Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A comparative study of the expression of metabotropic glutamate receptor 2/3 (mGluR2/3) was done in the hippocampus of rats and mice after pilocarpine-induced status epilepticus (APISE), and of patients with mesial temporal lobe epilepsy. At 1 day APISE, there was a marked increase in mGluR2/3 immunoreactivity in the stratum lacunosum moleculare (SLM) of CA1 area and in the middle one-third of the molecular layer (MM) of the dentate gyrus. Immuno-electron microscopic study showed degenerating mGluR2/3 positive axons in the SLM of CA1 area at 1 day APISE. From 7 days, mGluR2/3 immunopositive product decreased, and by 31 days APISE, it almost disappeared in two-thirds of the SLM near CA2. In the mouse model at 2 months APISE, mGluR2/3 immunopositive product in two-thirds of the SLM near the stratum radiatum disappeared, and so did in the whole SLM of CA1 area in patients with mesial temporal lobe epilepsy. Neuropharmacological study by intravenous injection of mGluR2/3 agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC] at different doses at 1h during pilocarpine induced status epilepticus showed that (2R,4R)-APDC could not stop seizures and neuronal death in the hilus of the dentate gyrus. The present study, therefore, suggests that the reduction of mGluR2/3 immunopositive product in the SLM of CA1 is a consequence of neuronal loss in either the entorhinal cortex or CA1 area of the hippocampus, and at the dosage range from 12.5 to 600 mg/kg, (2R,4R)-APDC may not be effective in the prevention of seizures or neuronal death in the hilus of the dentate gyrus.
 ...
PMID:Metabotropic glutamate receptor 2/3 in the hippocampus of patients with mesial temporal lobe epilepsy, and of rats and mice after pilocarpine-induced status epilepticus. 1524 18

Epilepsy is a chronic neurological disorder that has many known types, including generalized epilepsies that involve cortical and subcortical structures. A proportion of patients have seizures that are resistant to traditional anti-epilepsy drugs, which mainly target ion channels or postsynaptic receptors. This resistance to conventional therapies makes it important to identify novel targets for the treatment of epilepsy. Given the involvement of the neurotransmitter glutamate in the etiology of epilepsy, targets that control glutamatergic neurotransmission are of special interest. The metabotropic glutamate receptors (mGluRs) are of a family of eight G-protein-coupled receptors that serve unique regulatory functions at synapses that use the neurotransmitter glutamate. Their distribution within the central nervous system provides a platform for both presynaptic control of glutamate release, as well as postsynaptic control of neuronal responses to glutamate. In recent years, substantial efforts have been made towards developing selective agonists and antagonists which may be useful for targeting specific receptor subtypes in an attempt to harness the therapeutic potential of these receptors. We examine the possibility of intervening at these receptors by considering the specific example of absence seizures, a form of generalized, non-convulsive seizure that involves the thalamus. Views of the etiology of absence seizures have evolved over time from the "centrencephalic" concept of a diffuse subcortical pacemaker toward the "cortical focus" theory in which cortical hyperexcitability leads the thalamus into the 3-4 Hz rhythms that are characteristic of absence seizures. Since the cortex communicates with the thalamus via a massive glutamatergic projection, ionotropic glutamate receptor (iGluR) blockade has held promise, but the global nature of iGluR intervention has precluded the clinical effectiveness of drugs that block iGluRs. In contrast, mGluRs, because they modulate iGluRs at glutamatergic synapses only under certain conditions, may quell seizure activity by selectively reducing hyperactive glutamatergic synaptic communication within the cortex and thalamus without significantly affecting normal response rates. In this article, we review the circuitry and events leading to absence seizure generation within the corticothalamic network, we present a comprehensive review of the synaptic location and function of mGluRs within the thalamus and cerebral cortex, and review the current knowledge of mGluR modulation and seizure generation. We conclude by reviewing the potential advantages of Group II mGluRs, specifically mGluR2, in the treatment of both convulsive and non-convulsive seizures.
 ...
PMID:Metabotropic glutamate receptors as a strategic target for the treatment of epilepsy. 1678 41

