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)

Epilepsy is a serious neurological disorder in human beings and the long-term pathological events remain largely obscure. We are interested in elucidating long-term brain injury that may occur in the temporal lobe epilepsy, and time-course of neuronal death was examined in a mouse pilocarpine model of chronic epilepsy by Fluoro-Jade C (FJC) dye that can specifically stain the degenerative neurons in the central nervous system. The FJC stain combined with immunohistochemistry to neuronal nuclear specific protein revealed that pilocarpine-induced status epilepticus (SE) resulted in massive degenerative death of neuronal cells in brains with their dense distribution in the cerebral cortex and hippocampus. The FJC-positive degenerating neurons, most of them also expressed apoptosis signaling molecules such as caspase-9 and activated caspase-3, occurred at 4h, increased into peak levels at 12h-3d, and then gradually went down at 7d-14d after onset of SE. More interestingly, a large percentage (about 88%) of FJC-positive degenerative neurons were GABAergic as indicated with their immunoreactivity to glutamic acid decarboxylase-67, implying that inhibitory function of GABAergic neural system might by seriously damaged in brains subject to SE attack in this mouse pilocarpine model. Taken together with previous studies, time-course of degenerative neurons in the mouse pilocarpine model by Fluoro-Jade C staining further benefits understanding of long-term brain pathological changes and recurrent seizure mechanism, and may also result in finding the most suitable time-window in therapeutic manipulation of the chronic epilepsy in human beings.
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PMID:Time-course of neuronal death in the mouse pilocarpine model of chronic epilepsy using Fluoro-Jade C staining. 1870 38

Repeated electroconvulsive seizure (ECS), a model for electroconvulsive therapy (ECT), exerts neuroprotective and proliferative effects in the brain. This trophic action of ECS requires inhibition of apoptotic activity, in addition to activation of survival signals. c-Myc plays an important role in apoptosis of neurons, in cooperation with the Bcl-2 family proteins, and its activity and stability are regulated by phosphorylation and ubiquitination. We examined c-Myc and related proteins responsible for apoptosis after repeated ECS. In the rat frontal cortex, repeated ECS for 10 days reduced the total amount of c-Myc, while increasing phosphorylation of c-Myc at Thr58, which reportedly induces degradation of c-Myc. As expected, ubiquitination of both phosphorylated and total c-Myc increased after 10 days ECS, suggesting that ECS may reduce c-Myc protein level via ubiquitination-proteasomal degradation. Bcl-2 family proteins, caspase, and poly(ADP-ribose) polymerase (PARP) were investigated to determine the consequence of down-regulating c-Myc. Protein levels of Bcl-2, Bcl-X(L), Bax, and Bad showed no change, and cleavage of caspase-3 and PARP were not induced. However, phosphorylation of Bad at Ser-155 and binding of Bad to 14-3-3 increased without binding to Bcl-X(L) after repeated ECS, implying that repeated ECS sequesters apoptotic Bad and frees pro-survival Bcl-XL. Taken together, c-Myc down-regulation via ubiquitination-proteasomal degradation and Bad inactivation by binding to 14-3-3 may be anti-apoptotic mechanisms elicited by repeated ECS in the rat frontal cortex. This finding further supports the trophic effect of ECS blocking apoptosis as a possible therapeutic effect of ECT.
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PMID:Repeated electroconvulsive seizure induces c-Myc down-regulation and Bad inactivation in the rat frontal cortex. 1877 56

ATRX, a chromatin remodeling protein of the Snf2 family, participates in diverse cellular functions including regulation of gene expression and chromosome alignment during mitosis and meiosis. Mutations in the human gene cause alpha thalassemia mental retardation, X-linked (ATR-X) syndrome, a rare disorder characterized by severe cognitive deficits, microcephaly and epileptic seizures. Conditional inactivation of the Atrx gene in the mouse forebrain leads to neonatal lethality and defective neurogenesis manifested by increased cell death and reduced cellularity in the developing neocortex and hippocampus. Here, we show that Atrx-null forebrains do not generate dentate granule cells due to a reduction in precursor cell number and abnormal migration of differentiating granule cells. In addition, fewer GABA-producing interneurons are generated that migrate from the ventral telencephalon to the cortex and hippocampus. Staining for cleaved caspase 3 demonstrated increased apoptosis in both the hippocampal hem and basal telencephalon concurrent with p53 pathway activation. Elimination of the tumor suppressor protein p53 in double knock-out mice rescued cell death in the embryonic telencephalon but only partially ameliorated the Atrx-null phenotypes at birth. Together, these findings show that ATRX deficiency leads to p53-dependent neuronal apoptosis which is responsible for some but not all of the phenotypic consequences of ATRX deficiency in the forebrain.
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PMID:Neuronal death resulting from targeted disruption of the Snf2 protein ATRX is mediated by p53. 1902 49

