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)

The anterior part of the piriform cortex (the APC) has been the focus of cortical-level studies of olfactory coding and associative processes and has attracted considerable attention as a result of a unique capacity to initiate generalized tonic-clonic seizures. Based on analysis of cytoarchitecture, connections, and immunocytochemical markers, a new subdivision of the APC and an associated deep nucleus are distinguished in the rat. As a result of its ventrorostral location in the APC, the new subdivision is termed the APC(VR). The deep nucleus is termed the pre-endopiriform nucleus (pEn) based on location and certain parallels to the endopiriform nucleus. The APC(VR) has unique features of interest for normal function: immunostaining suggests that it receives input from tufted cells in the olfactory bulb in addition to mitral cells, and it provides a heavy, rather selective projection from the piriform cortex to the ventrolateral orbital cortex (VLO), a prefrontal area where chemosensory, visual, and spatial information converges. The APC(VR) also has di- and tri-synaptic projections to the VLO via the pEn and the submedial thalamic nucleus. The pEn is of particular interest from a pathological standpoint because it corresponds in location to the physiologically defined "deep piriform cortex" ("area tempestas") from which convulsants initiate temporal lobe seizures, and blockade reduces ischemic damage to the hippocampus. Immunostaining revealed novel features of the pEn and APC(VR) that could alter excitability, including a near-absence of gamma-aminobutyric acid (GABA)ergic "cartridge" endings on axon initial segments, few cholecystokinin (CCK)-positive basket cells, and very low gamma-aminobutyric acid transporter-1 (GAT1)-like immunoreactivity. Normal functions of the APC(VR)-pEn may require a shaping of neuronal activity by inhibitory processes in a fashion that renders this region susceptible to pathological behavior.
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PMID:A new subdivision of anterior piriform cortex and associated deep nucleus with novel features of interest for olfaction and epilepsy. 1133 30

To identify the roles of gamma-aminobutyric acid (GABA) transporter in epileptogenesis and the recovery mechanisms in spontaneous seizure, a chronological and comparative analysis of GABA transporters (GAT) expression was conducted. GAT-1 immunoreactivity was more strongly detected in the pre-seizure group of seizure sensitive (SS) gerbils than that seen in the seizure resistant group. 30 min postictal, the density of GAT-1 immunoreactivity was significantly decreased in the hippocampal complex, as compared to pre-seizure group. 12 h after seizure on-set, the GAT immunodensity recovered to the pre-seizure level. Following the onset of seizure, GAT-3 immunoreactivity remained unchanged. These results suggest that the increase of GAT-1 expression in the SS gerbil hippocampus may affect epileptogenesis in this animal, and the alteration of immunoreactivity following seizure may be compensatory responses to modulate seizure activity.
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PMID:The changes in the expressions of gamma-aminobutyric acid transporters in the gerbil hippocampal complex following spontaneous seizure. 1152 50

Reorganization of excitatory and inhibitory circuits in the hippocampal formation following seizure-induced neuronal loss has been proposed to underlie the development of chronic seizures in temporal lobe epilepsy (TLE). Here, we investigated whether specific morphological alterations of the GABAergic system can be related to the onset of spontaneous recurrent seizures (SRS) in the rat lithium-pilocarpine model of TLE. Immunohistochemical staining for markers of interneurons and their projections, including parvalbumin (PV), calretinin (CR), calbindin (CB), glutamic acid decarboxylase (GAD), and type 1 GABA transporter (GAT1), was performed in brain sections of rats treated with lithium-pilocarpine and sacrificed after 24 h, during the silent phase (6 and 12 days), or after the onset of SRS (10-18 days after treatment). Semiquantitative analysis revealed a selective loss of interneurons in the stratum oriens of CA1, associated with a reduction of GAT1 staining in the stratum radiatum and stratum oriens. In contrast, interneurons in CA3 were largely preserved, although GAT1 staining was also reduced. These changes occurred within 6 days after treatment and were therefore insufficient to cause SRS. In the dentate gyrus, extensive cell loss occurred in the hilus. The pericellular innervation of granule cells by PV-positive axons was markedly reduced, although the loss of PV-interneurons was only partial. Most strikingly, the density of GABAergic axons, positive for both GAD and GAT1, was dramatically increased in the inner molecular layer. This change emerged during the silent period, but was most marked in animals with SRS. Finally, supernumerary CB-positive neurons were detected in the hilus, selectively in rats with SRS. These findings suggest that alterations of GABAergic circuits occur early after lithium-pilocarpine-induced status epilepticus and contribute to epileptogenesis. In particular, the reorganization of GABAergic axons in the dentate gyrus might contribute to synchronize hyperexcitability induced by the interneuron loss during the silent period, leading to the onset of chronic seizures.
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PMID:Alterations of hippocampal GAbaergic system contribute to development of spontaneous recurrent seizures in the rat lithium-pilocarpine model of temporal lobe epilepsy. 1153 Aug 50

