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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as a potent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic moieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximately phosphonic > tetrazole > mercaptoacetic > hydroxamic >> other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern for glycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distance the more AMPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacological profile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent to the reference NBQX.
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PMID:Structure-activity relationships in a series of 2(1H)-quinolones bearing different acidic function in the 3-position: 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid, a new potent and selective AMPA/kainate antagonist with neuroprotective properties. 856 8

Endogenous extracellular adenosine provides some protection against excitotoxicity in the central nervous system, but it appears to be incomplete. Potentiating the formation of extracellular adenosine that occurs when excitatory amino acid receptors are activated might provide additional protection. We studied the effects of AICAR (AICA riboside, acadesine) and of inhibitors of adenosine metabolism on the release of adenosine from rat cortical slices. AICAR had no effects on basal N-methyl-D-aspartate (NMDA)- or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA)-evoked adenosine release, but it increased kainate-evoked adenosine release 1.4-fold. This selective action of AICAR may make it useful for treating kainate receptor-mediated excitotoxicity. Inhibition of adenosine kinase with either 20 microM 5'-amino-5'-deoxyadenosine or 5'-iodotubercidin had a much greater effect on excitatory amino acid-evoked adenosine release than on basal adenosine release. Inhibition of adenosine kinase increased excitatory amino acid-evoked adenosine release 3-7-fold whereas inhibition of adenosine deaminase only increased evoked adenosine release 2-2.5-fold. Finally, 0.2 microM 5'-iodotubercidin and 200 microM 2'-deoxycoformycin caused similar increases in the basal rates of extracellular adenosine formation, but 5'-iodotubercidin produced over twice as much potentiation of the rate of NMDA-evoked adenosine formation than did 2'-deoxycoformycin. These findings suggest that adenosine kinase inhibitors may produce an event-specific potentiation of evoked adenosine formation, i.e. more effect on evoked formation than on basal formation. If so, adenosine kinase inhibitors may prove useful for preventing/treating diseases associated with excessive excitation in the brain, such as seizures, excitotoxicity and neurodegeneration.
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PMID:Potentiation of excitatory amino acid-evoked adenosine release from rat cortex by inhibitors of adenosine kinase and adenosine deaminase and by acadesine. 880 8

1. Microelectrode recording and fluorescence measurement with voltage-sensitive dyes were employed in horizontal hippocampal slices from rat to investigate responses in the dentate gyrus to molecular layer and hilar stimulation. 2. Both field potential and dye fluorescence measurement revealed that electrical stimulation of the molecular layer produced strong excitation throughout large regions of the dentate gyrus at considerable distances from the site of stimulation. 3. Treatment of slices with the excitatory amino acid receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and (+/-)-2-amino-5-phosphonovaleric acid (APV) unmasked dye fluorescence signals in the outer and middle molecular layers corresponding to action potentials in axons, presumably belonging to the perforant path. The spread of these axonal signals away from the site of stimulation was far less extensive than the spread of control signals through the same regions before blockade of excitatory synapses. Large control responses could be seen in regions distant from the stimulation site where the axonal signals were not detectable. A lack of correlation between control signals and axonal signals revealed by DNQX and APV supports the hypothesis that responses in distal regions of the molecular layer were not dependent on perforant path axons. 4. The perforant path was cut by producing a lesion in the outer two-thirds of the molecular layer. Both dye fluorescence and microelectrode recording showed that stimulation on one side of the lesion could produce signals on the same side as well as across the lesion. The lesion did not block the spread of excitation through the molecular layer. Across the lesion from the site of stimulation, negative-going field potentials were observed to peak in the inner molecular layer, which is the major field of projection of hilar mossy cells. 5. Electrical stimulation in the hilus adjacent to the granule cell layer evoked dye fluorescence responses in the molecular layer. Stimulation at this site evoked negative-going field potentials that peaked in the inner molecular layer. These signals were sensitive to excitatory amino acid receptor antagonists but not to gamma-aminobutyric acid-A (GABAA) receptor antagonists. 6. Activation of excitatory amino acid receptors in the hilus by focal application of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) elicited negative-going field potentials in the granule cell layer and depolarization of granule cells. Field potentials were blocked by tetrodotoxin (TTX), indicating that they were not caused by direct activation of receptors on granule cells, but rather by synapses from hilar neurons on granule cells. 7. These results taken together with previous studies of hilar mossy cells suggest a fundamental circuit consisting of granule cells exciting hilar mossy cells, which then excite more granule cells. This circuit provides positive feedback and can be considered a form of "recurrent excitation" unique to the dentate gyrus. The robustness of this circuit in hippocampal slices under control conditions suggest that mossy cell excitation of granule cells could play an important role in the normal activity of the hippocampus, and, when inhibition is compromised, this circuit could contribute to the generation and spread of seizures.
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PMID:Positive feedback from hilar mossy cells to granule cells in the dentate gyrus revealed by voltage-sensitive dye and microelectrode recording. 883 47

