UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we show that single, physiologically-active and non-convulsive doses of the three GABA(B) receptor antagonists CGP 36742, CGP 56433A and CGP 56999A increase NGF and BDNF mRNA levels by 200-400% and protein levels by 200-250% in rat neocortex, hippocampus as well as spinal cord. In all areas examined the increase in NGF protein preceded that of BDNF. Peak levels of both neurotrophins are transient and occur between 24 and 72 h, depending on the region. In contrast, NT-3 protein concentrations in the neocortex and hippocampus were decreased significantly to 50% of control values within 48-96 h. The decrease in the spinal cord was less than 30% and did not reach significant levels. These data clearly demonstrate that GABA(B) receptor antagonists induce a specific neurotrophin expression in the central nervous system at physiologically relevant doses, as opposed to the extreme conditions of seizure paradigms. The results are in line with the concept that neuronal neurotrophin synthesis and release in brain are controlled by afferent nerve activity. GABA(B) receptor antagonists could therefore be a valuable new approach to selectively increase endogenous neurotrophin levels in the central nervous system.
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PMID:GABA(B) receptor antagonists elevate both mRNA and protein levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) in brain and spinal cord of rats. 1069 11

The expression of brain-derived neurotrophic factor and the alpha subunit of calcium/calmodulin-dependent protein kinase II mRNA in hippocampi obtained during surgical resections for intractable temporal lobe epilepsy were examined. Both calcium/calmodulin-dependent protein kinase II and brain-derived neurotrophic factor are localized heavily within the hippocampus and have been implicated in regulating hippocampal activity (Kang and Schuman [1995] Science 267:1658-1662; Suzuki [1994] Intl J Biochem 26:735-744). Also, the autocrine and paracrine actions of brain-derived neurotrophic factor within the central nervous system make it a likely candidate for mediating morphologic changes typically seen in the epileptic hippocampus. Quantitative assessments of mRNA levels in epileptic hippocampi relative to autopsy controls were made by using normalized densitometric analysis of in situ hybridization. In addition, correlations between clinical data and mRNA levels were studied. Relative to autopsy control tissue, decreased hybridization to mRNA of the alpha subunit of calcium/calmodulin-dependent protein kinase II and increased hybridization to brain-derived neurotrophic factor mRNA were found throughout the granule cells of the epileptic hippocampus. There also was a significant negative correlation between the duration of epilepsy and the expression of mRNA for brain-derived neurotrophic factor. These results are similar qualitatively to those found in animal models of epilepsy and suggest that chronic seizure activity in humans leads to persistent alterations in gene expression. Furthermore, these alterations in gene expression may play a role in the etiology of the epileptic condition.
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PMID:Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy. 1071 70

Insight into the mechanisms of action of neurotrophic growth factors has been obtained through the identification and characterization of gene products that are regulated or modified at the transcriptional, translational, and/or posttranslational level in response to neurotrophin treatment. VGF (non-acronymic) was identified approximately 15 years ago as a nerve growth factor (NGF)-regulated transcript in rat PC12 pheochromocytoma cells. Subsequent studies have demonstrated that neurotrophins such as NGF and brain-derived neurotrophic factor induce vgf gene expression relatively rapidly in PC12 cells and cultured cortical neurons, respectively, in comparison to less robust regulation by epidermal growth factor (EGF) and insulin, growth factors which do not trigger the neuronal differentiation of PC12 cells. vgf gene expression is stimulated in vitro by NGF and the ras/map kinase signaling cascade through a CREB-dependent mechanism, while in vivo, VGF mRNA levels are regulated by neuronal activity, including long-term potentiation, seizure, and injury. Both the mRNA and encoded approximately 68-kDa protein (VGF) are selectively synthesized in neuroendocrine and neuronal cells. The predicted VGF sequence is rich in paired basic amino acid residues that are potential sites for proteolytic processing, and VGF undergoes regulated release from dense core secretory vesicles. Although VGF mRNA is synthesized widely, by neurons in the brain, spinal cord, and peripheral nervous system, its expression is particularly abundant in the hypothalamus. In addition, VGF peptides are found in hypophysial, adrenal medullary, gastrointestinal, and pancreatic endocrine cells, suggesting important neuroendocrine functions. Recent analysis of VGF knockout mice indeed demonstrates that VGF plays a critical role in the control of energy homeostasis. VGF knockout mice are thin, small, hypermetabolic, hyperactive, and relatively infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic pro-opiomelanocortin, neuropeptide Y, and agouti-related peptide expression. Coupled with the demonstration that VGF mRNA levels are induced in the normal mouse hypothalamic arcuate nuclei in response to fasting, important central and peripheral roles for VGF in the regulation of metabolism are suggested. Here we review previous studies of VGF in the broader context of its newly recognized role in the control of energy balance and propose several models and experimental approaches that may better define the mechanisms of action of VGF.
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PMID:VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance. 1088 40

