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 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

ICA69 (islet cell Ag 69 kDa) is a diabetes-associated autoantigen with high expression levels in beta cells and brain. Its function is unknown, but knockout of its Caenorhabditis elegans homologue, ric-19, compromised neurotransmission. We disrupted the murine gene, ica-1, in 129-strain mice. These animals aged normally, but speed-congenic ICA69(null) nonobese diabetic (NOD) mice developed mid-life lethality, reminiscent of NOD-specific, late lethal seizures in glutamic acid decarboxylase 65-deficient mice. In contrast to wild-type and heterozygous animals, ICA69(null) NOD congenics fail to generate, even after immunization, cross-reactive T cells that recognize the dominant Tep69 epitope in ICA69, and its environmental mimicry Ag, the ABBOS epitope in BSA. This antigenic mimicry is thus driven by the endogenous self Ag, and not initiated by the environmental mimic. Insulitis, spontaneous, and adoptively transferred diabetes develop normally in ICA69(null) NOD congenics. Like glutamic acid decarboxylase 65, ICA69 is not an obligate autoantigen in diabetes. Unexpectedly, ICA69(null) NOD mice were resistant to cyclophosphamide (CY)-accelerated diabetes. Transplantation experiments with hemopoietic and islet tissue linked CY resistance to ICA69 deficiency in islets. CY-accelerated diabetes involves not only ablation of lymphoid cells, but ICA69-dependent drug toxicity in beta cells that boosts autoreactivity in the regenerating lymphoid system.
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PMID:ICA69(null) nonobese diabetic mice develop diabetes, but resist disease acceleration by cyclophosphamide. 1175 95

A 6-year-old boy presented with epilepsia partialis continua 6 months after diagnosis of type 1 diabetes. Anti-glutamic acid decarboxylase 65 antibodies were found in his serum and cerebrospinal fluid. Anti-epileptic agents did not improve his seizures. High-dose steroids, plasmapheresis, and intravenous immunoglobulin resulted in decreased anti-glutamic acid decarboxylase 65 antibody levels and resolution of his seizures.
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PMID:Type 1 diabetes mellitus and epilepsia partialis continua in a 6-year-old boy with elevated anti-GAD65 antibodies. 1187 78

We present a female infant with seizures responsive to pyridoxal phosphate but that are resistant to pyridoxine. The mechanism by which pyridoxal phosphate controls seizures in this patient is unknown. Her seizures are perhaps not solely caused by pyridoxal phosphate deficiency. It is suggested that in addition to glutamic acid decarboxylase abnormality, the path from the absorption, transportation, phosphorylation, and oxidation of pyridoxine to pyridoxal phosphate in this patient might be defective. It should be considered whether pyridoxal phosphate can be the drug of choice instead of pyridoxine in treating patients suspected of pyridoxine-dependent epilepsy to reduce failure rate and further delay in seizure control.
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PMID:Pyridoxal phosphate-responsive epilepsy with resistance to pyridoxine. 1189 81

To identify the roles of pyridoxine-5'-phosphate (PNP) oxidase in epileptogenesis and the recovery mechanisms in spontaneous seizure, a chronological and comparative analysis of PNP oxidase expression was conducted. PNP oxidase immunoreactivity in a preseizure group of seizure-sensitive (SS) gerbils was detected more strongly than that in a seizure-resistant (SR) group. The density of PNP oxidase immunoreactivity in a 30 min postictal group was significantly lower than that in a preseizure group. In a 12 hr postictal group, PNP oxidase immunodensity had recovered to a preseizure level. The overexpression of PNP oxidase in the hippocampus of preseizure SS gerbils suggests that PNP or pyridoxal 5'-phosphate plays an important role in the modulation of glutamic acid decarboxylase activity and gamma-aminobutyric acid reuptake as mediated by membrane transporter via neurons. In addition, this change in the PNP oxidase immunoreactivity following seizure may be a compensatory response designed to reduce epileptic activity in this animal.
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PMID:Chronological changes in pyridoxine-5'-phosphate oxidase immunoreactivity in the seizure-sensitive gerbil hippocampus. 1211 39