The effects of nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (NNA) on seizures induced by excitatory amino acids, bicuculline, pentylenetetrazol and pilocarpine were studied in mice. NNA (10 and 40 mg kg-1, i.p.) enhanced the susceptibility to intracerebroventricular (i.c.v.) kainate (KA) which was reflected by a decrease in its convulsant dose 50% (CD50) from 0.66 nmol to 0.38 and 0.29 nmol/mouse, respectively. Also, NNA (40 mg kg-1) increased the KA-induced mortality. Conversely, NNA (40 mg kg-1) produced an anticonvulsant effect against i.c.v. glutamate whose CD50 value was significantly elevated from 0.49 mumol to 0.84 mumol/mouse. The convulsive activity of i.c.v. N-methyl-D-aspartic acid (NDMA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) was not affected by the pretreatment with NNA (40 mg kg-1). NNA (5-40 mg kg-1) also potentiated the convulsive action of systematic KA and KA-induced mortality but (up to 40 mg kg-1) remained without effect on seizures produced by bicuculline, N-methyl-D, L-aspartic acid (NMDLA), pentylenetetrazol, and pilocarpine. Only bicuculline-produced lethality was significantly enhanced. It may be concluded that the manipulation of the NO level affects differently seizures arising from a diffuse stimulation of glutamate receptors and seizures resulting from an activation of an individual subtype of these receptors. It is noteworthy that in the majority of convulsive tests used in this study, NNA exerted no modulatory effect.
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PMID:NG-nitro-L-arginine differentially affects glutamate- or kainate-induced seizures. 890 65

Our objective was to characterize the neurotoxic actions of systemically administered domoic acid on different excitatory amino acid receptors, and to compare the receptor selectivity of domoate with the related compound kainic acid. Groups of mice were injected with various ligands selective for N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid-kainate (AMPA/kainate) receptors prior to injection of equitoxic doses of domoic acid or kainic acid. Domoic acid toxicity was not significantly altered by pretreatment with any NMDA receptor selective antagonists, with the exception of 3-(2-carboxypiperazine-4-yl)propyl-1 -phosphonic acid. Consistent with its characterization as an AMPA/kainate agonist, domoate toxicity was significantly antagonized by all non-NMDA receptor antagonists tested. Non-NMDA receptor antagonists that do not distinguish between high- and low-affinity [3H]kainic acid binding (i.e., quinoxalinediones) were equally effective at reducing domoic acid and kainic acid toxicity. However, the novel isatinoxime NS-102, which has been shown to interact selectively with low-affinity [3H]kainic acid binding sites, produced a selective dose-related antagonism of domoic acid toxicity relative to kainic acid. NS-102 produced significant reductions in overall toxicity, onset of motor seizures, and hippocampal CA3 cell damage induced by domoic acid at NS-102 doses that did not antagonize kainic acid induced toxicity. We conclude that domoic acid toxicity in vivo is mediated largely by a subclass of non-NMDA receptors that are selectively antagonized by NS-102.
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PMID:Selective reduction in domoic acid toxicity in vivo by a novel non-N-methyl-D-aspartate receptor antagonist. 896 Mar 97

