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)

Kindling, an animal model of epilepsy, results in an increased volume of the hilus of the dentate gyrus and sprouting of the mossy fiber pathway in the hippocampus. Our previous studies have revealed that chronic infusion of neurotrophins can regulate not only seizure development, but also these kindling-induced structural changes. Kindling, in turn, can alter the expression of neurotrophins and their receptors. We previously showed that intraventricular administration of a synthetic peptide that interferes with nerve growth factor stability and thus its binding to TrkA and p75(NTR) receptors suppressed kindling and sprouting. However, the precise involvement of TrkA, p75(NTR), and downstream signaling effectors of neurotrophins on kindling, sprouting and hilar changes are unknown. One of these downstream effectors is Ras. In the present study, we find that intraventricular infusion of the synthetic peptide Reo3Y, which binds to p65/p95 receptors and causes a rapid inactivation of Ras protein, impairs development of perforant path kindling, reduces the growth in afterdischarge duration, blocks kindling-induced mossy fiber sprouting in area CA3 of hippocampus and in inner molecular layer of the dentate gyrus, and prevents kindling-induced increases in hilar area. These results are consistent with a mediation of neurotrophin effects on kindling, hilar area, and axonal sprouting via Trk receptors, and suggest important roles for Ras in kindling and in kindling-induced structural changes.
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PMID:A ligand of the p65/p95 receptor suppresses perforant path kindling, kindling-induced mossy fiber sprouting, and hilar area changes in adult rats. 1283 69

Zinc induces in cultured cortical neurons both p75(NTR) and p75(NTR)-associated death executor (NADE), which together contribute to caspase-dependent neuronal apoptosis. Since zinc neurotoxicity may contribute to neuronal death following seizures, we examined whether p75(NTR) and NADE are co-induced also in rat hippocampal neurons degenerating after seizures. Staining of brain sections with a zinc-specific fluorescent dye (N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide) and acid fuchsin revealed zinc accumulation in degenerating neuronal cell bodies in CA1 and CA3 of hippocampus 24 h after kainate injection. Both anti-p75(NTR) and anti-NADE immunoreactivities appeared in zinc-accumulating/degenerating neurons in both areas. Intraventricular injection of CaEDTA, without altering the severity or time course of kainate-induced seizures, markedly attenuated the induction of p75(NTR)/NADE in hippocampus, which correlated with the decrease of caspase-3 activation and zinc accumulation/cell death. The present study has demonstrated that p75(NTR) and NADE are co-induced in neurons degenerating after kainate-induced seizures in rats, likely in a zinc-dependent manner.
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PMID:Co-induction of p75(NTR) and the associated death executor NADE in degenerating hippocampal neurons after kainate-induced seizures in the rat. 1287 43

To study the role of neurotrophin-responsive neurons in brain growth and developmental resistance to seizure-induced injury, we infused saporin-conjugated 192-IgG (192 IgG-saporin), a monoclonal antibody directed at the P75 neurotrophin receptors (p75(NTR)), into the ventricles of postnatal day 8 (P8) rat pups. 7-10 days after immunotoxin treatment, loss of p75(NTR) immunoreactivity was associated with depletion of basal forebrain cholinergic projection to the neocortex and hippocampus. Kainic acid (KA)-induced seizures on P15 resulted in hippocampal neuronal injury in the majority of toxin-treated animals (13/16), but only rarely in saline-injected controls (2/25) (P < 0.001). In addition, widespread cerebral atrophy and a significant decrease in brain weight with preserved body weight were observed. Volumetric analysis of the hippocampal hilar region revealed a 2-fold reduction in perikaryal size and a 1.7-fold increase in cell packing density after 192 IgG-saporin injection. These observations indicate that neurotrophin-responsive neurons including basal forebrain magnocellular cholinergic neurons may be critical for normal brain growth and play a protective role in preventing excitotoxic neuronal injury during development.
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PMID:Susceptibility to seizure-induced injury and acquired microencephaly following intraventricular injection of saporin-conjugated 192 IgG in developing rat brain. 1602 71

