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)

Pathophysiological activity and various kinds of traumatic insults are known to have deleterious long-term effects on neuronal Cl- regulation, which can lead to a suppression of fast postsynaptic GABAergic responses. Brain-derived neurotrophic factor (BDNF) increases neuronal excitability through a conjunction of mechanisms that include regulation of the efficacy of GABAergic transmission. Here, we show that exposure of rat hippocampal slice cultures and acute slices to exogenous BDNF or neurotrophin-4 produces a TrkB-mediated fall in the neuron-specific K+-Cl- cotransporter KCC2 mRNA and protein, as well as a consequent impairment in neuronal Cl- extrusion capacity. After kindling-induced seizures in vivo, the expression of KCC2 is down-regulated in the mouse hippocampus with a spatiotemporal profile complementary to the up-regulation of TrkB and BDNF. The present data demonstrate a novel mechanism whereby BDNF/TrkB signaling suppresses chloride-dependent fast GABAergic inhibition, which most likely contributes to the well-known role of TrkB-activated signaling cascades in the induction and establishment of epileptic activity.
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PMID:BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion. 1247 84

Brain-derived neurotrophic factor (BDNF) appears to be both regulated by and a regulator of epileptogenesis. In the flurothyl (HFE) model of kindling mice exposed to successive flurothyl trials over 8 days express a rapid, long-lasting reduction in generalized seizure threshold and a more slowly evolving change in seizure phenotype in response to subsequent flurothyl exposure. The BDNF genotype of particular mouse strains appears to influence the epileptogenic progression in this model. Thus, we hypothesized that BDNF signaling pathways are altered by flurothyl-induced seizures. Following HFE kindling, fully kindled (eight seizures) adult male C57BI/6J mice had significantly elevated whole brain BDNF levels through at least 28 days after their final seizure. Mice that received only four HFE seizures (not kindled) had elevated BDNF levels, but only at 1 day post-seizure (DPSz), while BDNF levels were not significantly altered in mice receiving just one HFE seizure at any time point studied. Regional expression patterns of BDNF in the hippocampus, hypothalamus, and frontal cortex were also elevated by one DPSz and returned to control values by 14 DPSz in mice that received four HFE seizures. No changes were seen in the cerebellum, striatum, or piriform cortex. In contrast, fully kindled mice had significantly elevated BDNF levels within the hippocampus, hypothalamus, neocortex, and striatum that remained elevated through at least 14 DPSz, while levels were unchanged in the cerebellum and piriform cortex. Regional results were confirmed using anti-BDNF immunohistochemistry (IHC). Despite changes in BDNF levels following HFE kindling, we were unable to demonstrate alterations either in full-length tyrosine kinase receptor B (TrkB) expression (Western blot and IHC) or in truncated TrkB (IHC) expression levels. Together, these data suggest a model of a positive feedback loop involving seizure activity and seizure number and persistently modified BDNF signaling pathways that influences seizure phenotypes within the HFE kindling paradigm. Thus, long-term elevations in BDNF may be responsible in part for epileptogenic processes and the development of human refractory epilepsies.
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PMID:Persistent regional increases in brain-derived neurotrophic factor in the flurothyl model of epileptogenesis are dependent upon the kindling status of the animal. 1458 Sep 53

The amygdala-kindling model has been proposed as a model of sensitization processes with relevance to epilepsy as well as affective disorders. Levetiracetam is a novel anticonvulsant drug that delays the process of kindling, i.e., possesses antiepileptogenic properties. Preliminary reports also suggest a mood-stabilizing potential for levetiracetam. Brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) are central modulators of seizure activity, which undergo plastic changes during kindling epileptogenesis. Consequently, we investigated the regulation of BDNF and NPY mRNA and Y1-, Y2-, and Y5-like receptor binding in the hippocampus of vehicle-pretreated, partially and fully amygdala-kindled rats and corresponding levetiracetam-pretreated rats (40 mg/kg i.p.). The present data indicate that the process of kindling is associated with an upregulation of hippocampal BDNF and NPY mRNA levels and downregulation of Y1- and particularly Y5-like receptors. Pretreatment with levetiracetam markedly delays the progression of kindling and, in addition, exhibits a clear anticonvulsant effect. These effects are associated with abolition of the kindling-induced rise in BDNF and NPY mRNA and increasing levels of Y1- and particularly Y5-like receptors in all hippocampal subfields. Lastly, the present study reveals that an identical dose of levetiracetam reduced immobility in the rat forced swim test, the first experimental evidence indicative of an antidepressant and/or mood stabilizer-like profile of this drug. Considering that animal depression models display impairments in hippocampal NPY systems that become normalized following mood-stabilizing treatment, and that exogenous NPY exerts anticonvulsant as well as antidepressive-like activity in rodents, it is a heuristic possibility that increased hippocampal excitability and affective symptomatology may converge on an impaired hippocampal NPY function. Speculatively, the ability of levetiracetam to increase hippocampal Y1- and Y5-like receptor levels may have implications for the antiepileptic properties of levetiracetam, as well as its purported mood-stabilizing properties.
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PMID:Levetiracetam prevents changes in levels of brain-derived neurotrophic factor and neuropeptide Y mRNA and of Y1- and Y5-like receptors in the hippocampus of rats undergoing amygdala kindling: implications for antiepileptogenic and mood-stabilizing properties. 1512 22

