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)

Indirect evidence from in vitro studies implicates a functional role for matrix metalloproteinases (MMPs) in the central nervous system (CNS), including induction of neuronal migration during development and enhancement of neurite extension. Few reports have documented the expression of these enzymes in the brain, especially after injury in vivo. The objective of this study was to determine whether MMPs are expressed in various regional areas of rat brain after administration of the neurotoxin, kainic acid. Limbic motor seizures and neuronal degeneration were induced in Sprague-Dawley rats by systemic administration of kainate (10 mg/kg). Rats were subsequently divided into convulsive and non-convulsive groups, after observing their behaviour in response to the drug. Animals were killed 6, 12, 24, 72 and 168 h (7 days) after injection of kainate. Gelatinases were extracted from various brain regions and assayed by gelatin-substrate zymography. Levels of glial fibrillary acidic protein (GFAP) in corresponding regions were measured by ELISA. In the absence of treatment, MMP-2 and MMP-9 activities were expressed differentially in various brain regions with the highest levels in the hippocampus and the lowest in the cerebellum. In areas from convulsive rats, MMP-9 activity was markedly elevated at 6 h, and reached a maximum at 12 h after injection of kainate (8.1-fold hippocampus, 7.7-fold diencephalon, 7.2-fold striatum, 5.7-fold frontal cortex, 5.5-fold cerebellum, 2.6-fold midbrain). MMP-2 activity was induced more than two-fold in the hippocampus, diencephalon and striatum, to a lesser extent in the frontal cortex and midbrain, and was unchanged in the cerebellum, 72 h after injection. Neither MMP activity was altered in any brain region derived from non-convulsive rats. Treatment with the GABAA antagonist, bicuculline, resulted in increased levels of MMP-9, 12 h after drug administration, but no change in levels of MMP-2 up to 3 days following treatment. GFAP levels were induced 3 days after kainic acid injection in brain regions where MMP-2 was elevated. Nissl staining displayed the classical, regional neurodegeneration in kainate-treated animals that exhibited seizures. No obvious degeneration was detected in kainate-treated, non-convulsive rats or bicuculline-treated animals. These data demonstrate that MMP-9 and MMP-2 are differentially expressed with respect to time after kainic acid injection, and suggest that they are regulated by convulsion and/or neurodegenerative-associated mechanisms, respectively. Although similar in catalytic activity, MMP-9 and MMP-2 may play different roles in response to kainic acid-induced seizure and neuronal degeneration.
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PMID:Regional and differential expression of gelatinases in rat brain after systemic kainic acid or bicuculline administration. 982 49

After intracerebral injection, some toxic secreted phospholipases A2 (sPLA2) can induce epileptic seizures which bases are currently ill known. We undertook the detailed study of the central neurotoxicity of paradoxin (PDX), an analog of taipoxin, in rodents. Since literature strongly suggests a high variability in the sPLA2 epileptogenic properties, we compared, in an acute model, PDX with crotoxin (CTX), known to induce seizures and that may bind to similar neuronal receptors. Related toxic enzymes (ammodytoxin A, ATX A, and CTX subunit CB) and the non neurotoxic sPLA2 from pancreas and PLA2 analog ammodytin L (AML) were also tested. Despite being highly neurotoxic, PDX did not induce either convulsions or long-lasting seizure fits. The results obtained with the other enzymes showed that toxic sPLA2s can effectively be differentiated based on two criteria: the presence of cortically recorded epileptic paroxysmal discharges (E) and convulsions (C). We thus propose to classify the toxic sPLA2s into different groups depending on their epileptogenic properties: E-C-(PDX), E+C+ (CTX, CB), and E-C+ (ATX A). The non toxic AML and pancreatic enzyme were E-C-. Moreover, the results obtained with AML, and preliminarily with chemically inhibited CB, suggested that phospholipid hydrolysis is important to trigger seizures and convulsions. However, PDX and CTX that possess highly different epileptogenic properties exerted comparable, although slightly different, catalytic activities. Similarly, histological evaluations of the brain of PDX and CTX-treated rats (H&E staining, GFAP immunodetection, hsp70 and c-fos mRNA detection) did not provide satisfactory clues to explain these large differences. Further studies are strongly required.
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PMID:Secreted phospholipase A2-induced neurotoxicity and epileptic seizures after intracerebral administration: an unexplained heterogeneity as emphasized with paradoxin and crotoxin. 985 69