Seizure-induced damage elicits a loss of hippocampal neurons mediated to a great extent by the p75 neurotrophin receptor (NTR). Proneurotrophins, which are potent apoptosis-inducing ligands for p75(NTR), were increased in the hippocampus, particularly in astrocytes, by pilocarpine-induced seizures; and infusion of anti-pro-NGF dramatically attenuated neuronal loss after seizures. The p75(NTR) is expressed in many different cell types in the nervous system, and can mediate a variety of different cellular functions by recruiting specific intracellular binding proteins to activate distinct signaling pathways. In this study, we demonstrate that neurotrophin receptor-interacting factor (NRIF) mediates apoptotic signaling via p75(NTR) in hippocampal neurons in vitro and in vivo. After seizure-induced injury, NRIF(-/-) mice showed an increase in p75(NTR) expression in the hippocampus; however, these neurons failed to undergo apoptosis in contrast to wild-type mice. Treatment of cultured hippocampal neurons with proneurotrophins induced association of NRIF with p75(NTR) and subsequent translocation of NRIF to the nucleus, which was dependent on cleavage of the receptor. Neurons lacking NRIF were resistant to p75(NTR)-mediated apoptosis in vitro and in vivo. In addition, we demonstrate some mechanistic differences in p75(NTR) signaling in hippocampal neurons compared with other cell types. Overall, these studies demonstrate the requirement for NRIF to signal p75(NTR)-mediated apoptosis of hippocampal neurons and that blocking pro-NGF can inhibit neuronal loss after seizures.
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PMID:Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures. 1881 71

The p75 neurotrophin receptor has been implicated in the regulation of multiple cellular functions that differ depending on the cell context. We have observed that p75(NTR) is strongly induced on astrocytes as well as neurons in the hippocampal CA3 region after seizures; however, the function of this receptor on these glial cells has not been defined. We have employed a primary culture system to investigate the effects of neurotrophins on astrocytes. Treatment of hippocampal astrocytes with nerve growth factor (NGF) caused a reduction in cell number, but did not elicit an apoptotic response, in contrast to hippocampal neurons. Instead, activation of p75(NTR) by NGF attenuated proliferation induced by mitogens such as EGF or serum. These studies demonstrate the cell type specificity of neurotrophin functions in the brain.
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PMID:Nerve growth factor attenuates proliferation of astrocytes via the p75 neurotrophin receptor. 1922 90

Neurons respond to numerous factors in their environment that influence their survival and function during development and in the mature brain. Among these factors, the neurotrophins have been shown to support neuronal survival and function, acting primarily through the Trk family of receptor tyrosine kinases. However, recent studies have established that the uncleaved neurotrophin precursors, the proneurotrophins, can be secreted and induce apoptosis via the p75 neurotrophin receptor, suggesting that the balance of secreted mature and proneurotrophins has a critical impact on neuronal survival or death. Epileptic seizures elicit increases in both proneurotrophin secretion and p75(NTR) expression, shifting the balance of these factors toward signaling cell death. This review will discuss the evidence that this ligand-receptor system plays an important role in neuronal loss following seizures.
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PMID:Proneurotrophins, seizures, and neuronal apoptosis. 2036 Jun 2

