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)

Unilateral injection of kainic acid (KA) into the dorsal hippocampus of adult mice induces spontaneous recurrent partial seizures and replicates histopathological changes observed in human mesial temporal lobe epilepsy (MTLE) (Bouilleret V et al., Neuroscience 1999; 89:717-729). Alterations in pre- and postsynaptic components of GABAergic neurotransmission were investigated immunohistochemically at different time points (1-120 days) in this mouse model of MTLE. Markers of GABAergic interneurons (parvalbumin, calbindin-D28k, and calretinin), the type-1 GABA transporter (GAT1), and major GABA(A)-receptor subunits expressed in the hippocampal formation were analyzed. Acutely, KA injection produced a profound loss of hilar cells but only limited damage to CA1 and CA3 pyramidal cells. In addition, parvalbumin and calbindin-D28k staining of interneurons disappeared irreversibly in CA1 and dentate gyrus (DG), whereas calretinin staining was spared. The prominent GABA(A)-receptor alpha1 subunit staining of interneurons also disappeared after KA treatment, suggesting acute degeneration of these cells. Likewise, GAT1 immunoreactivity revealed degenerating terminals at 24 h post-KA in CA1 and DC and subsided almost completely thereafter. Loss of CA1 and, to a lesser extent, CA3 neurons became evident at 7-15 days post-KA. It was more accentuated after 1 month, accompanied by a corresponding reduction of GABA(A)-receptor staining. In contrast, DC granule cells were markedly enlarged and dispersed in the molecular layer and exhibited a prominent increase in GABA(A)-receptor subunit staining. After 4 months, the dorsal CA1 area was lost almost entirely, CA3 was reduced, and the DG represented most of the remaining dorsal hippocampal formation. No significant morphological alterations were detected contralaterally. These results suggest that loss of hilar cells and GABAergic neurons contributes to epileptogenesis in this model of MTLE. In contrast, long-term degeneration of pyramidal cells and granule cell dispersion may reflect distinct responses to recurrent seizures. Finally, GABA(A)-receptor upregulation in the DG may represent a compensatory response persisting for several months in epileptic mice.
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PMID:Early loss of interneurons and delayed subunit-specific changes in GABA(A)-receptor expression in a mouse model of mesial temporal lobe epilepsy. 1090

To study the role of hippocampal gamma-aminobutyric acid (GABA) transporters in epileptogenesis, we induced chronic seizures by ferric cation injection into the rat amygdaloid body. We used western blotting to measure alterations in the expression of hippocampal GABA transporter proteins GAT-1 and GAT-3. GAT-1 increased bilaterally (from 150 to 250%) at 5 to 15 days after injection, but returned to control levels by 30 days. In contrast, GAT-3 also significantly increased bilaterally at 5 days and 15 days, but remained elevated bilaterally at 30 days after injection. Alterations in GAT-1 levels are apparently transient responses to seizure activity that occur during the acute phase of epileptogenesis. However, we propose that regulation of the GAT-3 subtype transporter was chronically elevated (at least 30 days), represents an effect of epileptogenesis induced by ferric ion injected into the amygdaloid body.
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PMID:Hippocampal gamma-aminobutyric acid transporter alterations following focal epileptogenesis induced in rat amygdala. 1092 14