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

Although the granule cells of the dentate gyrus are glutamatergic, they contain the machinery for the synthesis and vesiculation of GABA. Furthermore, glutamic acid decarboxylase and the vesicular GABA transporter mRNA are expressed in the granule cells and mossy fibers in an activity-dependent manner, suggesting that these cells release GABA in addition to glutamate. Supporting this hypothesis, we found that seizures induce simultaneous glutamatergic and GABAergic transmission in the mossy fiber projection. To further explore this expression of inhibition, we looked for the presence and expression of endogenous GABA in a synaptosomal preparation enriched with mossy fiber nerve endings of kindled rats. We also studied the capacity of this preparation to capture and release [(3)H]GABA under control conditions and after kindling epilepsy. In accordance with our hypothesis we show that the mossy fiber synaptosomal preparation of the kindled rats has a significantly higher content of endogenous GABA than controls. We also found that the protein content in the mossy fiber synaptosomal preparation of kindled rats was significantly augmented, which is consistent with mossy fiber sprouting. Due to this, the total [(3)H]GABA incorporated in the synaptosomal preparation was also augmented. However, [(3)H]GABA uptake (expressed in % radioactivity/mg protein) and its evoked release were similar in both groups. With the present results, we provide further support for the hypothesis of the emergence of GABAergic transmission in the mossy fiber synapse that can constitute a protective mechanism in response to seizures.
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PMID:The expression of GABA in mossy fiber synaptosomes coincides with the seizure-induced expression of GABAergic transmission in the mossy fiber synapse. 1242 29

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

The granule cells of the dentate gyrus (DG) are considered to be glutamatergic, but they contain glutamic acid decarboxylase, gamma-amino butyric acid (GABA), and the vesicular GABA transporter mRNA. Their expression is regulated in an activity-dependent manner and coincides with the appearance of GABAergic transmission from the mossy fibers (MF) to pyramidal cells in area CA3. These data support the hypothesis that MF are able to release glutamate and GABA. Following the principle that a given neuron releases the same neurotransmitter(s) onto all its targets, we here demonstrate the emergence, after a generalized convulsive seizure, of MF GABAergic signaling sensitive to activation mGluR-III onto pyramidal cells and interneurons of CA3. Despite this, excitation overrides inhibition in interneurons, preventing disinhibition. Furthermore, on blockade of GABA and glutamate ionotropic receptors, an M1-cholinergic depolarizing signal is also revealed in both targets, which postsynaptically modulates the glutamatergic and GABAergic fast neurotransmission. The emergence of these nonglutamatergic signals depends on protein synthesis. In contrast to cholinergic responses evoked by associational/commissural fibers activation, cholinergic transmission evoked by DG stimulation is only observed after seizures and is strongly depressed by the activation of mGluR-II, whereas both are depressed by M2-AChR activation. With immunohistological experiments, we show that this cholinergic pathway runs parallel to the MF. Thus seizures compromise a delicate balance of excitation and inhibition, on which a complex interaction of different neurotransmitters emerges to counteract excitation at pre- and postsynaptic sites. Particularly, MF GABAergic inhibition emerges to exert an overall inhibitory action on CA3.
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PMID:Activity-dependent induction of multitransmitter signaling onto pyramidal cells and interneurons of hippocampal area CA3. 1261 45

Pyridoxine-dependent seizures have been recognised for 40 years, but the clinical and biochemical features are still not understood. It is a rare recessively inherited condition where classically a baby starts convulsing in utero and continues to do so after birth, until given pyridoxine. Many of these early onset cases also have an acute encephalopathy and other clinical features. Late onset cases are now recognised with a less severe form of the condition. Seizures can break through with intercurrent illness but otherwise remain controlled on pharmacologic doses of pyridoxine. The long-term outcome is affected by several factors including whether onset is early or late and how soon pyridoxine is given. Biochemical studies have been sparse, on very small numbers. There does not appear to be any defect in the uptake or metabolism of pyridoxine or pyridoxal phosphate (PLP). For a long time glutamic acid decarboxylase (GAD), a pyridoxal-dependent enzyme, has been suspected to be the abnormal gene product, but glutamate and gamma-aminobutyric acid (GABA) studies on the cerebrospinal fluid (CSF) have been contradictory and recent genetic studies have not found any linkage to the two brain isoforms. A recent report describes raised pipecolic acid levels in patients but how this ties in is unexplained.
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PMID:Pyridoxine-dependent seizures: a clinical and biochemical conundrum. 1268 5


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