In order to establish the relative distribution of a GFAP-negative population of astrocytes, and its change in gliotic tissue, sections of the stratum radiatum of the CA1 hippocampal layer of male, adult, Wistar rats were analyzed by immunocytochemical methods. Ten micrometer-thick sections were triple-stained to detect nuclei, glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). In another set of experiments, the rats received a one-time intraperitoneal injection of kainic acid that caused epileptic seizures. With the use of a behavioral protocol, animals with substantial neuronal loss in the pyramidal layer were selected. Five days after the injection these rats were analyzed similarly to control rats. We find that GFAP-positive cells are a subpopulation of GS-positive cells and that the GFAP-negative subpopulation is quite large (40%). After gliosis the density of GFAP-negative, GS-positive cells stays stable, whereas the GFAP-positive population triples. These experiments confirm electrophysiological experiments showing a distinct, GFAP-negative subset of astrocytes that remains consistent even after injury-induced gliosis and accompanying up-regulation of GFAP.
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PMID:Immunocytochemical evidence for a distinct GFAP-negative subpopulation of astrocytes in the adult rat hippocampus. 987 Mar 36

Changes in brain extracellular space (ECS) volume, composition, and geometry are a consequence of neuronal activity, of glial K+, pH, and amino acid homeostasis, and of changes in glial cell morphology, proliferation, and function. They occur as a result of repetitive neuronal activity, seizures, anoxia, injury, inflammation, and many other pathological states in the CNS, and may significantly affect signal transmission in the CNS. Activity-related or CNS damage-related cellular swelling is compensated for by ECS volume shrinkage and, as a consequence, by a decrease in the apparent diffusion coefficients (ADCs) of neuroactive substances diffusing in the ECS. Changes in cellular morphology, such as occur during aging, could also result in changes of ECS volume and geometry. We provide evidence for limited diffusion in rat cortex, corpus callosum, and hippocampus in the aging brain that correlates with changes in glial volume and the extracellular matrix. In all structures, the mean ECS volume fraction alpha (alpha = ECS volume/total tissue volume) and nonspecific uptake k' are significantly lower in aged rats (26-32 months old) than in young adult brain. Compared to young adult brain, in the aged brain we found an increase in GFAP staining and hypertrophied astrocytes with thicker processes which, in the hippocampus, lost their radial organization. The tortuosity (lambda = square root of D/ADC) was lower in the cortex and CA3 region. Immunohistochemical staining for fibronectin and chondroitin sulfate proteoglycans revealed a substantial decrease that could account for a decrease in diffusion barriers. Diffusion parameters alpha, lambda, and k' in the aging brain after cardiac arrest changed substantially faster than in the young adult brain, although the final values were not significantly different. This suggests that the smaller extracellular space during aging results in a greater susceptibility of the aging brain to anoxia/ischemia, apparently due to a faster extracellular acidosis and accumulation of K+ and toxic substances, for example, glutamate. We conclude that during aging the movement of substances is more hindered in the narrower clefts. This is partly compensated for by a decrease in the diffusion barriers that may be formed by macromolecules of the extracellular matrix. Diffusion parameters can affect the efficacy of synaptic as well as extrasynaptic transmission by a greater accumulation of substances, because they diffuse away from a source more slowly, or induce damage to nerve cells if these substances reach toxic concentrations. Diffusion parameters are also of importance in the "crosstalk" between synapses, which has been hypothesized to be of importance during LTP and LTD. We can, therefore, assume that the observed changes in ECS diffusion parameters during aging can contribute to functional deficits and memory loss.
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PMID:Diffusion constraints and neuron-glia interaction during aging. 995 27