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that mediates synaptic plasticity and excitability in the CNS. Recent evidence has shown that increased BDNF levels can lead to hyperexcitability and epileptiform activities, while suppression of BDNF function in transgenic mice or by antagonist administration retards the development of seizures. However, several groups, including our own, have reported that increasing BDNF levels by continuous intrahippocampal infusion inhibits epileptogenesis. It is possible that the continuous administration of BDNF produces a down-regulation of its high-affinity TrkB receptor, leading to a decrease of neuronal responsiveness to BDNF. If so, then animals should respond differently to bolus injections of BDNF, which presumably do not alter Trk expression, compared with continuous infusion. To test this hypothesis, we compared the effects of intrahippocampal BDNF continuous infusion and bolus injections on kindling induction. We showed that continuous infusion of BDNF inhibited the development of behavioral seizures and decreased the level of phosphorylated Trks or TrkB receptors. In contrast, multiple bolus microinjections of BDNF accelerated kindling development and did not affect the level of phosphorylated Trks or TrkB receptors. Our results indicate that different administration protocols yield opposite effects of BDNF on neuronal excitability, epileptogenesis and Trk expression. Unlike nerve growth factor and neurotrophin-3, which affect mossy fiber sprouting, we found that BDNF administration had no effect on the mossy fiber system in naive or kindled rats. Such results suggest that the effects of BDNF on epileptogenesis are not modulated by its effect on sprouting, but rather by its effects on excitability.
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PMID:The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes. 1518 2

Brain-derived neurotrophic factor (BDNF) is expressed at high levels in the hippocampus, where it has been implicated in physiological functions such as the modulation of synaptic strength as well as in the pathophysiology of epileptic seizures. BDNF expression is highly regulated and the BDNF gene can generate multiple transcript isoforms by alternate splicing of four 5' exons (exons I-IV) to one 3' exon (exon V). To gain insight into the regulation of different BDNF transcripts in specific hippocampal subfields during postnatal development, exon-specific riboprobes were used. Our data shows that BDNF exon I and exon II mRNAs are regulated in hippocampal subfields during postnatal development, in contrast to BDNF exon III and exon IV mRNA, which remain relatively stable through this period. Further, exons I and II show distinct temporal patterns of expression in the hippocampus: BDNF I mRNA peaks in adulthood in contrast to BDNF II mRNA which peaks at postnatal day 14 (P14). Finally, we have addressed whether kainate treatment in postnatal pups and adults regulates BDNF through the recruitment of the same, or distinct, BDNF promoters. Our data indicates that kainate-induced seizures induce strikingly different expression of distinct BDNF transcripts, both in magnitude as well as spatial patterns in the hippocampal subfields, of pups as compared to adults. These results suggest that kainate-mediated seizures differentially recruit BDNF promoters in the developing postnatal hippocampus in contrast to the adult hippocampus to achieve a hippocampal subfield specific regulation of exon-specific BDNF mRNAs.
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PMID:Differential regulation of multiple brain-derived neurotrophic factor transcripts in the postnatal and adult rat hippocampus during development, and in response to kainate administration. 1551 87

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family which interacts with high-affinity protein kinase receptors (Trk) and the unselective p75(NGFR) receptor. The BDNF gene has a complex structure with multiple regulatory elements and four promoters that are differentially expressed in central or peripheral tissue. BDNF expression is regulated by neuronal activity or peripheral hormones. Neurotrophins regulate the survival and differentiation of neurons during development but growing evidence indicates that they are also involved in several functions in adulthood, including plasticity processes. BDNF expression in the central nervous system (CNS) is modified by various kinds of brain insult (stress, ischemia, seizure activity, hypoglycemia, etc.) and alterations in its expression may contribute to some pathologies such as depression, epilepsy, Alzheimer's, and Parkinson's disease. Apart from very traumatic situations, the brain functioning is resilient to stress and capable of adaptive plasticity. Neurotrophins might act as plasticity mediators enhancing this trait which seems to be crucial in adaptive processes. In addition to documenting all of the topics mentioned above in the CNS, we review the state of the art concerning neurotrophins and their receptors, including our personal contribution which is essentially focused on the stress response.
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PMID:Physiology of BDNF: focus on hypothalamic function. 1557 56