Glutamate receptor-mediated excitotoxicity is linked to the activation of multiple receptors including those activated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate. In this study, the novel glutamate receptor antagonist, as its active isomer (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahyd roisoquinoline-3- carboxylic acid ((-)LY293558) and it's +/- racemate (LY215490), was examined for neuroprotectant effects against excitotoxic injury in vitro and in vivo. This agent selectively protected against AMPA and kainate injury in cultured primary rat hippocampal neurons, an in vivo rat striatal neurotoxicity model, and against agonist-evoked seizures in mice. Thus, (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydr -oisguino-line-3-carboxylic acid represents a novel receptor selective and potent systemically active AMPA/kainate receptor antagonist for exploring neuroprotection via non-NMDA receptor mechanisms.
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PMID:Selective protection against AMPA- and kainate-evoked neurotoxicity by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahyd roisoquinoline- 3-carboxylic acid (LY293558) and its racemate (LY215490). 901 84

The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the initiation and propagation of limbic motor seizures in rats was examined by the intracerebral and systemic administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline (NBQX), a selective antagonist of the AMPA subtype of glutamate receptor. Limbic motor seizures were evoked focally by the application of the gamma-aminobutyric acid receptor antagonist, bicuculline, into area tempestas, an epileptogenic site in the deep anterior piriform cortex. Before eliciting seizures, NBQX was applied focally into either 1) area tempestas or 2) perirhinal or posterior piriform cortex ipsilateral to the area tempestas from which seizures were evoked. In addition, pretreatment with i.p. NBQX was evaluated for anticonvulsant actions against area tempestas-evoked clonic or systemically evoked tonic seizures. In all conditions, a dose-dependent decrease in the severity of seizures was obtained with NBQX. With focal intracerebral administration, a dose of 500 pmol of NBQX consistently protected against limbic motor seizures, with partial protection achieved with 100 pmol. After i.p. administration, 2.5 and 5.0 mg/kg significantly protected the rats from both limbic motor seizures and tonic extensor seizures. No overt disturbance of spontaneous behavior was associated with the anticonvulsant doses of NBQX. Moreover, both forebrain substrates of limbic motor seizures and hindbrain substrates of tonic extensor seizures were highly susceptible to disruption by NBQX. The results indicate that AMPA subtype of glutamate receptors are crucial mediators of seizure propagation via perirhinal and piriform cortics.
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PMID:A crucial role of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures. 906 29

Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. 1-(4'-Aminophenyl)- (38) and 1-(3'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin- 4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED50 values against tonus evoked by auditory stimulation were 12.6 micromol/kg for derivative 38, 18.3 micromol/kg for 39, and 25.3 micromol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [3H]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.
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PMID:1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones: novel AMPA receptor antagonists. 911