Epileptiform discharges and behavioral seizures may be the consequences of the presence of either excessive excitation associated with the neurotransmitter glutamate or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove these amino acids from the synaptic cleft. The glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino acids carrier-1 (EAAC-1) limit excitation initiated by synaptic release of glutamate. Transporter proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3) remove GABA from synaptic regions. To assess the molecular effects of the antiepileptic drug valproate, albino rats with chronic, spontaneous, recurrent seizures induced by amygdalar injection of FeCl3 were treated for 14 days with either valproic acid or with saline as an injection control. Regions of the hippocampus were assayed for glutamate and GABA transporters by western blot. While epileptogenesis is thought to correlate with the downregulation of GLAST and upregulation of EAAC-1, valproate caused an increase in the quantity of GLAST protein measured in the hippocampus. Valproate treatment decreased GLT-1 in both control and experimental animals in both hippocampi. EAAC-1 was unchanged by valproate treatment. GABA transporters GAT-1 and GAT-3 in the hippocampus were upregulated by FeCl3 injection into the amygdala. However, valproate caused the downregulation of these GABA transporters in both control and experimental animals. Altered molecular regulation of glutamate appears to be critical in the development of sustained, spontaneous limbic seizures. Our data suggest that valproate may have unique mechanisms of action; specifically, it may affect the removal of glutamate by upregulating GLAST and decreasing GABA transport, which could result in increased tissue concentrations of GABA.
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PMID:Molecular regulation of glutamate and GABA transporter proteins by valproic acid in rat hippocampus during epileptogenesis. 1095 23

The present study examines the effect of tiagabine (a selective inhibitor of GABA transporter 1, GAT-1), SNAP-5114 (a semi-selective inhibitor of rat GAT-3/mouse GAT4) and NNC 05-2045 (a non-selective GABA uptake inhibitor) in modulating GABA levels in the hippocampus and thalamus. Anticonvulsant effects of the same compounds were assessed (after intranigral administration) after maximal electroshock (MES) in juvenile rats. Anticonvulsant effects were also tested after intraperitoneal (i.p.) administration against audiogenic seizures in DBA/2 mice and against pentylentetrazole (PTZ)-induced tonic convulsions or MES in NMRI mice. Tiagabine (30 microM, perfused through the microdialysis probe in halothane anaesthetized rats) increased GABA levels to (% basal+/-SEM) 645+/-69 in the hippocampus and 409+/-61 in the thalamus. SNAP-5114 (100 microM) increased GABA levels in the thalamus (% basal+/-SEM) to 247+/-27 but had no effect on hippocampal GABA-levels. NNC 05-2045 (100 microM) increased GABA levels both in the hippocampus (% basal+/-SEM, 251+/-51) and in the thalamus (298+/-27). All compounds protected against tonic hindlimb extension (THE) in juvenile male rats after intranigral administration. Sound induced convulsions in DBA/2 mice were dose-dependently inhibited by all compounds (administered intraperitoneal, i.p.) with ED(50) values of 1, 6 and 110 micromol/kg, for tiagabine, NNC 05-2045 and SNAP-5114, respectively. Tiagabine and NNC 05-2045 but not SNAP-5114 protected against PTZ-induced tonic convulsions whereas only NNC 05-2045 protected against MES-induced tonic convulsions in NMRI mice. However, tiagabine and NNC 05-2045 exerted a synergistic effect in the MES model. These findings substantiate and extend previous findings of different effects of selective versus non-selective GABA uptake inhibitors in animal models of epilepsy.
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PMID:GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. 1097 24

GABA neurotransmission is terminated by high affinity transport mediated by a number of carriers on neurons and astrocytes. So far four different carriers have been cloned and their cellular distribution has been partly worked out. It is generally believed that GAT-1 (mouse homologue GAT1) is the quantitatively most important of the transporters and it is primarily present on GABAergic neurons but also to some extent on astrocytes. The pharmacological properties of neuronal and astrocytic GABA uptake have been studied extensively and recently the GABA analogue N-methyl-Exo-THPO has been reported to act as a selective and potent (IC50 28 microM) astroglial GABA transport inhibitor with a 15-fold selectivity. It has moreover been reported to act as an anticonvulsant in animal models of epilepsy. This may underline the functional importance of astrocytic GABA uptake in relation to seizure activity.
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PMID:Pharmacological and functional characterization of astrocytic GABA transport: a short review. 1105 98