The gamma-aminobutyric acid (GABA) system plays an important role in the early development of the hippocampal formation. The immunohistochemical expression of gamma-aminobutyric acid transporter-1, GAT-1, in the human developing temporal cortex was examined, and the distribution of GAT-1 was compared with that of the 67-kDa isoform of glutamic acid decarboxylase as a marker of GABAergic neurons. Four postmortem tissue specimens from young patients with hippocampal sclerosis were also examined. GAT-1 immunoreactivity was present, with a few puncta, in the neuropil of the stratum oriens and in the molecular layer of the dentate gyrus from 21-22 weeks of gestation, and in the stratum lacunosum-moleculare from 26 weeks of gestation. The peak expression of GAT-1 was seen in early infancy and that of glutamic acid decarboxylase in the perinatal period. These findings may reflect the development of GABAergic inhibitory systems, and may be related to the seizure susceptibility in infancy and early childhood. In the temporal lobes with hippocampal sclerosis, GAT-1 immunoreactivity of the neuropil was preserved in the vicinity of the neuronal loss of the hippocampus. This finding may result from the neurotrophic function of GAT-1 and may be related to its ability of neuronal repair and plasticity in childhood.
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PMID:Development of GABAergic neurons and their transporter in human temporal cortex. 1174 14

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in CNS can elevate level of neuronal excitability by the mechanisms of hyperpolarization. Gabaergic hypothesis of epileptogenesis influenced development of a group of gabamimetic antiepileptic drugs (AEDs). Powerful conventional AEDs barbiturates and benzodiazepines can directly activate GABA-A receptor but their usefulness is limited by development of dependence and tolerance to antiseizure activity. The second generation AEDs have been achieved by a rationale synthesis of compounds that could mimic or augment the activity of endogenous GABA. Vigabatrin (VGB) irreversibly inhibits GABA-T activity, tiagabine (TGB) inhibits GABA-reuptake system (GAT-1) and gabapentin (GPT) enhances GABA turnover in CNS. New drugs with selective and specific influence on GABA neurotransmission are non-toxic and well-tolerated, but some side-effects (aggravation of seizures, visual field deficit and psychotic reactions) seems to be strictly connected with their pharmacodynamic properties. Absence and probably myoclonic seizures noted in about 10% of patients under VGB seems to be the result of disturbed GABA inhibition in thalamic interneurons and non-controlled hyperactivity of excitatory neocortex-thalamus-neocotrex circuits. Perimetric examination might reveal peripheral, persistent binasal visual field deficit in about 30% of patients treated with VGB. This is probably the effect of cytotoxic influence of enormous accumulation of GABA in retinal neurons. Barbiturates and benzodiazepines can exacerbate intellectual functioning and behaviour. Some emotional and reactive disturbances are more characteristic for newer drugs. Serious depressive reactions and psychoses were observed respectively in 12.5 and 2.5% epileptics under VGB and anecdotically after TGB or GPT therapy. Newer selective and specific gabamimetic AEDs play an essential role as add-on therapy of pharmaco-resistant epilepsy, but they did not bring significant qualitive change in the possibilities of pharmacotherapy.
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PMID:[Gabaergic hypothesis of epilepsy and clinical experience: controversial actions of the new generation gabamimetic antiepileptic drugs]. 1178 May 94

