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)

Based on the phenomenon of the abnormally increased transport of brain excitatory amino acids induced by the increased release of dopamine (DA) in the brain, the effects of intraperitoneal L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC), a non-selective excitatory amino acid transporter (EAAT) inhibitor, and (+/-)-threo-3-methylglutamic acid (MG), a specific EAAT2 inhibitor, were examined against methamphetamine (MA) and cocaine (COC) toxicity in mice. The MA (5 mg/kg)-increased activity counts, which included counts of both ambulatory and stereotyped behaviors, were attenuated by 10 and 20 mg/kg of PDC, but the COC (40 mg/kg)-increased activity counts were attenuated only by 20 mg/kg PDC. PDC (20 mg/kg) significantly attenuated both the mortality rate and the seizure score in acute MA (18 mg/kg) toxicity, but attenuated only the seizure score in acute COC (75 mg/kg) toxicity. PDC and MG (repeated doses of 5 and 10 mg/kg) attenuated the mortality rate (significant attenuation in the PDC group) and seizure score against repeated MA (12 mg/kg) toxicity, but had no effect on repeated COC (60 mg/kg) toxicity. Furthermore, MA (5 mg/kg) and COC (40 mg/kg) induced stressor-like and anxiogenic effects, the former of which were attenuated by PDC only (10 and 20 mg/kg in the MA group and 20 mg/kg in the COC group), and the latter of which were attenuated by both PDC and MG (for both drugs, 10 and 20 mg/kg in the MA group and 20 mg/kg in the COC group). Therefore, it was concluded that not only EAAT2 but also the other EAATs contributed to the occurrence of the MA-induced effects and part of the COC-induced effects, and that a non-selective EAAT inhibitor notably blocked the behavioral effects accompanying the MA-induced over-release of DA.
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PMID:Brain excitatory amino acid transporters (EAATs) and treatment of methamphetamine toxicity. 1475 Mar 60

Epileptic seizures can occur as a result of mitochondrial dysfunction. Mitochondria have vital functions such as energy generation, control of cell death, neurotransmitter synthesis, and free radical production. Which of these critical mitochondrial functions contributes to epileptic seizures is unknown. We demonstrate here that a subset of mice with partial deficiency of the mitochondrial superoxide dismutase (Sod2(-/+)) show increased incidence of spontaneous and handling-induced seizures that correlates with chronic mitochondrial oxidative stress (increased aconitase inactivation and 8-hydroxy-2'-deoxyguanosine formation in mitochondria) and diminished mitochondrial oxygen utilization. Before the age at which spontaneous seizures appear in a subset of the mice, Sod2(-/+) mice demonstrated increased susceptibility to behavioral seizures, mitochondrial aconitase inactivation, and neurodegeneration induced by the administration of kainate. These data suggest that chronic mitochondrial oxidative stress initiated by superoxide (O(2)(.-)) radicals is sufficient to increase seizure susceptibility due to aging, environmental stimulation, or excitotoxin administration. Sod2(-/+) mice showed an age-related decrease in the expression of glial glutamate transporters (GLT-1 and GLAST), suggesting that oxidant-induced inhibition of glutamate transport may play a mechanistic role in rendering some Sod2(-/+) mice susceptible to seizures. In summary, mitochondrial oxidative stress and resultant dysfunction may be an important mechanism underlying certain seizure disorders.
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PMID:Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(-/+) mice. 1498 Jun 99

To assess the molecular effects of the antiepileptic drug clobazam (CLB, 1,5-benzodiazepine), a benzodiazepine effective in the management of epilepsy, we performed a series of experiments using rats with chronic, spontaneous recurrent seizures induced by amygdalar injection of FeCl(3). Experimental animals were treated for 14 days with CLB. We then measured the expression of glutamate and GABA transporter proteins and evaluated the changes that occurred in these proteins using both experimental and control animals. CLB treatment was associated with an increase in the production of GLT-1 in the contra-lateral hippocampus of animals receiving amygdalar FeCl(3) and CLB treatment. CLB treatment up-regulated the GABA transporter GAT3 in the contra-lateral hippocampus of animals with chronic, recurrent seizures. In contrast, CLB had no effect on the expression of EAAC1 and GAT1 in the hippocampus or the cortex in control animal groups. Chronic epileptogenesis may be associated with down-regulation of the production of glial excitatory amino acid transporters, GLAST and GLT-1, proteins that cause increase in the basal extracellular concentrations of glutamate. Elevated GABA transporter expression results in increased reverse transport of GABA to the extracellular space during periods of excitation. In addition to allosteric activation of GABA(A) receptors, this study suggests that CLB might exhibit its antiepileptic action by increasing GLT-1 expression and GAT3 in the hippocampus of rats with chronic seizures.
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PMID:Molecular regulation of glutamate and GABA transporter proteins by clobazam during epileptogenesis in Fe(+++)-induced epileptic rats. 1627 41

