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)

To determine whether the transient opening of the blood-brain barrier (BBB) during epileptic seizures may lead to permanent neuronal changes, seizures of a few minutes' duration were induced by intravenous (i.v.) administration of 0.3 mg/kg bicuculline to conscious rats with indwelling catheters for blood pressure (BP) and blood gas monitoring. The rats were killed 5 min to 7 days later, and the distribution of endogenous plasma albumin, fibrinogen, and fibronectin in the brain was studied by immunohistochemistry. Parallel sections were scrutinized for evidence of light-microscopic structural changes in the tissue. Extensive multifocal extravasation of plasma proteins throughout the brain and brainstem was observed. The original clearly focal distribution became more diffuse with prolongation of the recovery time. In addition, the intensity of the immunoreactivity decreased, most likely due to drainage into the cerebrospinal fluid (CSF) in the ventricles and the subarachnoidal space of the extravasated proteins, but some antialbumin-positive material was still visible after 7 days. In areas with extravasation, many nerve cells, especially cerebellar Purkinje cells, became strongly positive for albumin. In some of these areas, neurons appeared to be irreversibly injured. Thus, considerable amounts of plasma proteins are extravasated even during short epileptic seizures, and albumin appear to remain in the tissue for a long time, especially in Purkinje cells. The Purkinje cell loss in chronic epilepsy may be caused partly by cumulative bouts of plasma extravasations.
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PMID:Parenchymal changes related to plasma protein extravasation in experimental seizures. 230 7

A number of important neurological diseases, including HIV-1 encephalitis, Alzheimer's disease, and brain trauma, are associated with increased cerebral expression of the multifunctional cytokine transforming growth factor-beta 1 (TGF-beta 1). To determine whether overexpression of TGF-beta 1 within the central nervous system (CNS) can contribute to the development of neuropathological alterations, a bioactive form of TGF-beta 1 was expressed in astrocytes of transgenic mice. Transgenic mice with high levels of cerebral TGF-beta 1 expression developed a severe communicating hydrocephalus, seizures, motor incoordination, and early runting. While unmanipulated heterozygous transgenic mice from a low expressor line showed no such alterations, increasing TGF-beta 1 expression in this line by injury-induced astroglial activation or generation of homozygous offspring did result in the abnormal phenotype. Notably, astroglial overexpression of TGF-beta 1 consistently induced a strong upmodulation of the extracellular matrix proteins laminin and fibronectin in the CNS, particularly in the vicinity of TGF-beta 1-expressing perivascular astrocytes, but was not associated with obvious CNS infiltration by hematogenous cells. While low levels of extracellular matrix protein expression may assist in CNS wound repair and regeneration, excessive extracellular matrix deposition could result in the development of hydrocephalus. As an effective inducer of extracellular matrix components, TGF-beta 1 may also contribute to the development of other neuropathological alterations, eg, the formation of amyloid plaques in Alzheimer's disease.
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PMID:Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1. 760 85

Extracellular matrix proteins are induced by activity in adult brain but the time course of these responses, and hence the possibility of their involvement in use-dependent synaptic plasticity, is not known. To evaluate this issue, the influence of seizures on fibronectin expression was evaluated in the adult and developing hippocampus. In adult rats, kainic acid-induced seizures increased fibronectin mRNA and immunoreactivity (ir) by about 1 h after the first behavioral seizure. In situ hybridization analysis indicated that fibronectin mRNA was increased in broadly distributed glial cells as well as within discrete neuronal populations that normally express this transcript. Western blots demonstrated that increased fibronectin-ir was evident in both soluble and non-soluble fractions at the same time point. Immunocytochemical colocalization confirmed that fibronectin-ir was indeed elevated in broadly distributed glial fibrillary acidic protein-ir astroglia. Seizures had no detectable effect on fibronectin-ir in the hippocampus of nine day old rats. Together with previous results, the above findings suggest that intense physiological activity triggers a 'matrix response' (i.e., release proteases, activate integrins, secrete matrix proteins) that is sufficiently rapid to participate in the consolidation of long-term potentiation (LTP). The absence of such reactions in the immature hippocampus is in accord with the hypothesis that matrix proteins generated by mature astroglia impose temporal and spatial limitations on axonal remodeling.
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PMID:Seizure induced synthesis of fibronectin is rapid and age dependent: implications for long-term potentiation and sprouting. 981 31