The ketogenic diet (KD) is an alternative treatment for medically refractory epilepsy. Despite numerous mechanistic hypotheses advanced to explain the anticonvulsant action of the KD, few studies to date have addressed the molecular changes in brain following KD treatment. Here, we present recent experimental results based on systemic administration of kainic acid (KA) in rodents. KA typically induces acute limbic seizures and results in cellular and molecular alterations, accompanied by neuronal death mainly in limbic structures, similar to what has been observed in surgically resected temporal lobe tissue in epileptic patients. We have reported that neuronal degeneration induced by KA is ameliorated by KD treatment via diverse protective mechanisms, including inhibition of caspase-3-mediated apoptosis in hippocampal neurons. Neuroprotective strategies such as the KD, if implemented early, might exert an antiepileptogenic effect, and could prevent associated learning and memory deficits.
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PMID:Neuroprotective effects of the ketogenic diet. 1904 8

Fibroblast growth factor 2 (FGF-2) has multiple, pleiotropic effects on the nervous system that include neurogenesis, neuroprotection and neuroplasticity. Thus, alteration in FGF-2 expression patterns may have a profound impact in brain function, both in normal physiology and in pathology. Here, we used FGF-2 transgenic mice (TgFGF2) to study the effects of endogenous FGF-2 overexpression on susceptibility to seizures and to the pathological consequences of seizures. TgFGF2 mice display increased FGF-2 expression in hippocampal pyramidal neurons and dentate granule cells. Increased density of glutamatergic synaptic vesicles was observed in the hippocampus of TgFGF2 mice, and electrophysiological data (input/output curves and patch-clamp recordings in CA1) confirmed an increase in excitatory inputs in CA1, suggesting the presence of a latent hyperexcitability. Indeed, TgFGF2 mice displayed increased susceptibility to kainate-induced seizures compared with wild-type (WT) littermates, in that latency to generalized seizure onset was reduced, whereas behavioral seizure scores and lethality were increased. Finally, WT and TgFGF2 mice with similar seizure scores were used for examining seizure-induced cellular consequences. Neurogenesis and mossy fiber sprouting were not significantly different between the two groups. In contrast, cell damage (assessed with Fluoro-Jade B, silver impregnation and anti-caspase 3 immunohistochemistry) was significantly lower in TgFGF2 mice, especially in the areas of overexpression (CA1 and CA3), indicating reduction of seizure-induced necrosis and apoptosis. These data suggest that FGF-2 may be implicated in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring ictogenesis but reducing seizure-induced cell death.
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PMID:Fgf-2 overexpression increases excitability and seizure susceptibility but decreases seizure-induced cell loss. 1905 2

Prolonged and repetitive epileptic activity is causally linked to neuronal cell death in the brain and is most marked in vulnerable subfields of the hippocampus. The Bcl-2 family protein Bim, a proapoptotic member of the BCL-2 homology domain 3-only subfamily, has been implicated as an important mediator of neuronal cell damage in various pathological conditions, although its role in epilepsy-associated cell death is not understood. We performed intrahippocampal stereotaxic injections of the glutamate analog kainic acid as an in vivo model of acute excitotoxicity to assess neuronal injury in Bim-deficient and control wild-type mice. A variety of cell death parameters including chromatin condensation, TdT-mediated dUTP nick end labeling, and caspase-3 activity was assessed. We found no differences in the extent of hippocampal neuronal death parameters between the 2 groups. Moreover, electroencephalographic recordings after kainic acid injection revealed indistinguishable patterns of seizure activity in Bim-deficient and wild-type animals. These in vivo and histological data suggest that Bim is not critically involved in excitotoxicity-induced acute neuronal cell injury.
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PMID:The proapoptotic BCL-2 homology domain 3-only protein Bim is not critical for acute excitotoxic cell death. 1910 41

