Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been postulated, consistent with the ubiquitous presence of glutamatergic neurons in the brain, that defects in glutamatergic neurotransmission are associated with many human neurological and psychiatric disorders. This review evaluates the possible application of ligands acting on glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate (KA) receptors to minimise the pathology and/or symptoms of various diseases. Glutamate activation of AMPA receptors is thought to mediate most fast synaptic neurotransmission in the brain, while transmission via KA receptors contributes only a minor component. Variants of the protein subunits forming these receptors greatly extend the pharmacological and electrophysiological properties of AMPA/KA receptors. Disease and drug use can differentially affect the expression of the subunits and their variants. Ligands bind to AMPA receptors by competing with glutamate at the glutamate binding site, or non-competitively at other sites on the proteins (allosteric modulators). Ligands showing selective competitive antagonist actions at the AMPA/ KA class of glutamate receptors were first reported in 1988, and the systemically active antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX) was first shown to have useful therapeutic effects on animal models of neurological diseases in 1990. Since then, newer antagonists with increased potency, higher specificity, increased water solubility, and a longer duration of action in vivo have been developed. Negative allosteric modulators such as the prototype GYKI-52466 also block AMPA receptors but have little action at KA receptors. Positive allosteric modulators enhance glutamatergic neurotransmission at AMPA receptors. Polyamines and adamantane derivatives bind within the ion channel of calcium-permeable AMPA receptors. The latest developments include ligands selective for KA receptors containing Glu-R5 subunits. Evidence for advantages of AMPA receptor antagonists over N-methyl-D-aspartate (NMDA) receptor antagonists for symptomatic treatment of neurological and psychiatric conditions, and for minimising neuronal loss occurring after acute neurological diseases, such as physical trauma, ischaemia or status epilepticus, have been shown in animal models. However, as yet AMPA receptor antagonists have not been shown to be effective in clinical trials. On the other hand, a limited number of clinical trials have been reported for AMPA receptor ligands that enhance glutamatergic neurotransmission by extending the ion channel opening time (positive allosteric modulators). These acute studies demonstrate enhanced memory capability in both young and aged humans, without any apparent serious adverse effects. The use of these allosteric modulators as antipsychotic drugs is also possible. However, the long term use of both direct agonists and positive allosteric modulators must be approached with considerable caution because of potential adverse effects.
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PMID:Pharmacology of AMPA/kainate receptor ligands and their therapeutic potential in neurological and psychiatric disorders. 1071 99

We obtained a neurotoxic fraction (AcTx) from star fruit (Averrhoa carambola) and studied its effects on GABAergic and glutamatergic transmission systems. AcTx had no effect on GABA/glutamate uptake or release, or on glutamate binding. However, it specifically inhibited GABA binding in a concentration-dependent manner (IC(50)=0.89muM). Video-electroencephalogram recordings demonstrated that following cortical administration of AcTx, animals showed behavioral changes, including tonic-clonic seizures, evolving into status epilepticus, accompanied by cortical epileptiform activity. Chemical characterization of AcTx showed that this compound is a nonproteic molecule with a molecular weight less than 500, differing from oxalic acid. This neurotoxic fraction of star fruit may be considered a new tool for neurochemical and neuroethological research.
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PMID:Convulsant activity and neurochemical alterations induced by a fraction obtained from fruit Averrhoa carambola (Oxalidaceae: Geraniales). 1584 46

Venoms of spiders and wasps are well recognized to present high affinity to the central nervous tissue of many mammalian species. Here we describe the effects of direct exposure of rat (Rattus norvegicus) brains to the crude and denatured venom of the Brazilian social wasp Polybia ignobilis. Lower doses of crude venom injected via intracerebroventricular (i.c.v.) inhibited the exploratory activity of animals, while higher doses provoked severe generalized tonic-clonic seizures, with hind limb extension. The status epilepticus lasted for few minutes leading the animals to respiratory depression and death. In contrast, the denatured venom was anticonvulsant against acute seizures induced by the i.c.v. injection of bicuculline, picrotoxin and kainic acid, but it was ineffective against seizures caused by systemic pentylenetetrazole. Moreover, the [3H]-glutamate binding in membranes from rat brain cortex was inhibited by the denatured venom in lower concentrations than the [3H]-GABA binding. The denatured venom contains free GABA and glutamate (34 and 802 pg/microg of venom, respectively), but they are not the major binding inhibitors. These interactions of venom components with GABA and glutamate receptors could be responsible for the anticonvulsant effects introducing the venom from P. ignobilis as a potential pharmacological source of anticonvulsant drugs.
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PMID:Anticonvulsant effects of the wasp Polybia ignobilis venom on chemically induced seizures and action on GABA and glutamate receptors. 1595 69

Several evidences have pointed to biochemical alterations in some brain structures after experimental Status Epilepticus (SE). Thus, the effects of pilocarpine-induced SE on the glutamate binding in the hippocampus and cortex of Wistar rats were evaluated. Groups of animals were submitted to a 3h SE induced by intrahippocampal microinjection of pilocarpine, which was interrupted by the administration of sodium thiopental. Two weeks later the animals were sacrificed and had their cerebral cortices and hippocampi removed in order to perform the binding experiments. The results show that the pilocarpine-induced SE provoked an increase in 2.5-fold in the B(max) values for glutamate binding in the cortex, but not in the hippocampus. Moreover, we observed a 4-fold increase for the Kd values in the hippocampus and a 2-fold increase in the cortex. These findings might indicate that the epileptogenesis involves alterations in the glutamate receptors that are not restricted to the limbic system. Moreover, changes in these receptors are not exclusively of number, but rather involve the affinity for their ligands.
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PMID:Glutamate binding is altered in hippocampus and cortex of Wistar rats after pilocarpine-induced Status Epilepticus. 1770 90