High affinity, gamma-aminobutyric acid (GABA) plasma membrane transporters (GATs) influence the availability of GABA, the main inhibitory neurotransmitter in the brain. Recent studies suggest a crucial role for GATs in maintaining levels of synaptic GABA in normal as well as abnormal (i.e., epileptic) adult brain. However, the role of GATs during development and specifically changes in their expression in response to developmental seizures are unknown. The present study examined GAT-1-immunolabeling in infant rats with two types of developmental seizures, one induced by corticotropin-releasing hormone (CRH) lasting about 2 h and the other by hyperthermia (a model of febrile seizures) lasting only 20 min. The number of GAT-1-immunoreactive (ir) neurons was increased in several forebrain regions 24 h after induction of seizures by CRH as compared to the control group. Increased numbers of detectable GAT-1-ir cell bodies were found in the hippocampal formation including the dentate gyrus and CA1, and in the neocortex, piriform cortex and amygdala. In contrast, hyperthermia-induced seizures did not cause significant changes in the number of detectable GAT-1-ir somata. The increase in GAT-1-ir somata in the CRH model and not in the hyperthermia model may reflect the difference in the duration of seizures. The brain regions where this increase occurs correlate with the occurrence of argyrophyllic neurons in the CRH model.
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PMID:Increased expression of gamma-aminobutyric acid transporter-1 in the forebrain of infant rats with corticotropin-releasing hormone-induced seizures but not in those with hyperthermia-induced seizures. 1107 87

We used northern and western blotting to measure the quantity of glutamate and GABA transporters mRNA and their proteins within the hippocampal tissue of rats with epileptogenesis. Chronic seizures were induced by amygdalar injection of kainic acid 60 days before death. We found that expression of the mRNA and protein of the glial glutamate transporters GLAST and GLT-1 were down-regulated in the kainic acid-administered group. In contrast, EAAC-1 and GAT-3 mRNA and their proteins were increased, while GAT-1 mRNA and protein were not changed. We performed in vivo microdialysis in the freely moving state. During the interictal state, the extracellular glutamate concentration was increased, whereas the GABA level was decreased in the kainic acid group. Following potassium-induced depolarization, glutamate overflow was higher and the recovery time to the basal release was prolonged in the kainic acid group relative to controls. Our data suggest that epileptogenesis in rats with kainic acid-induced chronic seizures is associated with the collapse of extracellular glutamate regulation caused by both molecular down-regulation and functional failure of glutamate transport.
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PMID:Collapse of extracellular glutamate regulation during epileptogenesis: down-regulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid. 1115 61

Epilepsy is common in the elderly. The incidence of epilepsy is age-dependent, with a peak during the first year of life and higher incidence in those older than 75 years. Cerebrovascular disease is a common cause of epilepsy in the elderly. Drug treatment of the elderly is a challenge because of pharmacokinetic changes with aging, including impaired drug protein binding or displacement of drug from protein binding sites, potentially causing drug toxicity as a result of increased free drug concentrations. With aging, hepatic mass and blood flow decline along with renal function. Established anticonvulsant drugs have adverse effects and drug interactions that can make treating the elderly difficult. Newly available anticonvulsants cause fewer drug-drug interactions and less toxicity. Gabapentin is not metabolised, is not bound to protein, and has a favourable adverse effect profile and thus may be useful in the treatment of elderly patients. Lamotrigine reduced seizures between 20 and 30% in trials. Dose response was between 300mg per day and 500mg per day. This drug was well tolerated in open-label trials. Rash occurred in younger patients. Oxcarbazepine is rapidly absorbed and is converted to a monohydroxy derivative. Use with hepatic enzyme-inducing drugs necessitates an increase in dose. This drug may be substituted for carbamazepine. Hyponatraemia has been reported and monitoring is suggested. Topiramate blocks voltage-dependent sustained repetitive firing and has an effect on the gamma-aminobutyric acid (GABA) receptors. It affects glutamate responses and inhibits carbonic anhydrase. Topiramate has a dose response pattern up to 400mg per day. Cognitive effects limits its use in some patients. Nephrolithiasis has occurred with this drug. Tiagabine blocks GABA transporter proteins. Clearance is rapid and metabolism complete. Hepatic dysfunction prolongs clearance. The use of tiagabine has not been reported in the elderly. Zonisamide is rapidly absorbed and protein binding is 50%. Plasma half-life is 55 hours but is reduced to about 30 hours by hepatic enzyme-inducing drugs. Responder rate is 45%. Adverse effects include drowsiness, altered thinking and nephrolithiasis. Treatment of the elderly requires obligatory polypharmacy with potential drug interactions. Changes in body physiology alter absorption, binding, metabolism and elimination of drugs. Concomitant illness and sensitivity to drug effects narrow the therapeutic range and complicate pharmacokinetics in elderly patients. Newer anticonvulsant drugs have advantages that may outweigh risks and have therapeutic profiles that may aid in the treatment of this special population of patients.
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PMID:Choice and use of newer anticonvulsant drugs in older patients. 1120 Mar 5