The effects of repeated neonatal seizures on metabotropic glutamate receptors (mGluRs) during critical periods of brain development are unknown. Therefore, we characterized the expression of Group I (mGluR1 and mGluR5) and Group II (mGluR2/3) metabotropic glutamate receptor proteins in the developing limbic system in response to a varied neonatal seizure history. Status epilepticus was induced with kainic acid (KA) either once (1x KA) on postnatal (P) day (P13), twice (2x KA) on P6 and P9 or P13, or three times (3x KA) on P6, P9, and P13. In control hippocampus, mGluR1alpha protein expression differed at all stages of development examined, whereas mGluR2/3 and mGluR5 protein expression patterns were mature by P15. After KA-induced status epilepticus, there was a significant elevation in mGluR1alpha protein expression within a select group of inhibitory interneurons of the CA1 stratum oriens-alveus that was enhanced with increasing number of neonatal seizures. mGluR2/3 and mGluR5 subtypes were unchanged. Increases were also observed within neurons of the amygdala and piriform cortex. Selective increases of mGluR1alpha subtypes within limbic structures may contribute to the resistance and tolerance of the immature hippocampus from damage. This may occur by excessive stimulation of excitatory synapses to collectively enhance the inhibitory drive of the immature brain by increasing GABA release. Data suggest that the mGluR1alpha subtype plays an important role in regulating hippocampal network activity after early-life seizures.
 ...
PMID:Distinct regulation of metabotropic glutamate receptor (mGluR1 alpha) in the developing limbic system following multiple early-life seizures. 1687 Jan 74

Metabotropic glutamate receptors (mGluR) play a role in synaptic transmission, neuronal modulation and plasticity but their action in epileptic activity is still controversial. On the other hand adenosine acts as a neuromodulator with endogenous anticonvulsive properties. Since cerebellum from epileptic patients has shown neuronal damage, sometimes associated with Purkinje cells loss, we have explored the effect of repetitive seizures on two types of mGluR in the cerebellum. Seizures were induced by the convulsant drug 3-mercaptopropionic acid (MP) and the effect of the adenosine analogue cyclopentyladenosine (CPA) alone or before MP administration (CPA+MP) were also evaluated. The expression of the receptors subtypes 2/3 (mGluR2/3) and 4a (mGluR4a) was assessed by immunocitochemistry. Granular cell layer was labeled with mGluR2/3 antibody and increased immunoreactivity was observed after MP (60%), CPA (53%) and CPA + MP (85%) treatments. Control cerebellum slices showed mGluR4a reactivity around Purkinje cells, while MP, CPA and CPA+MP treatment decreased this immunostaining. Repetitive administration of MP and CPA induces an increased cerebellar mGluR2/3 and a decreased mGluR4a immunostaining, suggesting a distinct participation of both receptors that may be related to the type of cell involved. A protective action and /or an apoptotic effect may not be discarded. CPA repetitive administration although increase seizure latency, cannot prevent seizure activity.
 ...
PMID:Differential expression of cerebellar metabotropic glutamate receptors mGLUR2/3 and mGLUR4a after the administration of a convulsant drug and the adenosine analogue cyclopentyladenosine. 1740 70

In alcoholic patients, ethanol is often consumed in a repeated cyclic pattern of intoxication followed by abstinence and the emergence of withdrawal symptoms. Repeated cycles of ethanol intoxication and withdrawal lead to a sensitization of central nervous system hyperexcitability as a result of an imbalance between inhibitory GABAergic transmission and excitatory glutamatergic transmission. Symptoms of alcohol withdrawal are usually treated pharmacologically with either benzodiazepines or anticonvulsant medications. However, recent evidence suggests that inhibition of glutamate transmission by stimulation of presynaptic inhibitory metabotropic glutamate receptors (i.e., mGluR2/3 receptors) or inhibition of mGluR5 receptors produces anticonvulsant effects. Therefore, the present study was designed to determine the effects the mGluR2/3 agonist LY379268 and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on ethanol withdrawal-induced seizure activity. Adult male C3H/He mice received chronic 16 h of ethanol vapor exposure in inhalation chambers followed by 8 h of withdrawal daily for 4 consecutive days. During the final (fourth) withdrawal cycle, mice were evaluated hourly for handling-induced convulsions (HIC), and were treated with vehicle, LY379268 (0.3, 1, and 3mg/kg) or MPEP (1, 3, and 10mg/kg) treatment at 4 and 8h into withdrawal. Significant reductions in overall HIC activity were not observed following administration of either compound. These results suggest that inhibition of glutamate transmission by mGluR2/3 agonists or mGluR5 antagonists does not alter HIC activity during withdrawal from repeated ethanol exposure, and as such these compounds may have limited usefulness in the treatment of central nervous system hyperexcitability during alcohol withdrawal.
 ...
PMID:Effects of the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on handling-induced convulsions during ethanol withdrawal in mice. 1842 Jan 13

