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)

Intravenous injection of N-methyl-D,L-aspartic acid (NMDLA) into mice produces characteristic convulsions followed by death. The present study was designed to determine the degree of blockade of these seizures/mortality by compounds acting at various subsites on the N-methyl-D-aspartic acid (NMDA) receptor complex (competitive and noncompetitive antagonists, as well as inhibitors of the strychnine-insensitive glycine subsite, and Zn++ subsite agonists), and also calcium channel blockers, clinically used anticonvulsants, plus selected compounds with activities or structures similar to specific agents chosen. Activity among compounds was correlated to in vitro potency regarding inhibition of binding of MK801 to the ionic channel subsite associated with the NMDA receptor. Furthermore, all compounds were examined for antiseizure properties with respect to tonic hindlimb extension elicited by maximal electroshock (MES) and clonus induced by pentylenetetrazol (PTZ). Drugs were subsequently classified according to their spectra of efficacy in these tests. The following characteristics emerged: 1) agents active at all 3 NMDA mechanisms (convulsions/mortality/MK801 binding) plus MES and PTZ, were MK801 and CPP [3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid]; 2) active at all the NMDA mechanisms and MES were ketamine and dextromethorphan; 3) active against NMDLA-induced convulsions/mortality, MES and PTZ, but not MK801 binding, were doxepin, desipramine and diazepam; 4) active against NMDLA-induced convulsions/mortality and MES were des-Me-doxepin, flunarizine and remacemide; 5) active against NMDLA-induced convulsions/mortality and PTZ was nisoldipine; 6) active against only NMDLA-induced convulsions/mortality were chlorpheniramine and iproniazid; 7) active in the MES and PTZ tests were phenobarbital, pentobarbital and valproate; 8) active in the MES test alone were phenytoin and carbamazepine; 9) active against PTZ only was ethosuximide; 10) active only in the in vitro MK801 binding assay were HA966, 7-Cl-kynurenate and AP7 (2-amino-7-phosphonoheptanoic acid); and 11) no demonstrable actions had AP4 (2-amino-4-phosphonobutyric acid) and mianserin. In conclusion, inhibition of NMDLA-induced convulsions/mortality in vivo is not necessarily correlated to a noncompetitive displacement of MK801 binding to NMDA receptor sites in vitro, nor is inhibition of NMDA-elicited convulsions/mortality correlated with a specific ability of a compound to inhibit either MES or PTZ seizures.
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PMID:Classification of compounds for prevention of NMDLA-induced seizures/mortality, or maximal electroshock and pentylenetetrazol seizures in mice and antagonism of MK801 binding in vitro. 145 42

The behavioral consequences of metabotropic glutamate receptor (mGluR) activation were investigated following intracerebral administration of the mGluR selective agonists (RS)3,5-dihydroxyphenyl-glycine (3,5-DHPG), (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD), (1R,3S)-1-aminocyclopentane-1,3-dicarboxylate (1R,3S-ACPD), L-2-amino-4-phosphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP) and (2S,3S,4S)alpha-(carboxycyclopropyl)glycine (L-CCGI) into the thalamus in mice. Injections of 3,5-DHPG, 1S,3R-ACPD and L-CCGI produced dose-dependent increases in limbic seizures with a potency order of 3,5-DHPG = 1S,3R-ACPD > L-CCGI. This effect of 1S,3R-ACPD was stereoselective, since the inactive isomer (1R,3S-ACPD) did not elicit seizure activity. Limbic seizures induced by the phosphoinositide-coupled mGluR subtype selective agonist 3,5-DHPG were attenuated by the mGluR antagonist L-2-amino-3-phosphonopropanoic acid (L-AP3) and dantrolene, inhibitors of mGluR-mediated intracellular calcium mobilization. Interestingly, L-AP4, L-SOP and low doses of L-CCGI also protected against 3,5-DHPG seizures. These data indicate that mGluR agonist-induced limbic seizures in mice are mediated by activation of phosphoinositide-coupled mGluRs. Furthermore, these seizures can be protected against by activation of mGluRs that are negatively-linked to cAMP formation.
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PMID:Induction or protection of limbic seizures in mice by mGluR subtype selective agonists. 853 55