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

Integrins are heterodimeric cell surface receptors composed of different alpha and beta subunits that mediate cell-cell and cell-extracellular matrix interactions. They have been implicated in the regulation of neuronal migration, differentiation, process outgrowth, and plasticity. The alpha8 integrin subunit associates exclusively with the beta1 subunit to form a receptor (alpha8beta1) for fibronectin, vitronectin, tenascin, and osteopontin. In a previous study, we demonstrated that hippocampal dentate hilar neurons are immunoreactive for alpha8. The present study identifies the major types of alpha8-immunoreactive hilar neurons and characterizes the effects of kainic acid-induced seizures on alpha8-immunoreactivity in these cells. Examination of the hilus in normal rats revealed alpha8-immunoreactivity in the somatodendritic compartments of large hilar neurons identified as mossy cells, including a subset of dendritic thorny excrescences that were contacted by large mossy fiber terminals. alpha8-immunoreactivity also was found in approximately 71% of somatostatin-containing hilar cells. Kainic acid-induced seizures dramatically and rapidly altered the levels and distribution of alpha8-immunoreactivity in hilar neurons. After 1.5 h of seizures, alpha8-immunoreactivity in their dendrites was reduced greatly. One day after kainic acid treatment, labeling was diminished throughout the somatodendritic compartments of most hilar cells. This decrease appeared to be transient, since alpha8 labeling returned to normal levels in surviving hilar neurons within 2 weeks of treatment. In addition, many alpha8-immunoreactive hilar neurons, particularly in caudal dentate regions, were lost 3-5 weeks after kainic acid treatment. Our findings suggest that alpha8beta1 may mediate adhesive interactions of the dendritic processes of mossy cells and somatostatin-containing hilar neurons with other cellular elements or with extracellular matrix components. They also suggest that alpha8 may be susceptible to activity-dependent proteolysis that could modulate its function in the somatodendritic compartment of these cells.
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PMID:Dentate hilar mossy cells and somatostatin-containing neurons are immunoreactive for the alpha8 integrin subunit: characterization in normal and kainic acid-treated rats. 1151 28

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder that presents with a facial port-wine stain and a leptomeningeal angioma. Fibronectin expression regulates angiogenesis and vasculogenesis and participates in brain tissue responses to ischemia and seizures. We therefore hypothesized that abnormal gene expression of fibronectin and other extracellular matrix genes would be found in SWS brain tissue and SWS port-wine skin fibroblasts. Fibronectin gene and protein expression from port-wine-derived fibroblasts were compared with that from normal skin-derived fibroblasts of four individuals with SWS using microarrays, reverse transcriptase-PCR, Western analysis, and immunocytochemistry. Fibronectin gene and/or protein expression from eight SWS surgical brain samples was compared with that in two surgical epilepsy brain samples and six postmortem brain samples using microarrays, reverse transcriptase-PCR, and Western analysis. The gene expression of fibronectin was significantly increased (p < 0.05) in the SWS port-wine-derived fibroblasts compared with that of fibroblasts from SWS normal skin. A trend for increased protein levels of fibronectin in port-wine fibroblasts was found by Western analysis. No difference in the pattern of fibronectin staining was detected. The gene expression of fibronectin was significantly increased (p < 0.05), and a trend for increased fibronectin protein expression was found in the SWS surgical brain samples compared with the postmortem controls. These results suggest a potential role for fibronectin in the pathogenesis of SWS and in the brain's response to chronic ischemic injury in SWS. The reproducible differences in fibronectin gene expression between the SWS port-wine-derived fibroblasts and the SWS normal skin-derived fibroblasts are consistent with the presence of a hypothesized somatic mutation underlying SWS.
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PMID:Increased fibronectin expression in sturge-weber syndrome fibroblasts and brain tissue. 1262 Nov 18

T cells may encounter glutamate, the major excitatory neurotransmitter in the nervous system, when patrolling the brain and in glutamate-rich peripheral organs. Moreover, glutamate levels increase in the CNS in many pathological conditions in which T cells exert either beneficial or detrimental effects. We discovered that normal human T cells, human T leukemia cells, and mouse anti-myelin basic protein T cells express high levels of glutamate ion channel receptor (ionotropic) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3). The evidence for GluR3 on T cells includes GluR3-specific RT-PCR, Western blot, immunocytochemical staining and flow cytometry. Sequencing showed that the T cell-expressed GluR3 is identical with the brain GluR3. Glutamate (10 nM), in the absence of any additional molecule, triggered T cell function: integrin-mediated T cell adhesion to laminin and fibronectin, a function normally performed by activated T cells only. The effect of glutamate was mimicked by AMPA receptor-agonists and blocked specifically by the selective receptor-antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-dione (NBQX), and by relevant anti-integrin mAbs. Glutamate also increased the CXCR4-mediated T cell chemotactic migration toward the key chemokine CXCL12/stromal cell-derived factor-1. GluR3 expression on normal, cancer and autoimmune-associated T cells and the ability of glutamate to directly activate T cell function could be of substantial scientific and clinical importance to normal neuroimmune dialogues and to CNS diseases and injury, and especially to: 1) T cell transmigration to the CNS and patrolling in the brain, 2) T cell-mediated multiple sclerosis, and 3) autoimmune epilepsy, as neurotoxic anti-GluR3 Abs are found and suspected to cause/potentiate seizures and neuropathology in several types of human epilepsies. Thus far, GluR3 was found only on neurons and glia cells; our results reveal a novel peripheral source of this antigenic receptor.
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PMID:Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. 1268 73