Autism, a childhood-onset neurodevelopmental disorder, is characterized by disturbances in socialization and language skills, as well as in perception. Several studies indicate the importance of both genetic and environmental factors in the development of idiopathic autism, but the underlying pathogenesis of this disorder is still unknown. Brain-derived neurotrophic factor (BDNF) is important for normal neuronal development. Early BDNF hyperactivity may play an etiological role in autism early in life. This hypothesis is supported by the finding that serum and brain tissue BDNF levels are increased in autism compared with normal controls. Furthermore, BDNF hyperactivity may be associated with early brain outgrowth, increased prevalence of seizures in autism, and similar behaviors observed in autism and fragile X syndrome. Further studies of serum BDNF levels and genetic studies of the BDNF signaling pathway may help to clarify the role of BDNF in the pathogenesis of autism. Attempts to prove the BDNF hyperactivity hypothesis may lead investigators in a new direction for the study of the pathogenesis of autism and the development of an effective intervention of this disorder.
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PMID:Is autism caused by early hyperactivity of brain-derived neurotrophic factor? 1589 22

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has drawn much attention as a potential therapeutic target for temporal lobe epilepsy (TLE). TLE seizures are produced by synchronized hyperactivity of neuron populations due to the disruption of a balance between excitatory and inhibitory synaptic transmissions. In epileptogenesis-related brain areas, including the hippocampus, BDNF is up-regulated in the course of the development of epilepsy and induces a collapse of balanced excitation and inhibition, eventually exerting its epileptogenic effects. On the other hand, several reports demonstrate that intrahippocampal infusion of BDNF can attenuate (or retard) the development of epilepsy. This antiepileptogenic effect seems to be mediated mainly by an increase in the expression of neuropeptide Y. These contrasting effects of BDNF have prevented us from concluding whether inhibition or enhancement of BDNF signaling finally achieves the prevention of TLE. To address this question, it is essential to evaluate how BDNF changes its influences depending on conditions, for example, cell specificity, neural networks, and expression timing and loci. In this article, the authors review BDNF-induced acute and long-lasting changes seen in epileptic circuits from the anatomical and functional points of view.
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PMID:To BDNF or not to BDNF: that is the epileptic hippocampus. 1606 15

Brain-derived neurotrophic factor (BDNF) has important functions in the development of the nervous system and in brain plasticity-related processes such as memory, learning, and drug addiction. Despite the fact that the function and regulation of rodent BDNF gene expression have received close attention during the last decade, knowledge of the structural organization of mouse and rat BDNF gene has remained incomplete. We have identified and characterized several mouse and rat BDNF transcripts containing novel 5' untranslated exons and introduced a new numbering system for mouse and rat BDNF exons. According to our results both mouse and rat BDNF gene consist of eight 5' untranslated exons and one protein coding 3' exon. Transcription of the gene results in BDNF transcripts containing one of the eight 5' exons spliced to the protein coding exon and in a transcript containing only 5' extended protein coding exon. We also report the distinct tissue-specific expression profiles of each of the mouse and rat 5' exon-specific transcripts in different brain regions and nonneural tissues. In addition, we show that kainic acid-induced seizures that lead to changes in cellular Ca(2+) levels as well as inhibition of DNA methylation and histone deacetylation contribute to the differential regulation of the expression of BDNF transcripts. Finally, we confirm that mouse and rat BDNF gene loci do not encode antisense mRNA transcripts, suggesting that mechanisms of regulation for rodent and human BDNF genes differ substantially.
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PMID:Mouse and rat BDNF gene structure and expression revisited. 1714 51

Brain-derived neurotrophic factor (BDNF) may exert contrasting effects depending on its different subcellular sites of action (soma, dendrites, axons). These contrasting effects may explain contradictory findings, for example that BDNF may favour or oppose epileptogenesis. We determined the distribution of five BDNF splice variants in the soma and dendrites of rat hippocampal principal neurons, after application of stimuli that prompt BDNF mRNA accumulation in dendrites (epileptogenic seizures). Under basal conditions, no BDNF mRNA splice variant was detectable in dendrites, while specific splice variants were found in dendrites in response to epileptogenic seizures. Three hours after pilocarpine administration, exon VI and exon II splice variants were found in dendrites, while exons I and IV transcripts displayed a strictly somatic localization. Three hours after kainate administration, only exon VI was found in dendrites. These data suggest that the regulated expression of different splice variants may provide a spatial code to ensure the delivery of BDNF to precise destinations in the cell soma or along the dendrites.
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PMID:BDNF mRNA splice variants display activity-dependent targeting to distinct hippocampal laminae. 1791 21


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