In vivo dialysis and in vitro electrophysiological studies suggest that GABA uptake is altered in the dentate gyrus of human temporal lobe epileptics characterized with mesial temporal sclerosis (MTLE). Concordantly, anatomical studies have shown that the pattern of GABA-transporter immunoreactivity is also altered in this region. This decrease in GABA uptake, presumably due to a change in the GABA transporter system, may help preserve inhibitory tone interictally. However, transporter reversal can also occur under several conditions, including elevations in [K(+)]o, which occurs during seizures. Thus GABA transporters could contribute to seizure termination and propagation through heterotransport. To test whether GABA transport is compromised in both the forward (uptake) and reverse (heterotransport) direction in the sclerotic epileptic dentate gyrus, the physiological effects of microapplied GABA and nipecotic acid (NPA; a compound that induces heterotransport) were examined in granule cells in hippocampal slices from kainate (KA)-induced epileptic rats and patients with temporal lobe epilepsy (TLE). GABA- and NPA-induced responses were prolonged in granule cells from epileptic rats versus controls (51.3 and 31.3% increase, respectively) while the conductance change evoked with NPA microapplication was reduced by 40%. Furthermore the ratio of GABA/NPA conductance, but not duration, was significantly >1 in epileptic rats but not controls, suggesting a compromise in transporter function in both directions. Similar changes were observed in tissue resected from epileptic patients with medial temporal sclerosis but not in those without the anatomical changes associated with MTLE. These data suggest that the GABA transporter system is functionally compromised in both the forward and reverse directions in the dentate gyrus of chronically epileptic tissue characterized by mesial temporal sclerosis. This alteration may enhance inhibitory tone interically yet be permissive for seizure propagation due to a decreased probability for GABA heterotransport during seizures.
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PMID:GABA uptake and heterotransport are impaired in the dentate gyrus of epileptic rats and humans with temporal lobe sclerosis. 1128 77

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter, and the GABAergic synaptic transmission is normally terminated by the rapid uptake through GABA transporters. With transgenic mice ubiquitously overexpressing GABA transporter subtype I (GAT1), the present study explored the pathophysiological role of GAT1 in epileptogenesis. Though displaying no spontaneous seizure activity, these mice exhibit altered electroencephalographic patterns and increased susceptibility to seizure induced by kainic acid. In addition, the GABA(A) receptor and glutamate transporters are up-regulated in transgenic mice, which perhaps reflects a compensatory or corrective change to the elevated level of GAT1. These preliminary findings support the hypothesis that excitatory and inhibitory neurotransmission, and seizure susceptibility can be altered by neurotransmitter transporters.
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PMID:Overexpression of gamma-aminobutyric acid transporter subtype I leads to susceptibility to kainic acid-induced seizure in transgenic mice. 1130 26


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