Proneurotrophins and mature neurotrophins activate different signaling pathways with distinct effects on their target cells: proneurotrophins can induce apoptotic signaling via p75(NTR), whereas mature neurotrophins activate Trk receptors to influence survival and differentiation. Here, we demonstrate that the PTEN (phosphatase and tensin homolog deleted on chromosome 10) phosphatase represents a novel switch between the survival and apoptotic signaling pathways in rat CNS neurons. Simultaneous activation of p75(NTR) by proNGF and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation. Apoptosis induced by p75(NTR) required suppression of TrkB-induced phosphoinositide-3 kinase signaling, mediated by induction of PTEN, for apoptosis to proceed. Inhibition of PTEN restored the ability of BDNF to phosphorylate Akt and protect cultured basal forebrain neurons from proNGF-induced death. In vivo, inhibition or knockdown of PTEN after pilocarpine-induced seizures protected CNS neurons from p75(NTR)-mediated death, demonstrating that PTEN is a crucial factor mediating the balance between p75(NTR)-induced apoptotic signaling and Trk-mediated survival signaling in brain neurons.
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PMID:ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. 2108 16

Neurotrophins can influence multiple cellular functions depending on the cellular context and the specific receptors they interact with. These neurotrophic factors have been extensively studied for their ability to support neuronal survival via Trk receptors and to induce apoptosis via the p75(NTR). However, the p75(NTR) is also detected on cell populations that do not undergo apoptosis in response to neurotrophins. In particular, the authors have detected p75(NTR) expression on astrocytes during development and after seizure-induced injury. In this study, the authors investigated the role of Nerve growth factor (NGF) in regulating astrocyte proliferation and in influencing specific aspects of the cell cycle. The authors have demonstrated that NGF prevents the induction of cyclins and their association with specific cyclin-dependent kinases, and thereby prevents progression through the G1 phase of the cell cycle. Since the authors have previously shown that p75(NTR) but not TrkA, is expressed in astrocytes, these data suggest that activation of p75(NTR) promotes withdrawal of astrocytes from the cell cycle, which may have important consequences during development and after injury.
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PMID:Nerve growth factor induces cell cycle arrest of astrocytes. 2195 22

The neurotrophin nerve growth factor (NGF) regulates neuronal growth, differentiation, and survival during development. However, the precursor of NGF, proNGF, is a potent apoptotic ligand for the p75 neurotrophin receptor (p75(NTR))-sortilin complex. The mechanisms that regulate cleavage of proNGF, therefore, are critical determinants of whether this factor promotes neuronal survival or death. In this study, we demonstrate that, following kainic acid-induced seizures, the proNGF processing enzyme matrix metalloproteinase 7 (MMP-7) and its inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinase 1) are regulated in a manner that prevents proneurotrophin cleavage and leads to increased proNGF in the extracellular milieu. Furthermore, we demonstrate both in vitro and in vivo that exogenous MMP-7 enhances proNGF cleavage and provides neuroprotection following kainic acid treatment. These data demonstrate that increased extracellular proNGF levels following seizures are stabilized by altered MMP-7 enzymatic activity, leading to increased neuronal death via activation of p75(NTR).
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PMID:Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. 2259 20

Pilocarpine injection induces epileptic seizures in rodents, an experimental paradigm extensively used to model temporal lobe epilepsy in humans. It includes conspicuous neuronal death in the forebrain and previous work has demonstrated an involvement of the neurotrophin receptor p75(NTR) in this process. Following the identification of Galectin-1 (Gal-1) as a downstream effector of p75(NTR), we examine here the role of this endogenous lectin in pilocarpine-induced cell death in adult mice. We found that most somatostatin-positive neurons also express Gal-1 and that in mice lacking the corresponding gene Lgals1, pilocarpine-induced neuronal death was essentially abolished in the forebrain. We also found that the related lectin Galectin-3 (Gal-3) was strongly upregulated by pilocarpine in microglial cells. This upregulation was absent in Lgals1 mutants and our results with Lgals3-null animals show that Gal-3 is not required for neuronal death in the hippocampus. These findings provide new insights into the roles and regulation of endogenous lectins in the adult CNS and a surprisingly selective proapoptotic role of Gal-1 for a subpopulation of GABAergic interneurons.
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PMID:Seizure-induced neuronal death is suppressed in the absence of the endogenous lectin Galectin-1. 2311 94


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