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

1S,3R-1-Aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) and L-2-amino-4-phosphonobutyrate (L-AP4) are selective agonists of metabotropic glutamate receptors (mGluRs). 1S,3R-ACPD (200 nmol) injected into the amygdala (AM) of non-kindled rats produced immediate and transient seizures, characterized by immobility, searching, and wet-dog shakes. However, this ictal response was not observed in AM-kindled rats. Intra-AM injection of 1S,3R-ACPD (40 or 200 nmol) or L-AP4 (200 nmol) resulted in a delayed and marked suppression of kindled seizures, 3 days after 40 nmol of 1S,3R-ACPD, 1 day after 200 nmol of 1S,3R-ACPD, and from 1 to 3 days after 200 nmol of L-AP4. These and the previous findings suggest that: (1) the excitatory action of 1S,3R-ACPD in the AM, which may be mediated by the postsynaptic mGluRs, is reduced after completion of kindling; (2) 1S,3R-ACPD and L-AP4 exert anti-convulsant action in the AM, presumably by activating the presynaptic as well as postsynaptic mGluRs.
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PMID:Anticonvulsant action of metabotropic glutamate receptor agonists in kindled amygdala of rats. 892 73

Modulation of excitatory synaptic transmission by presynaptic metabotropic glutamate receptors (mGluRs) was examined in brain slices from control rats and rats with amygdala-kindled seizures. Using whole-cell voltage-clamp and current-clamp recordings, this study shows for the first time that in control and kindled basolateral amygdala neurons, two pharmacologically distinct presynaptic mGluRs mediate depression of synaptic transmission. Moreover, in kindled neurons, agonists at either group II- or group III-like mGluRs exhibit a 28- to 30-fold increase in potency and suppress synaptically evoked bursting. The group II mGluR agonist (2S,3S,4S)-2-(carboxycyclopropyl)glycine (L-CCG) dose-dependently depressed monosynaptic EPSCs evoked by stimulation in the lateral amygdala with EC50 values of 36 nM (control) and 1.2 nM (kindled neurons). The group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) was less potent, with EC50 values of 297 nM (control) and 10.8 nM (kindled neurons). The effects of L-CCG and L-AP4 were fully reversible. Neither L-CCG (0.0001-10 microM) nor L-AP4 (0.001-50 microM) caused membrane currents or changes in the current-voltage relationship. The novel mGluR antagonists (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)-glycine (MCCG; 100 microM) and (S)-2-methyl-2-amino-4-phosphonobutyrate (MAP4; 100 microM) selectively reversed the inhibition by L-CCG and L-AP4 to 81.3 +/- 12% and 65.3 +/- 6.6% of predrug, respectively. MCCG and MAP4 (100-300 microM) themselves did not significantly affect synaptic transmission. The exquisite sensitivity of agonists in the kindling model of epilepsy and the lack of evidence for endogenous receptor activation suggest that presynaptic group II- and group III-like mGluRs might be useful targets for suppression of excessive synaptic activation in neurological disorders such as epilepsy.
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PMID:Epileptogenesis in vivo enhances the sensitivity of inhibitory presynaptic metabotropic glutamate receptors in basolateral amygdala neurons in vitro. 899 53