Glutamate-receptor-mediated synaptic transmission was studied in morphologically identified hippocampal dentate granule cells (DGCs; n = 31) with the use of whole cell patch-clamp recording and intracellular injection of biocytin or Lucifer yellow in slices prepared from surgically removed medial temporal lobe specimens of epileptic patients (14 specimens from 14 patients). In the current-clamp recording, low-frequency stimulation of the perforant path generated depolarizing postsynaptic potentials that consisted of excitatory postsynaptic potentials and phase-inverted inhibitory postsynaptic potentials mediated by the gamma-aminobutyric acid-A (GABA(A)) receptor at a resting membrane potential of -62.7 +/- 2.0 (SE) mV. In the voltage-clamp recording, two glutamate conductances, a fast alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor-mediated excitatory postsynaptic current (EPSC; AMPA EPSC) and a slowly developing N-methyl-D-aspartate (NMDA)-receptor-mediated EPSC (NMDA EPSC), were isolated in the presence of a GABA(A) receptor antagonist. NMDA EPSCs showed a voltage-dependent increase in conductance with depolarization by exhibiting an N-shaped current-voltage relationship. The slope conductance of the NMDA EPSC ranged from 1.1 to 9.4 nS in 31 DGCs, reaching up to twice the size of the AMPA conductance. This widely varying size of the NMDA conductance resulted in the generation of double-peaked EPSCs and a nonlinear increase of the slope conductance of up to 37.5 nS with positive membrane potentials, which resembled "paroxysmal currents," in a subpopulation of the neurons. In contrast, AMPA EPSCs, which were isolated in the presence of an NMDA receptor antagonist (2-amino-5-phosphonovaleric acid), showed voltage-independent linear changes in the current-voltage relationship and were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. The AMPA conductance showed little variance, regardless of the size of the NMDA conductance of a given neuron. The average AMPA slope conductance was 5.28 +/- 0.65 (SE) nS in 31 human DGCs. This value was similar to AMPA EPSC conductances in normal rat DGCs (5.35 +/- 0.52 nS, mean +/- SE; n = 55). Dendritic morphology and spine density were quantified in the individual DGCs to assess epileptic pathology. Dendritic spine density showed an inverse correlation (r2 = 0.705) with a slower rise time and a longer half-width of the excitatory postsynaptic potentials mediated by the NMDA receptor. It is concluded that both AMPA and NMDA EPSCs contribute to human DGC synaptic transmission in epileptic hippocampus. However, a wide range of changes in the slope conductance of the NMDA EPSCs suggests that the NMDA-receptor-mediated conductance could be altered in human epileptic DGCs. These changes may influence the generation of chronic subthreshold epileptogenic synaptic activity and give rise to pathological excitation leading to epileptic seizures and dendritic pathology.
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PMID:Glutamate currents in morphologically identified human dentate granule cells in temporal lobe epilepsy. 921 80

Persistent hyperexcitability follows synchronized bursting induced in the CA3 region of hippocampal slices by perfusion with high concentrations (2000 IU/ml) of the GABAA antagonist, penicillin. This hyperexcitable state is characterized by: i) slow recovery from bursting following penicillin washout; ii) persistent "post-burst" field potential oscillations and iii) increased probability of spontaneous bursting with ordinarily sub-convulsant doses of GABAA antagonists. An N-methyl-D-aspartate-independent type of long-term potentiation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate excitatory postsynaptic potentials occurred following bursting. However, similar increases in excitatory postsynaptic potential magnitude also occurred after a subconvulsant dose of penicillin (500 IU/ml) which did not produce the other features of persistent hyperexcitability. Furthermore, long-term potentiation either increased or remained stable after bursting stopped, whereas, post-burst oscillations gradually diminished with time. Low doses of the AMPA/kainate antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, which restored the potentiated excitatory postsynaptic potentials to control levels, reduced but did not eliminate the post-burst oscillation. Tetanus-induced long-term potentiation did not reproduce the hyperexcitable state seen after bursting. These findings indicate that the epileptiform bursting caused by blocking GABAA-mediated inhibition induces long-term potentiation which is partially responsible for persistent burst-induced hyperexcitability but is not sufficient to entirely explain it. The hippocampus which is critical for normal memory is also frequently the generator of intractable epileptic seizures. Seizure-like discharges in the hippocampus induced long-lasting increases in synaptic efficacy similar to those thought to underlie normal memory. This form of long-term potentiation contributed to the network oscillations characteristics of the hyperexcitable state persisting after epileptiform activity but was not sufficient to entirely explain them. Epileptic seizures may engage normal memory mechanisms which increase neuronal excitability and predispose the hippocampal network to further seizures. This may, in part, account for the propensity for hippocampal seizure foci to become intractable.
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PMID:The role of long-term potentiation in persistent epileptiform burst-induced hyperexcitability following GABAA receptor blockade. 933 Mar 72


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