Natural polyamines, spermidine and spermine, and their precursor putrescine, are of considerable importance for the developing and mature nervous system. They exhibit a number of neurophysiological and metabolic effects in the nervous system, including control of nucleic acid and protein synthesis, modulation of ionic channels and calcium-dependent transmitter release. The polyamine system is also known to be involved in various brain pathologic events (seizures, stroke, Alzheimer's disease and others). While cerebral polyamine concentrations and the activities of polyamine-metabolizing enzymes have been studied in great detail, much less is known about the cells that are responsible for cerebral polyamine synthesis and interconversion. With the present review the attempt is made to show how exact knowledge about the regional distribution and cellular localization of polyamines and the polyamine-synthesizing enzymatic machinery (and especially of L-ornithine decarboxylase) may help to better understand the functional interplay between polyamines and other endogenous agents (transmitters, receptors, growth factors neuroactive drugs etc.). Polyamines have been localized both in neurones and glial cells. However, the main cellular locus of the ODC is the neuron--both in the immature and adult central nervous system. Each period of normal brain development and ageing seems to have its own, characteristic temporo-spatial pattern of neuronal ODC expression. During strong functional activation (kindling, epileptic seizures, neural transplantation) astrocytes and other non-neuronal cells do also express ODC and other polyamine-metabolizing enzymes. Astroglial expression of ODC is accompanied by an increase in glial fibrillary acidic protein in these cells. This shift in the cellular mechanisms of polyamine metabolism is currently far from being understood. In human brain diseases (Alzheimer's disease, schizophrenia) certain neurones show an increased expression of ODC, the first and rate-limiting enzyme of polyamine metabolism. Since polyamines are structurally related to psychoactive drugs (neuroleptics, antidepressants) the polyamine system might be of importance as a putative target for drug intervention in psychiatry.
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PMID:The cellular localization of the L-ornithine decarboxylase/polyamine system in normal and diseased central nervous systems. 1021 98

Glial cells are believed to play a major role in the regulation of the extracellular potassium concentration ([K+]o), particularly when the [K+]o is increased. Using ion-selective electrodes, we compared the [K+]o changes in the dentate gyrus of urethane-anaesthetized adult rats in the presence of reactive astrocytes and after reduction of glial function. The regulation of [K+]o in the dentate gyrus was determined by measuring the ceiling level of [K+]o and the half-time of recovery of [K+]o during and after seizures produced by 20 Hz trains of stimulation to the angular bundle. Reactive astrocytes were induced by repeated seizures and their presence was confirmed by a qualitative increase in glial fibrillary acidic protein (GFAP) and vimentin immunoreactivity. To inhibit glial function, fluorocitrate (FC), a reversible metabolic inhibitor, or alpha-aminoadipate (alpha-AA), an irreversible toxin, was injected into the dentate gyrus region, and the regulation of [K+]o was monitored for 8 h or 2 days later, respectively. After alpha-aminoadipate, loss of astrocytes in the dentate gyrus was demonstrated by loss of staining for GFAP. In the presence of reactive astrocytes there was no significant change in the peak [K+]o during seizures or the half-time of recovery of [K+]o after seizures compared to control animals. alpha-Aminoadipate significantly slowed the rate of recovery of [K+]o, but did not change the ceiling [K+]o. Fluorocitrate reversibly decreased the ceiling [K+]o, but also slowed the rate of recovery of [K+]o. Overall our results suggest that normal glial function is required for the recovery of elevated [K+]o after seizures in vivo.
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PMID:Astrocytic regulation of the recovery of extracellular potassium after seizures in vivo. 1021 21

Glutamate is the major excitatory neurotransmitter in the central nervous system and is implicated in the pathogenesis of neurodegenerative diseases. Five human glutamate transporters have been cloned and are responsible for the removal of potentially excitotoxic excess glutamate from the extracellular space. In this study we consider whether there are selective changes in the expression of the glutamate transporters in the medial temporal cortex and hippocampus from temporal lobe epilepsy patients, which might contribute to the development or maintenance of seizures. Since disruption of the glial transporter excitatory amino acid transporter 2 in mice results in lethal spontaneous seizures, we were interested primarily in studying changes in this transporter. Using in situ hybridization we show that there was no reduction in the level of excitatory amino acid transporter 2 encoding messenger RNA in the temporal lobe epilepsy cases compared to post mortem controls and indeed there was a relative increase in content of excitatory amino acid transporter 2 messenger RNA per cell in temporal lobe epilepsy cases. Western blotting showed that there was no change in the excitatory amino acid transporter 2 protein content in temporal lobe epilepsy cases as compared to post mortem controls. A small reduction in the level of the second astroglial transporter protein, excitatory amino acid transporter 1, was observed in temporal lobe epilepsy cases. Surprisingly, immunohistochemical experiments using a polyclonal antiexcitatory amino acid transporter 2 antibody, showed a different localization of this protein in epilepsy derived tissue as compared to post mortem controls although glial markers such as glial fibrillary acidic protein and glutamine synthase showed similar patterns of staining. However, repeating this experiment using control tissue from non-temporal lobe epilepsy biopsies demonstrated that this change in the excitatory amino acid transporter 2 transporter localization occurred post mortem. These data suggest that major changes in the level of expression of the glutamate transporters do not play an important role in the development of human temporal lobe epilepsy but may be implicated the aetiology of other types of epilepsy.
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PMID:Expression of the glutamate transporters in human temporal lobe epilepsy. 1033 23

