antagonist of the polyamine site within the NMDA receptor complex) possessed some anticonvulsive activity against electroconvulsions but failed to enhance the antielectroshock efficacy of conventional antiepileptics. AMPA/KA receptor antagonists (NBQX and GYKI 52466), similarly to NMDA antagonists, potentiated the protective action of antiepileptic drugs against maximal electroshock and these combinations were generally devoid of unwanted effects.
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PMID:Excitatory amino acid antagonists and the anticonvulsive activity of conventional antiepileptic drugs. 871 57

The neural basis underlying the cognitive side effects of ECT is unknown. Recent studies suggest that the memory dysfunction may be caused by alterations in hippocampal synaptic efficacy [20]. In situ hybridisation was used to examine the possible receptor mechanisms responsible for this effect. Repeated ECS markedly increased mRNA expression for the GluR1 subunit of the AMPA receptor, but not the NMDAR1A-G subtypes of the NMDA receptor, relative to control treatments. This effect was present 24 h after the last seizure and may be responsible for the expression of the ECS-induced increase in synaptic efficacy.
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PMID:Repeated ECS induces GluR1 mRNA but not NMDAR1A-G mRNA in the rat hippocampus. 871 76

The anticonvulsant effect of 1-naphthylacetyl spermine (1-NA-Spm), an analogue of Joro spider toxin, against amygdaloid kindled seizures was studied in rats. 1-NA-Spm (10, 20 and 40 micrograms/rat) dose-dependently improved kindled seizures and shortened the afterdischarge duration 30 min after the administration. The anticonvulsant effect was observed even one day after the drug, and then gradually disappeared within 4 days. The present findings demonstrate that 1-NA-Spm acts as a potent and long-acting anticonvulsant against amygdaloid kindled seizures, and also suggest, together with the previous findings, that the calcium-permeable AMPA receptors, which are selectively antagonized by 1-NA-Spm, play a critical role in the seizure generation mechanism of amygdaloid kindling.
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PMID:Potent and long-lasting anticonvulsant effects of 1-naphthylacetyl spermine, an analogue of Joro spider toxin, against amygdaloid kindled seizures in rats. 872 May 8

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.
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PMID:[Role of excitatory amino acids in neuropathology]. 872 78


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