The protective effect of amygdaloid (focally administered) doses of the presynaptic metabotropic glutamate receptor agonist, L-2-amino-4-phosphonobutyrate (L-AP4) was tested on the development of electrical kindling and in fully kindled animals. L-AP4 inhibited epileptogenesis at 10 nmol in 0.5 microl buffer, by preventing the increase in both seizure score and afterdischarge duration. The effects were reversible after withdrawal of the drug, with all treated animals subsequently progressing to the fully kindled state at the same rate as control animals. The same concentration of the drug was also effective when injected into fully kindled animals. It significantly decreased the mean seizure score by 88% (P < 0.005) and increased the mean generalized seizure threshold (GST) by 85% (P < 0.005). The increase in GST was accompanied by a significant delay before the onset of generalized seizure and by a 37% reduction in generalized seizure duration. MPPG ((RS)-alpha-methyl-4-phosphonophenyl glycine) a selective antagonist of L-AP4 at glutamate pre-synaptic receptors inhibited the depressant effect of L-AP4 in a dose-dependent manner. MPPG (10 nmol) inhibited the antiseizure activity of L-AP4, whilst MPPG (40 nmol) reduced both the anti-epileptogenic and antiseizure activities of L-AP4. MPPG (40 nmol) by itself had no effect on generalized seizure activity, and it had no detectable influence on the normal rate of kindled epileptogenesis. During in vitro studies using a microsuperfusion method, L-AP4 inhibited depolarization-induced release of [3H]D-aspartate from rat cortical synaptosomes (IC50 125.1 microM) and decreased the depolarization-evoked uptake of 45Ca2+ in a dose-dependent manner. Both actions of L-AP4 were reduced by the selective antagonist MPPG. When applied alone MPPG (200 microM) had no detectable action on veratridine-evoked 45Ca2+ uptake by the synaptosomes. These results suggest the mechanisms by which presynaptically active glutamate receptor agonists block the development of the chronically epileptic state induced by electrical kindling, and indicate that their anticonvulsive activity is due to inhibition of presynaptic glutamate and/or aspartate release following blockade of presynaptic Ca2+ entry.
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PMID:Anti-epileptogenic and anticonvulsant activity of L-2-amino-4-phosphonobutyrate, a presynaptic glutamate receptor agonist. 917 88

Long-lasting modifications of synaptic transmission can be induced in the amygdala by electrical stimulation as done in the long-term potentiation (LTP) model of learning and memory and the kindling model of epilepsy. The present study reports for the first time a long-lasting potentiation (LLP) of synaptic transmission that is induced pharmacologically by the activation of group III metabotropic glutamate receptors (mGluRs) in basolateral amygdala (BLA) neurons. In whole cell voltage-clamp mode, BLA neurons were recorded in brain slices from control rats and rats with amygdala-kindled seizures. The group III mGluR agonist -2-amino-4-phosphonobutyrate (-AP4, 10 microM) induced LLP of monosynaptic excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation in the lateral amygdala (maximum 258 +/- 50% of predrug control; means +/- SE) in control (n = 7) but not in kindled neurons(n = 6). LLP was measured 15 min after the superfusion of -AP4, lasted for >45 min, and was not accompanied by postsynaptic membrane changes. -AP4 induced LLP was prevented by the group III mGluR antagonist (S)-2-methyl-2-amino-4-phosphonobutyrate (MAP4; 100 microM, n = 6) but not the group II mGluR antagonist (2S, 3S,4S)-2-methyl-2-carboxycyclopropylglycine (MCCG; 100 microM, n = 3). LLP was not observed after superfusion of the group II mGluR agonist (2S,3S,4S)-2-(carboxycyclopropyl)glycine (-CCG; 1.0 and 10 microM) in either control (n = 13) or kindled (n = 10) neurons. If the underlying mechanisms and the functional significance of pharmacologically induced LLP are similar to those of LTP, the loss of -AP4 induced LLP in kindled neurons may be a neurobiological correlate of learning and memory deficits in kindled animals and long-term alterations of brain functions in patients with epilepsies.
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PMID:Loss of long-lasting potentiation mediated by group III mGluRs in amygdala neurons in kindling-induced epileptogenesis. 940 64