High seizure susceptibility in El mice is associated with disinhibition in the dentate gyrus (DG) and paired-pulse facilitation in the CA3 area in hippocampal slices [Brain Res. 745 (1997) 165; Brain Res. 779 (1998) 324]. A decrease in gamma-aminobutyric acid (GABA)-mediated inhibition and an increase in excitatory inputs to the major neurons seem to be the responsible mechanisms, respectively, for these phenomena. In this study, we examined the effects of tiagabine, an inhibitor of GABA transporter, on hyperexcitation in vivo and in slice preparations. Tiagabine (0.3-0.5 mg/kg) suppressed the occurrence of seizures to about 20% of controls with an ED(50) value of about 0.17 mg/kg. In addition, perfusion of hippocampal slices with tiagabine (20 microM) counteracted the paired-pulse facilitation in the CA3 region over the entire range of interpulse intervals (P<0.05, two-way ANOVA) and reduced the disinhibition in the DG measured at 10 and 20 ms during short interpulse intervals (P<0.005, paired t-test). The CA1 region in the El mice, as well as in a non-epileptic parental strain of ddY mice did not respond to the drug. However, frequency potentiation of CA3 was enhanced in both strains (P<0.05, paired t-test). Our results suggest that within the hippocampus the antiepileptic action of tiagabine is selectively suppressive for hyperexcitability of DG and CA3, which are responsible for seizure-susceptibility in El mice.
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PMID:Selective suppression of hippocampal region hyperexcitability related to seizure susceptibility in epileptic El mice by the GABA-transporter inhibitor tiagabine. 1217 63

A wealth of previous studies reported pathological alterations in extrahippocampal regions in mesial temporal lobe epilepsy. Previous experimental findings have also demonstrated that the entorhinal cortex and the neocortex are damaged in different animal models of acute limbic seizures. The present study was aimed at verifying possible alterations in neocortical areas, and, in particular, structural changes of GABAergic interneurons in the sensorimotor cortex, in pilocarpine-induced chronic epilepsy in the rat. Series of sections were Nissl stained and processed for immunocytochemistry using antibodies that recognize nonphosphorylated neurofilament (SMI311), glial fibrillary acidic protein (GFAP), the calcium-binding protein parvalbumin (PV) which is expressed by a subset of cortical GABAergic neurons, the GABA transporter (GAT1), and isoform 65 of glutamic acid decarboxylase (GAD65), the GABA synthetic enzyme. Epileptic rats showed decreased cortical thickness, and diffuse gliosis was observed with GFAP antibody. Neurofilament alterations were also detected in sections processed using SMI311 antiserum. In addition, a diffuse decrease of PV, GAD65, and GAT1 immunoreactivity was observed in the sensorimotor cortex. Altered expression of PV, GAD65, and GAT1 pointed out specific neocortical disturbances in GABAergic inhibition, which could play a crucial role in seizure generation and expression. Thus, the present findings indicate that damage of GABAergic interneurons could be strictly associated with neocortical hyperexcitability in temporal lobe epilepsy.
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PMID:Alterations of the neocortical GABAergic system in the pilocarpine model of temporal lobe epilepsy: neuronal damage and immunocytochemical changes in chronic epileptic rats. 1218 20