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a therapeutic tool in various neurological and psychiatric disorders, and we recently found that it has a neuroprotective effect both in vitro and in vivo. However, the neurochemical mechanisms underlying the therapeutic effects are still unknown. We investigated the effects of long-term rTMS on the expression of brain-derived neurotrophic factor (BDNF), cholecystokinin (CCK), and neuropeptide tyrosine (NPY) mRNA in rat brain. In situ hybridization revealed a significant increase in BDNF mRNA in the hippocampal areas CA3 and CA3c, the granule cell layer, as well as in the parietal and the piriform cortex after rTMS. BDNF-like immunoreactivity was markedly increased in the same areas. A significant increase in CCK mRNA was observed in all brain regions examined. NPY mRNA expression, in contrast, was not altered. The present results suggest that BDNF may contribute to the neuroprotective effects of rTMS. Furthermore, the rTMS-induced changes in BDNF and CCK expression are similar to those reported after antidepressant drug treatment and electroconvulsive seizures, suggesting that a common molecular mechanism may underlie different antidepressant treatment strategies.
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PMID:Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain. 1088 47

Kindling is a model of the neural plasticity that occurs following stimulation to the brain, which can result in epileptogenesis. The amygdala (Am), one of the most sensitive structures from which to induce electrical kindling, is comprised of distinct nuclei that possess differences in threshold for seizure initiation, unique cellular and molecular morphology, and specific neuroanatomical connections within the amygdala and, to other cortical and subcortical brain structures. The aim of this study was to map the spread of epileptiform activity throughout the ipsilateral and contralateral hemispheres during the transition stage between oral automatisms and generalized clonic seizures, by measuring changes in mRNA expression for c-fos, NGFI-A, and BDNF. The stimulating electrode was implanted in either the basolateral (BL) or the lateral (CeL) or medial (CeM) subdivisions of the central nucleus of the amygdala. The rats were kindled once daily using afterdischarge-threshold electrical stimulation until the first forelimb clonic seizure was induced. They were sacrificed 30 min later, and their brains were prepared for in situ hybridization to measure mRNA expression of c-fos, NGFI-A and BDNF. The results demonstrate that: (1) the threshold to elicit an afterdischarge from the BL was lower than that of either the medial (CeM) or lateral (CeL) subdivisions of the Ce, which did not differ from each other; (2) the patterns of mRNA expression for c-fos, NGFI-A and BDNF were highly similar to each other when the stimulation site was the BL or the CeL, and included mainly limbic cortical and subcortical areas ipsilateral to the electrode; (3) c-fos was the only probe to be expressed in the contralateral hemisphere following the first motor seizure, and the pattern of its expression reflected a subset of structures recruited in the ipsilateral hemisphere including the claustrum, insular and perirhinal cortices; (4) unexpectedly, stimulation of the CeM elicited seizures and afterdischarges of shorter duration than those evoked by stimulation of the BL or CeL, and failed to increase mRNA expression for any of the probes in the hippocampus or in the contralateral hemisphere. A neuroanatomical model of Am-induced seizure propagation is proposed suggesting that the Claust-Ins-PRh play a pivotal role during the transition between oral automatisms and generalized clonic convulsions.
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PMID:Specific amygdaloid nuclei are involved in suppression or propagation of epileptiform activity during transition stage between oral automatisms and generalized clonic seizures. 1091 5

Epileptic seizures increase the expression of brain-derived neurotrophic factor in the hippocampus. Since this neurotrophin exerts modulatory effects on neuronal excitability in this structure, it may play an important role in hippocampal epileptogenesis. This question was addressed by studying the effects of chronic infusions of recombinant brain-derived neurotrophic factor and brain-derived neurotrophic factor antisense in the hippocampus during the first seven days of hippocampal kindling. Infusion with brain-derived neurotrophic factor (6-24 microg/day) significantly delayed the progression of standard hippocampal kindling and strongly suppressed seizures induced by rapid hippocampal kindling. These suppressive effects were dose dependent, long lasting, not secondary to neuronal toxicity and specific to this neurotrophin, as nerve growth factor accelerated hippocampal kindling progression. They also appeared to be specific to the hippocampus, as infusion of brain-derived neurotrophic factor (48 microg/day) in the amygdala only resulted in a slight and transient delay of amygdala kindling. Conversely to the protective effects of exogenous brain-derived neurotrophic factor, chronic hippocampal infusion of antisense oligodeoxynucleotides (12 nmol/day), resulting in reduced expression of endogenous brain-derived neurotrophic factor in the hippocampus, aggravated seizures during hippocampal kindling. Taken together, our results lead us to suggest that the seizure-induced increase in brain-derived neurotrophic factor expression in the hippocampus may constitute an endogenous regulatory mechanism able to restrain hippocampal epileptogenesis.
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PMID:Brain-derived neurotrophic factor delays hippocampal kindling in the rat. 1103 11