In order to shorten the list of candidate drugs with anticonvulsant potential against nerve agents, critical subreceptors in seizure controlling brain regions should be specified. Epileptiform activity does not spread randomly throughout the brain, but appears to be generated and propagated by specific anatomical routes. Nerve agents evoke seizure activity in the forebrain that progresses to the hind brain resulting in tonic-clonic convulsions. In some recent studies, it was shown that lesion of the area tempestas (AT), medial septum (MS), perirhinal cortex (PRC), or posterior piriform cortex (PPC) produces anticonvulsant effects (prevention of convulsions or delayed onset of convulsions) in rats exposed to soman, whereas damage to nucleus accumbens, nucleus basalis magnocellularis, amygdala, hippocampus, or entorhinal cortex does not cause anticonvulsant impact. These results are in compliance with findings that seizures can be generated in AT, MS, PRC, and PPC by means of nerve agents, chemoconvulsants, or kindling. Results from microinfusion studies show that anticonvulsant efficacy is obtained by GABA(A) modulators or cholinergic antagonists (M1-M5) in AT, cholinergic antagonists (M1-M5) in MS, combined glutamatergic (NMDA) and cholinergic antagonist (M1-M4), AMPA antagonist, or modulators of metabotropic glutamate receptors (mGluR5, mGluR2/3) in PRC, and cholinergic antagonist (M1-M5) or GABA(A) agonist in PPC. Calculation of impact factors for the most potent drugs (percentage of positive effects in the seizure controlling sites) showed that scopolamine and procyclidine were ranking highest (75) followed by muscimol (50), NBQX (33), and caramiphen (33). Potential strategies for prophylactic and post-exposure treatments are discussed.
 ...
PMID:Identification of neuronal target areas for nerve agents and specification of receptors for pharmacological treatment. 2062 20

Current treatment of nerve agent poisoning with ionotropic drugs proves inadequate, and alternative treatment strategies are searched for. Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride), a metabotropic glutamate receptor 5 antagonist, and DCG-IV ((2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine), a metabotropic glutamate receptor 2/3 agonist, when administered systemically in combinations with HI-6 (1-[([4-(aminocarbonyl)pyridino]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) and procyclidine or HI-6 and levetiracetam relative to the combination of HI-6, procyclidine, and levetiracetam. The results showed that MPEP or DCG-IV combined with HI-6 and procyclidine resulted in substantial antidotal efficacy when administered 20 min after onset of seizures elicited by soman. MPEP or DCG-IV combined with HI-6 and levetiracetam did not terminate seizures and preserve lives. When given 20 min before challenge with soman, DCG-IV in combination with HI-6 and procyclidine provided protection, whereas MPEP combined with HI-6 and procyclidine did not. Combinations with metabotropic glutamate receptor modulators did not achieve the same high level of antidotal efficacy as the combination of HI-6, procyclidine, and levetiracetam. MPEP alone inhibited pseudocholinesterase activity in the brain markedly. A positive correlation was found between latency to seizure onset or full protection and level of pseudocholinesterase activity in brain. MPEP and DCG-IV can serve as effective anticonvulsants against nerve agent poisoning when combined with HI-6 and procyclidine. Metabotropic glutamate receptor modulators may represent an alternative or supplement to treatment with ionotropic drugs.
 ...
PMID:Capacities of metabotropic glutamate modulators in counteracting soman-induced seizures in rats. 2402 36

Novel treatments for epilepsy are necessary because many epilepsy patients are resistant to medication. Metabotropic glutamate receptors (mGluRs), specifically mGluR 2 and 3, may serve as antiepileptic drug targets because of their role in controlling synaptic release. In this study, we administered a Group 2 mGluR agonist, LY379268, one of two mGluR2-specific positive allosteric modulators, BINA or CBiPES, or a cocktail of both BINA and LY379268 in a series of experiments using the pilocarpine model of SE. In one study, groups received treatments 15 min prior to pilocarpine, while in a second study groups received treatments after SE had been initiated to determine whether the drugs could reduce development and progression of SE. We measured bouts of stage 5 seizures, latency to the first seizure, and the maximum Racine score to characterize the seizure severity. We analyzed mouse EEG with implanted electrodes using a power analysis. We found that pretreatment and posttreatment with LY379268 was effective at reducing both behavioral correlates and power in EEG bandwidths associated with seizure, while CBiPES was less effective and BINA was ineffective. These data generally support continued development of mGluR2 pharmacology for novel antiepileptic drugs, though further study with additional drugs and concentrations will be necessary.
 ...
PMID:Activation of group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus. 2430


<< Previous 1 2