Children with brain malformations often exhibit an intractable form of epilepsy. Although alterations in cellular physiology and abnormal histology associated with brain malformations has been studied extensively, synaptic function in malformed brain regions remains poorly understood. We used an animal model, rats exposed to methylazoxymethanol (MAM) in utero, featuring loss of lamination and distinct nodular heterotopia to examine inhibitory synaptic function in the malformed brain. Previous in vitro and in vivo studies demonstrated an enhanced susceptibility to seizure activity and neuronal hyperexcitability in these animals. Here we demonstrate that inhibitory synaptic function is enhanced in rats exposed to MAM in utero. Using in vitro hippocampal slices and whole-cell voltage-clamp recordings from visualized neurons, we observed a dramatic prolongation of GABAergic IPSCs onto heterotopic neurons. Spontaneous IPSC decay time constants were increased by 195% and evoked IPSC decay time constants by 220% compared with age-matched control CA1 pyramidal cells; no change in IPSC amplitude or rise time was observed. GABA transport inhibitors (tiagabine and NO-711) prolonged evoked IPSC decay kinetics of control CA1 pyramidal cells (or normotopic cells) but had no effect on heterotopic neurons. Immunohistochemical staining for GABA transporters (GAT-1 and GAT-3) revealed a low level of expression in heterotopic cell regions, suggesting a reduced ability for GABA reuptake at these synapses. Together, our data demonstrate that GABA-mediated synaptic function at heterotopic synapses is altered and suggests that inhibitory systems are enhanced in the malformed brain.
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PMID:Heterotopic neurons with altered inhibitory synaptic function in an animal model of malformation-associated epilepsy. 1219 83

Knock-out Otx1 mice show brain hypoplasia, spontaneous epileptic seizures and abnormalities of the dorsal region of the neocortex. We investigated structural alterations in excitatory and inhibitory circuits in somatosensory cortex of Otx1(-/-) mice by immunocytochemistry using light, confocal and electron microscopy. Immunostaining for non-phosphorylated neurofilament SMI311 and subunit 1 of the NMDA receptor - used as markers of pyramidal neurons - showed reduced layer V pyramidal cells and ectopic pyramidal cells in layers II and III of the mutant cortex. Immunostaining for calcium-binding proteins calbindin, calretinin and parvalbumin - markers of non-overlapping types of GABAergic interneurons - showed no differences between wild-type and knock-out cortex for calbindin and calretinin neurons, while parvalbumin neurons were only patchily distributed in Otx1(-/-) cortex. The pattern of positivity of the GABAergic marker glutamic acid decarboxylase in Otx1(-/-) cortex was also altered and similar to that of parvalbumin. GABA transporter 1 immunoreactivity was greater in Otx1(-/-) than wild-type; quantitation of structures immunoreactive for this transporter in layer V showed that they were increased overall in Otx1(-/-) but the density of inhibitory terminals on pyramidal neurons in the same layer labeled with this transporter was similar to that in wild-type mice. No differences in the distribution or intensity of the glial markers GABA transporter 3 or glial fibrillary acidic protein were found. The defects found in the cortical GABAergic system of the Otx1(-/-) mouse can plausibly explain the cortical hyperexcitability that produces seizures in these animals.
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PMID:Morphological organization of somatosensory cortex in Otx1(-/-) mice. 1243 5

Gabapentin (GBP) has been shown to reduce paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which is a proconvulsant effect, and to shorten the afterdischarge duration, which is an antiepileptic effect. The mechanism by which GBP exerts these effects is not known, but a number of possibilities have been proposed. Here we tested the ability of vigabatrin (VGB), a GABA transaminase inhibitor, and SKF89976A, a selective GAT-1 blocker, to alter the effectiveness of GBP in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. VGB, alone at 100 mg/kg, had no effect on the evoked potentials or paired-pulse inhibition in the dentate gyrus, but did block lengthening of the afterdischarge. Pretreatment with VGB had no effect on the ability of GBP to reduce paired-pulse inhibition, but blocked the effect of GBP on seizure duration. SKF89976A, alone at 10 mg/kg, increased paired-pulse inhibition and blocked the lengthening of the afterdischarge in the seizure model. Pretreatment with SKF89976A had no effect on the actions of GBP on either paired-pulse inhibition or seizure duration. These results suggest that the action of GBP is not mediated through an inhibition of the GAT-1 transporter and probably not through an increase in basal levels of GABA. The data also suggest that the combination of VGB and GBP may be clinically less effective than the use of GBP alone.
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PMID:Modulation of the in vivo effects of gabapentin by vigabatrin and SKF89976A. 1245 29


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