Seizure disorders present an attractive gene therapy target, particularly because viral vectors such as adeno-associated virus (AAV) and lentivirus can stably transduce neurons. When we targeted the N-methyl-D-aspartic acid (NMDA) excitatory amino acid receptor with an AAV-delivered antisense oligonucleotide, however, the promoter determined whether focal seizure sensitivity was significantly attenuated or facilitated. One potential means to circumvent this liability would be to express an inhibitory neuroactive peptide and constitutively secrete the peptide from the transduced cell. The neuropeptide galanin can modulate seizure activity in vivo, and the laminar protein fibronectin is usually secreted through a constitutive pathway. Initially, inclusion of the fibronectin secretory signal sequence (FIB) in an AAV vector caused significant gene product secretion in vitro. More importantly, the combination of this secretory signal with the coding sequence for the active galanin peptide significantly attenuated in vivo focal seizure sensitivity, even with different promoters, and prevented kainic acid-induced hilar cell death. Thus, neuroactive peptide expression and local secretion provides a new gene therapy platform for the treatment of neurological disorders.
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PMID:Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. 1289 58

We have investigated changes in the extracellular matrix of the hippocampus associated with the early progression of epileptogenesis in a murine model of temporal lobe epilepsy using immunohistochemistry. In the first week following intrahippocampal injection of the glutamate agonist, domoate, there is a latent period at the end of which begins a sequential upregulation of extracellular matrix (ECM) molecules in the granule cell layer of the dentate gyrus, beginning with neurocan and tenascin-C. This expression precedes the characteristic dispersion of the granule cell layer which is evident at 14 days post-injection when the first recurrent seizures can be recorded. At this stage, an upregulation of the chondroitin sulfate proteoglycan, phosphacan, the DSD-1 chondroitin sulfate motif, and the HNK-1 oligosaccharide are also observed. The expression of these molecules is localized differentially in the epileptogenic dentate gyrus, especially in the sprouting molecular layer, where a strong upregulation of phosphacan, tenascin-C, and HNK-1 is observed but there is no expression of the proteoglycan, neurocan, nor of the DSD-1 chondroitin sulfate motif. Hence, it appears that granule cell layer dispersion is accompanied by a general increase in the ECM, while mossy fiber sprouting in the molecular layer is associated with a more restricted repertoire. In contrast to these changes, the expression of the ECM glycoproteins, laminin and fibronectin, both of which are frequently implicated in tissue remodelling events, showed no changes associated with either granule cell dispersion or mossy fiber sprouting, indicating that the epileptogenic plasticity of the hippocampus is accompanied by ECM interactions that are characteristic of the CNS.
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PMID:Differential upregulation of extracellular matrix molecules associated with the appearance of granule cell dispersion and mossy fiber sprouting during epileptogenesis in a murine model of temporal lobe epilepsy. 1550 89

Intractable temporal lobe epilepsy presents an ideal target for gene therapy, but therapeutic success depends upon the ability to suppress limbic seizure activity. Adeno-associated virus vectors (AAV) were constructed in which the fibronectin secretory signal sequence (FIB) preceded the coding sequence for galanin (AAV-FIB-GAL) or green fluorescent protein (AAV-FIB-GFP), constructs that express and constitutively secrete the gene product. Bilateral AAV-FIB-GAL infusion into the rat piriform cortex (2 microl/side) significantly attenuated kainic acid-induced seizures (10 mg/kg, ip) such that 11/12 rats exhibited no limbic seizures, while the remaining rat exhibited only a brief, single class III seizure. This AAV-FIB-GAL infusion also prevented electrographic seizure activity. In contrast, bilateral AAV-FIB-GFP infusion did not alter either behavioral or electrographic seizure activity. Since prior seizure exposure could influence vector efficacy, another group of rats received daily electrical stimulation of the piriform cortex until three consecutive class V seizures were elicited. Subsequently, AAV-FIB-GAL or AAV-FIB-GFP (3 microl/30 min) was infused into the area of the electrode. One week later the AAV-FIB-GAL rats exhibited a significant increase in the stimulation current necessary to evoke limbic seizure activity, while AAV-FIB-GFP did not alter the seizure threshold. Thus, AAV-mediated galanin expression and secretion significantly suppress limbic seizure activity in vivo.
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PMID:Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. 1673 Apr 75


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