Metabotropic glutamate receptors (mGluRs) provide a powerful control of synaptic transmission in the hippocampus and may serve as a target for drug development in human temporal lobe epilepsies. Agonists and antagonists at these receptors influence the development and propagation of seizures in some animal models of epilepsy. Experimental seizures can change the level of expression of mGluRs in the rat hippocampus. In the human dentate gyrus of patients suffering from temporal lobe epilepsy (TLE), group III mGluR mediated inhibition of synaptic transmission is almost lost in the sub-group with Ammon's horn sclerosis. We tested the modulation of synaptic transmission by the group III mGluR specific agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) in the dentate gyrus outer molecular layer in control and amygdala-kindled rats, a common model for TLE. Extracellular field potential recordings upon subthreshold stimulation of lateral perforant path fibers were measured simultaneously in the outer molecular layer and granule cell layer. Analysis of 'paired-pulse' characteristics in the absence and presence of L-AP4 and group III mGluR mediated inhibition of synaptic transmission in the lateral perforant path revealed no significant alterations in fully kindled rats. Since there is no evidence of altered L-AP4 responses, a loss of group III mGluR function, particularly that of subtype mGluR8, seems not necessary for the kindling epilepsy.
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PMID:Analysing metabotropic glutamate group III receptor mediated modulation of synaptic transmission in the amygdala-kindled dentate gyrus of the rat. 1006 95

The effect of intra-accumbens infusion of selective group I ((S)-3,5-dihydroxyphenylglycine, DHPG), group II ((2S,3S,4S)-CCG/(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine, L-CCG-I) and group III ((L-(+)-2-amino-4-phosphonobutyric acid, L-AP4) metabotropic glutamate (mGlu) receptor agonists was studied in male Wistar rats. A computerised electroencephalographic (EEG) power spectral analysis was performed. While DHPG (400 nmoles) induced EEG and behavioural limbic seizures, L-CCG-I (400 nmoles) and L-AP4 (800 nmoles) induced a 'depressant' EEG with an increase in relative power in the slow-frequency bands and a decrease in relative power in the high-frequency bands) and behavioural effects. These results show for the first time that the stimulation of groups I, II and III mGlu receptors located in the nucleus accumbens significantly influences the EEG tracing in rats.
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PMID:Selective agonists of metabotropic glutamate receptors elicit significant EEG effects when infused in the nucleus accumbens of rats. 1007 91

To clarify the contribution of metabotropic glutamate (mGlu) receptors in brain to benzodiazepine withdrawal signs, we now examine the effects in mice of selective ligands for three subgroups of mGlu receptor on the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. The seizure threshold for pentylenetetrazole was significantly decreased by the discontinuation of chronic diazepam treatment. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was significantly suppressed by intracerebroventricular (i.c.v.) pretreatment with the group 1 mGlu receptor antagonist, (S)-4-carboxyphenylglycine ((S)-4CPG: 56 and 100 nmol). These doses of (S)-4CPG did not alter the seizure threshold in chronically vehicle-treated (control) mice. Pretreatment i.c.v. with a presynaptic mGlu receptor agonist (the group 2 mGlu receptor agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)-glycine (L-CCG-I: 3.0 and 5.6 nmol) and the group 3 mGlu receptor agonist, L-amino-4-phosphonobutyric acid (L-AP4: 3.0 and 5.6 nmol)) failed to suppress the decrease in seizure threshold in diazepam-withdrawn mice, but increased the seizure threshold in control mice. Pretreatment i.c.v. with the group 1 mGlu receptor antagonist/group 2 mGlu receptor agonist, (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG: 56 and 100 nmol), significantly increased the seizure threshold in control mice and suppressed the decrease in seizure threshold in diazepam-withdrawn mice. These findings suggest that enhancement of group 1 mGlu receptor function and a decline in both group 2 and group 3 mGlu receptor functions may play an important role in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal.
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PMID:Role of metabotropic glutamate receptors in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. 1020 74


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