Various studies have shown that brain-derived neurotrophic factor (BDNF) increases neuronal excitability and is localized and upregulated in areas implicated in epileptogenesis. Seizure activity increases the expression of BDNF mRNA and protein, and recent studies have shown that interfering with BDNF signal transduction inhibits the development of the epileptic state in vivo. These results suggest that BDNF contributes to epileptogenesis. Further analysis of the cellular and molecular mechanisms by which BDNF influences excitability and connectivity in adult brain could provide novel concepts and targets for anticonvulsant or anti-epileptogenic therapy.
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PMID:BDNF and epilepsy: too much of a good thing? 1142 Dec 32

Recent evidence suggests hippocampal and possibly cortical atrophy is associated with major depression. Chronic electroconvulsive seizures (ECS) induce brain-derived neurotrophic factor (BDNF) expression and sprouting of the mossy fiber pathway in the hippocampus, effects that may be related to electroconvulsive therapy's (ECT) mechanism of action. The objective of this study was to investigate the role of NMDA (N-methyl-D-aspartate) receptor in mediating the ECS-induced mossy fiber sprouting and BDNF expression. Timm histochemistry and in situ hybridization methodologies were used to determine the effect of pretreatment with ketamine, an NMDA antagonist, on ECS-induced sprouting and BDNF expression. The results demonstrate the ability of ketamine pretreatment to attenuate ECS-induced sprouting in the dentate gyrus and BDNF expression in the medial prefrontal cortex and the dentate gyrus. In addition, we found a significant decrease in seizure duration with ketamine pretreatment. These data suggest that NMDA receptor activation contributes to both the regulation of neurotrophic factor expression and the morphological changes associated with seizure activity. However, other effects resulting from shortened seizure duration and seizure intensity cannot be excluded. These findings are of increasing interest, as they relate to the use of ECT in the treatment of depression, and the specific anesthetic agents that are used.
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PMID:ECS-Induced mossy fiber sprouting and BDNF expression are attenuated by ketamine pretreatment. 1128 11

We have recently characterized an animal model of status epilepticus induced by a single intraseptal injection of kainate. Under these conditions, there is a delayed expanding apoptotic hippocampal and amygdalar cell death. In order to further characterize this animal model, we have performed a detailed time-course analysis of the appearance of cell death, brain-derived neurotrophic factor messenger RNA expression and astroglial and microglial response in different brain areas related to the limbic system. We found a long-lasting delayed apoptotic cell death in the hippocampal formation, amygdala, medial thalamus, dorsal endopiriform nucleus and multiple cortical areas from two to 21 days post-injection. There was a spatiotemporal correlation between the appearance of cell death and induction of brain-derived neurotrophic factor messenger RNA expression in the areas studied, and interestingly this induction was found in non-degenerating cells. We conclude that our animal model of status epilepticus exhibits remarkable features of recurrent seizure activity and provides evidence for a neuroprotective role of brain-derived neurotrophic factor against seizure-induced apoptotic cell death.
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PMID:Long-lasting induction of brain-derived neurotrophic factor is restricted to resistant cell populations in an animal model of status epilepticus. 1130 Dec 4

The perirhinal cortex has recently been implicated in the kindling of limbic generalized seizures. The following experiments in rats tested the selectivity of the perirhinal cortex's epileptogenic properties by comparing its kindling profile with those of the adjacent insular cortex, posterior (dorsolateral) claustrum and amygdala. The first experiment examined the kindling and EEG profiles, and found that both the claustrum and insular cortex demonstrated rapid epileptogenic properties similar to the perirhinal cortex, including very rapid kindling rates and short latencies to convulsion. Furthermore, electrical stimulation of all three structures led to a two-phase progression through stage-5 seizures which had characteristics of both neocortical and amygdaloid kindling. In a second experiment rats were suspended in a harness to allow for more detailed documentation of both forelimb and hindlimb convulsions. With this procedure we were able to detect subtle yet unique differences in convulsion characteristics from each of the kindled sites and stage-5 seizure phases. Some of these convulsive parameters were correlated with changes in FosB/DeltaFosB protein and BDNF mRNA expression measured two hours after the last convulsion. Overall, it appears that the perirhinal cortex is not unique in its property of rapid epileptogenesis. Moreover, the posterior claustrum exhibited the fastest kindling and most vigorous patterns of clonus, suggesting that it may be even more intimately associated with the motor substrates responsible for limbic seizure generalization than is the perirhinal cortex.
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PMID:Kindling of claustrum and insular cortex: comparison to perirhinal cortex in the rat. 1132 45

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