Intracerebral microdialysis combined with electroencephalographic recordings was performed on 4 dogs of a familial idiopathic epileptic Shetland sheepdog colony to identify the kinds of neurotransmitters responsible for seizure activity. Immunohistochemistry using glutamate (Glu), glutamate transporter (GLT-1 and GLAST), and glutamine synthetase (GS) antibodies was also carried out on the cerebrum of four familial dogs that died of status epilepticus (SE). High values for extracellular levels of Glu and aspartate (ASP) were detected in association with an increased number of spikes and sharp waves during hyperventilation in 3 of 4 the familial epileptic dogs. The values of other amino acids analyzed were not altered in any of the familial epileptic dogs. Immunohistochemically, Glu-positive granules were occasionally found in the perineuronal spaces of the cerebral cortex in 3 of the familial epileptic dogs that died of SE. Immunostains for GLT-1 antibody predominantly decreased in the cerebral cortex and lateral nucleus of the thalamus in all the dogs that died of SE, whereas there were no differences detected in immunolabellings for GLAST and GS antibodies between familial epileptic dogs and controls. These results suggest that an extracellular release of both Glu and Asp may play an important role in the occurrence of seizure activity in this epileptic colony, and that a decreased expression of astrocytic GLT-1 may be related to development of SE.
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PMID:Changes in extracellular neurotransmitters in the cerebrum of familial idiopathic epileptic shetland sheepdogs using an intracerebral microdialysis technique and immunohistochemical study for glutamate metabolism. 1632 23

Temporal lobe epilepsy (TLE) with hippocampal sclerosis is associated with high extracellular glutamate levels, which could trigger seizures. Down-regulation of glial glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) in sclerotic hippocampi may account for such increases. Their distribution was compared immunohistochemically in non-sclerotic and sclerotic hippocampi and localized only in astrocytes, with weaker immunoreactivity for both transporters in areas associated with pronounced neuronal loss, especially in CA1, but no decrease or even an increase in areas with less neuronal loss, like CA2 and the subiculum in the sclerotic group. Such compensatory changes in immunoreactivity may account for the lack of differences between the groups in immunoblot studies as blots show the average concentrations in the samples. These data suggest that differences in glial glutamate transporter distribution between the two groups of hippocampi may be an insufficient explanation for the high levels of extracellular glutamate in sclerotic seizure foci observed through in vivo dialysis studies.
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PMID:Changes in glial glutamate transporters in human epileptogenic hippocampus: inadequate explanation for high extracellular glutamate during seizures. 1711 31

Seizures are relatively common in the first weeks of life and can have lasting effects on brain development due to glutamate excitotoxicity. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake in the brain and mice with this gene deleted die from seizures. Therefore, we reasoned that developmental changes in the expression of EAAT2 might correlate with the period of increased susceptibility to seizures in humans, reflecting a changing vulnerability to excitotoxic insults. Expression levels of eight splice forms of EAAT2 were measured using quantitative RT-PCR from human prefrontal cortex and hippocampus at 1-2 months, 1-2 years, 8 years, 15-16 years, and 18-22 years of age. There was a significant increase in expression of most isoforms between 1-2 months and 1-2 years with isoform-specific patterns after that period. The increase in EAAT2 expression during the first 2 years of life corresponds to a period of maximal synapse formation and other changes in the glutamatergic system such as increased NMDA receptor expression. Moreover, the low expression of EAAT2 in the first months of life corresponds to the period of maximum susceptibility to seizures.
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PMID:Early rapid rise in EAAT2 expression follows the period of maximal seizure susceptibility in human brain. 1712