Caspase-3 expression was determined in the hippocampus of electrically kindled rats with and without topiramate treatment. Bipolar electrotrodes were implanted for chronic stimulation of the basolateral amygdala (BLA) to achieve a kindled state. Seizure and behavioral responses were observed, and video-electroencephalograms were recorded during and after kindling. After topiramate treatment (80 mg/kg, p.o.), the hippocampi were extracted and caspase-3 mRNA analyzed by semiquantitative RT-PCR. Caspase-3 immunoreactivity was determined with immunohistochemical staining. Topiramate treatment resulted in a significant decrease in the mean duration of seizures from 52 s in kindled rats to 13 s. The after-discharge duration was significantly decreased by 70% after topiramate treatment. Significant upregulations of both caspase-3 mRNA and caspase-3 immunoreactivity were observed in the kindled rats. These kindling-mediated increases in caspase-3 were prevented by topiramate treatment, and these levels were not different from those of sham-operated controls. In BLA-kindled rats, mRNA and immunoreactivity for caspase-3 were increased. Treatment with topiramate prevented the kindling-associated increases in caspase-3 as well as the increases in seizure duration and after-discharge duration. These data suggest that topiramate may have a neuroprotective role in addition to its action as an anticonvulsant.
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PMID:The effects of topiramate on caspase-3 expression in hippocampus of basolateral amygdala (BLA) electrical kindled epilepsy rat. 1914 80

Status epilepticus results in mitochondrial damage or dysfunction and preferential neuronal cell loss in the hippocampus. Since a critical determinant of the eventual cell death fate resides in intracellular ATP concentration, we investigated whether mitochondrial integrity and level of energy metabolism are related with apoptotic cell death in specific hippocampal neuronal populations. A kainic acid (KA)-induced experimental temporal lobe status epilepticus model was used. Qualitative and quantitative analysis of DNA fragmentation, TUNEL immunohistochemistry, double immunofluorescence staining for activated caspase-3, electron microscopy or measurement of ATP level in the bilateral hippocampus was carried out 1, 3 or 7 days after microinjection unilaterally of a low dose of KA (0.5 nmol) into the CA3 hippocampal subfield. Characteristic biochemical (DNA fragmentation), histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were presented bilaterally in the hippocampus 7 days after the elicitation of sustained hippocampal seizure activity by microinjection of KA into the unilateral CA3 subfield. At the same time, CA3 or CA1 subfield on either side manifested a maintained ATP level; alongside relatively intact mitochondria, rough endoplasmic reticulum, Golgi apparatus or cytoplasmic membrane in hippocampal neurons that exhibited ultrastructural features of apoptotic cell death. Our results demonstrated that preserved mitochondrial ultrastructural integrity and maintained energy metabolism during experimental temporal lobe status epilepticus is associated specifically with apoptotic, not necrotic, cell death in hippocampal CA3 or CA1 neurons.
Seizure 2009 Jul
PMID:Preservation of mitochondrial integrity and energy metabolism during experimental status epilepticus leads to neuronal apoptotic cell death in the hippocampus of the rat. 1937 59

Ghrelin, a 28-amino-acid peptide, is mainly secreted by the stomach. Evidence has shown ghrelin to have neuroprotective effects. However, whether ghrelin protects hippocampal neurons against cell death in pilocarpine-induced seizures is unknown. We used Nissl staining to show that ghrelin attenuated the neuronal loss caused by pilocarpine-induced seizures in the hippocampus. Ghrelin exerted the protective action through regulating the phosphatidylinositol-3-kinase and Akt pathway. Moreover, ghrelin treatment reversed the decreased ratio of Bcl-2 to Bax induced by seizures while inhibiting the activated caspase-3. Ghrelin can inhibit hippocampal neuronal damage caused by pilocarpine-induced seizures, which might have therapeutic value in seizures.
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PMID:Ghrelin protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. 1942 16

Neuronal damage after seizure is correlated with blood-brain barrier (BBB) leakage. Adiponectin (Ad) has shown protective effects on endothelial function. In this study, we investigated the effects of Ad on cell survival and BBB integrity in the mouse hippocampus after kainic acid (KA) treatment. Twenty-four hours after intracerebroventricular injection of recombinant Ad, mice were treated with KA, and then sacrificed 48 h later. Decreased serum Ad and increased hippocampal Ad receptor 1 in the hippocampus of KA-treated mice were prevented by Ad pretreatment. Using cresyl violet staining, TUNEL analysis, and immunostaining for caspase-3, histological evaluation revealed that the marked cell death noted in the hippocampus of KA-treated mice was not observed in KA-treated mice pretreated with Ad. Impairment of the BBB, which was demonstrated by the presence of IgG, was inhibited by Ad pretreatment. Immunohistochemical analysis indicated that KA caused up-regulation of hippocampal VEGF, eNOS, and NF-kappaB levels, all of which were reduced in animals that received Ad pretreatment. These data indicate that Ad preserves the integrity of the BBB and has neuroprotective effects in an animal model of seizures.
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PMID:Adiponectin protects hippocampal neurons against kainic acid-induced excitotoxicity. 1946 Apr 4


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