Astrocytic tumors, particularly gliosarcoma, may contain epithelial features in the form of trabecular, adenoid, papillary arrangement, and squamous metaplasia. A case of gliosarcoma with unusual epithelial feature is described. The patient was a 60-year-old male with frequent seizures. The mass was 4 cm and in the left frontal lobe. Trabecular or rarely adenoid arrangement of neoplastic astrocytes was present in the mucinous stroma, and there was a distinctive transition between the trabecular area and typical anaplastic astrocytoma. The tumor cells in the trabecular area showed positive immunostain for glial fibrillary acidic protein, but did not react with various kinds of cytokeratin. The sarcomatous area was undifferentiated and was not labeled by factor-VIII, desmin, and anti-smooth muscle actin. Occurrence and histogenesis of epithelial features in gliosarcoma are reviewed. The importance to recognize the existence of epithelial feature in malignant astrocytic tumor is emphasized.
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PMID:Gliosarcoma: a case with unusual epithelial feature. 1040 83

An autoantibody against canine brain tissue was detected in the cerebrospinal fluid (CSF) and serum of two Pug dogs (Nos. 1 and 2) by indirect immunofluorescence assay (IFA). Dog No. 1, a 2-year-old male, exhibited severe depression, ataxia, and generalized seizures and died 2 months after the onset of symptoms. Dog No. 2, a 9-month-old male, exhibited severe generalized seizures and died 17 months after the onset of symptoms. Histopathologic examination revealed a moderate to severe multifocal accumulation of lymphocytes, plasma cells, and a few neutrophils in both the gray and white matter of the cerebrum in dog No. 1. In dog No. 2, the cellular infiltrates were mild, but there was a severe, diffuse, and multifocal necrosis in the cerebral cortex with prominent astrocytosis. With the aid of IFA using fluorescein isothiocyanate-labeled antidog IgG goat serum and a confocal imaging system, specific reactions for glial cells were detected in the CSF of these Pug dogs but not in six canine control CSF samples. Double-labeling IFA using CSF from these Pug dogs and a rabbit antiserum against glial fibrillary acidic protein (GFAP) revealed that the autoantibody recognized GFAP-positive astrocytes and their cytoplasmic projections. By immunoblot analysis, the autoantibody from CSF of these Pug dogs recognized two common positive bands at 58 and 54 kd, which corresponded to the molecular mass of human GFAP. The role of this autoantibody for astrocytes is not yet clear. However, if the presence of the autoantibody is a specific feature of Pug dog encephalitis, it will be a useful clinical diagnostic marker and a key to the pathogenesis of this unique canine neurologic disease.
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PMID:Detection of an autoantibody from Pug dogs with necrotizing encephalitis (Pug dog encephalitis). 1042 Oct 96

Cytokines belonging to the type I interferon (e.g. interferon-alpha) family are important in the host response to infection and may have complex and broad ranging actions in the central nervous system (CNS) that may be beneficial or harmful. To better understand the impact of the CNS expression of the type I interferons (IFN), transgenic mice were developed that produce IFN-alpha(1) chronically from astrocytes. In two independent transgenic lines with moderate and low levels of astrocyte IFN-alpha mRNA expression respectively, a spectrum of transgene dose- and age-dependent structural and functional neurological alterations are induced. Structural changes include neurodegeneration with loss of cholinergic neurons, gliosis, angiopathy with mononuclear cell cuffing, progressive calcification affecting basal ganglia and cerebellum and the up-regulation of a number of IFN-alpha-regulated genes. At a functional level, in vivo and in vitro electrophysiological studies revealed impaired neuronal function and disturbed synaptic plasticity with pronounced hippocampal hyperexcitability. Severe behavioral alterations were also evident in higher expressor GFAP-IFNalpha mice which developed fatal seizures around 13 weeks of age precluding their further behavioral assessment. Modest impairments in discrimination learning were measured in lower expressor GFAP-IFNalpha mice at various ages (7-42 weeks). The behavioral and electrophysiological findings suggest regional changes in hippocampal excitability which may be linked to abnormal calcium metabolism and loss of cholinergic neurons in the GIFN mice. Thus, these transgenic mice provide a novel animal model in which to further evaluate the mechanisms that underlie the diverse actions of type I interferons in the intact CNS and to link specific structural changes with functional impairments.
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PMID:Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha. 1044 95


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