Excessive glutamatergic neurotransmission is considered an underlying factor of epilepsy. Energy-dependent glutamate transporters clear extracellular glutamate to limit neuronal excitability. Evidence suggests that reduced expression and/or activity of glutamate transporters contribute to hyperexcitability and progressive seizure activity in rats. By comparison, treatment with the anticonvulsant ketogenic diet (KD) results in increased mRNA expression of the neuronal glutamate transporter EAAC1, elevated energy reserves, and an increased resistance to seizures in rats. The goal of the current study was to determine whether the expression and/or re-uptake activity of glutamate transporters were elevated in hippocampal tissue of rats after KD treatment. Rats were fed either a ketogenic- or control diet for 4-5 weeks. Western blot analysis showed that protein levels of EAAC1, GLT-1 and GLAST glutamate transporters were not changed in hippocampus, cerebral cortex, or cerebellum after KD. Electron microscopic evidence indicated that the KD did not affect hippocampal EAAC1 distribution. In addition, the re-uptake activity of (3)H-glutamate into hippocampal proteoliposomes was similar in both KD and control tissue extracts. These multiple studies suggest that the anticonvulsant nature of the KD does not stem from enhanced glutamate re-uptake.
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PMID:Evidence against enhanced glutamate transport in the anticonvulsant mechanism of the ketogenic diet. 1741 86

We used western blotting to measure the quantity of glutamate and gamma-aminobutyric acid (GABA) transporters proteins within hippocampal tissue obtained from rats who had undergone epileptogenesis. Chronic seizures were induced by amygdalar injection of FeCl(3). We found that the glial glutamate transporters GLAST and GLT-1 were down-regulated at 60 days after initiation of chronic and recurrent seizures. However, the neuronal glutamate transporter EAAC-1 and the GABA transporter GAT-3 were increased. We performed in vivo microdialysis in freely moving animals to estimate in vivo redox state. We found that the hippocampal tissues were oxidized, resulting in even further impairment of glutamate transport. Our data show that epileptogenesis in rats resulting in chronic and recurrent seizures is associated with collapse of glutamate regulation caused by both the molecular down-regulation of glial glutamate transporters combined with the functional failure due to oxidation.
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PMID:Functional role for redox in the epileptogenesis: molecular regulation of glutamate in the hippocampus of FeCl3-induced limbic epilepsy model. 1748 25

Glutamate transporters function to maintain low levels of extracellular glutamate and play an important role in synaptic transmission at many synapses. Disruption of glutamate transporter function or expression can result in increased extracellular glutamate levels. Alterations in glutamate transporter expression have been reported in human epilepsy and animal seizure models. Functional electrophysiological changes that occur when transporter expression is disrupted in chronic epilepsy models have not been examined. Here, we used a freeze-induced model of cortical dysplasia to test the role of glutamate transporters in synaptic hyperexcitability. We report that inhibiting glutamate transporters with the non-selective antagonist, DL-threo-beta-benzylozyaspartic acid (TBOA) preferentially prolongs postsynaptic currents (PSCs) and decreases the threshold for evoking epileptiform activity in lesioned compared to control cortex. The effect of inhibiting uptake is mediated primarily by the glia glutamate transporter (GLT-1) since the selective antagonist dihydrokainate (DHK) mimicked the effects of TBOA. The effect of uptake inhibition is mediated by activation of N-methyl-D-aspartate (NMDA) receptors since D-(-)-2-amino-5-phosphonovaleric acid (APV) prevents TBOA-induced effects. Neurons in lesioned cortex also have a larger tonic NMDA current. These results indicate that chronic changes in glutamate transporters and NMDA receptors contribute to hyperexcitability in cortical dysplasia.
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PMID:Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia. 1867 19

Traumatic brain injury causes development of posttraumatic epilepsy. Bleeding within neuropil is followed by hemolysis and deposition of hemoglobin in neocortex. Iron from hemoglobin and transferring is deposited in brains of patients with posttraumatic epilepsy. Iron compounds form reactive free radical oxidants. Microinjection of ferric ions into rodent brain results in chronic recurrent seizures and liberation of glutamate into the neuropil, as is observed in humans with epilepsy. Termination of synaptic effects of glutamate is by removal via transporter proteins. EAAC-1 is within neurons while GLT-1 and GLAST are confined to glia. Persistent down regulation of GLAST production is present in hippocampal regions in chronic seizure models. Down regulation of GLAST may be fundamental to a sequence of free radical reactions initiated by brain injury with hemorrhage. Administration of antioxidants to animals causes interruption of the sequence of brain injury responses induced by hemorrhage, suggesting that such a strategy needs to be evaluated in patients with traumatic brain injury.
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PMID:Posttraumatic epilepsy: hemorrhage, free radicals and the molecular regulation of glutamate. 1878 8


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