Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to elucidate the distribution, time-course and mechanism(s) of status epilepticus-induced neuronal damage in the rat amygdaloid complex. Status epilepticus was induced with kainate (9 mg/kg, i.p.), and the behavioral and electrographic seizure activity of each rat was monitored via cortical electrodes attached to a continuous video electrocorticogram system. Rats were subsequently perfused 1, 2, 4, 8, 16, 24 or 48 h after kainate injection. The first signs of amygdaloid damage were seen in rats perfused 4 h after kainate injection, though the severity and temporal appearance of damage varied substantially between the different amygdaloid nuclei and their subdivisions. Second, terminal transferase dUTP nick-end labeling (TUNEL)-positive nuclei and laddering of DNA in gel electrophoresis appeared in the amygdala 8 and 16 h after kainate, respectively. The distribution and density of TUNEL-positive nuclei in the different amygdaloid nuclei correlated with the distribution of neuronal damage in Thionin- and silver-stained sections. Third, the immunoreactivity of Bax protein, a promoter of apoptotic neuronal death, increased in the vulnerable medial division of the lateral nucleus prior to the appearance of argyrophilic neurons and TUNEL-positive nuclei. Fourth, the severity of neuronal damage progressed in some, but not all, amygdaloid regions throughout the 48-h follow-up, even though the occurrence of high-amplitude and frequency discharges, which are typically associated with behavioral seizure activity, extinguished after 7 h. These data show that status epilepticus-induced neuronal damage in the amygdala is a dynamic region-specific process, the severity of which depends on the duration of seizure activity. At least one mechanism underlying the damage involves apoptosis, which continues long after the behavioral and electrographic seizures have subsided.
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PMID:Status epilepticus-induced neuronal damage in the rat amygdaloid complex: distribution, time-course and mechanisms. 1057 10

Prolonged seizures (status epilepticus) induced by kainic acid activate programmed cell death mechanisms, and it is believed that kainic acid-induced status epilepticus induces neuronal apoptosis. In order to test this hypothesis, adult rats were subjected to 3-h kainic acid-induced seizures, with 24- or 72-h recovery periods. Neuronal death was assessed by light microscopy with the Hematoxylin and Eosin stain and with in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL stain), by electron microscopy, and by agarose gel electrophoresis of DNA extracted from five vulnerable brain regions. Spontaneous and MK-801-induced apoptotic neurons from retrosplenial cortex of neonatal rats, evaluated by light and electron microscopy, were used as positive controls for apoptosis. Surprisingly, the large chromatin clumps of apoptotic neurons were TUNEL negative, whereas the cytoplasm showed light-to-moderate TUNEL staining, consistent with a lack of identifiable nuclear membranes ultrastructurally, and with intermingling of nuclear and cytoplasmic contents. Ultrastructurally, the acidophilic neurons produced by kainic acid-induced status epilepticus, identified with Hematoxylin and Eosin stain, were dark, shrunken and necrotic, with pyknotic nuclei containing small, dispersed chromatin clumps, and with cytoplasmic vacuoles, some of which were swollen, disrupted mitochondria. No apoptotic cells were seen. Acidophilic neurons were found in up to 20 of 23 brain regions examined and comprised 10-25% of the total number of neurons examined. A subset of these neurons (<10% of the total number of neurons in five of 23 regions) had TUNEL-positive nuclei 72h but not 24h after status epilepticus. Internucleosomal DNA cleavage (DNA "laddering") occurred in the four most damaged brain regions examined by electron microscopy 24h after SE and the three most damaged regions 72h after status epilepticus. Our results demonstrate that kainic acid-induced status epilepticus produces neuronal necrosis and not apoptosis in adult rats. The necrotic neurons show nuclear pyknosis, chromatin condensation and DNA laddering. Programmed cell death mechanisms activated by kainic acid-induced status epilepticus occur in neurons which become necrotic and could contribute to necrotic, as well as apoptotic, neuronal death.
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PMID:Kainic acid-induced seizures produce necrotic, not apoptotic, neurons with internucleosomal DNA cleavage: implications for programmed cell death mechanisms. 1085 10

The dentate gyrus (DG) is one of the few regions in the brain that continues to produce new neurons throughout adulthood. Seizures not only increase neurogenesis, but also lead to death of DG neurons. We investigated the relationship between cell death and neurogenesis following seizures in the DG of adult rats by blocking caspases, which are key components of apoptotic cell death. Multiple intracerebroventricular infusions of caspase inhibitors (pancaspase inhibitor zVADfmk, and caspase 3 and 9 inhibitor) prior to, just after, 1 day after, and 1 week following 2 h of lithium-pilocarpine-induced status epilepticus reduced the number of terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelled (TUNEL) cells and increased the number of bromodeoxyuridine (BrdU) -stained proliferated cells in the subgranular zone at 1 week. The caspase inhibitor-treated group did not differ from control at 2 days or 5 weeks following the epileptic insult. Our findings suggest that caspases modulate seizure-induced neurogenesis in the DG, probably by regulating apoptosis of newly born neurons, and that this action can be suppressed transiently by caspase inhibitors. Furthermore, although previous studies have indicated that increased neuronal death can trigger neurogenesis, we show here that reduction in apoptotic death may be associated with increased neurogenesis.
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PMID:Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. 1159 32

A caspase-3-activated DNase produces internucleosomal DNA cleavage (DNA laddering). We determined whether caspase-3 is activated by lithium-pilocarpine-induced status epilepticus in six brain regions with necrosis-induced DNA laddering. The thymuses of adult rats given methamphetamine or normal saline were used as controls for apoptosis. Some 6-8 h after methamphetamine treatment, thymocytes showed apoptosis by electron-microscopic examination, positive terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), DNA laddering, cleavage of caspase-3 into its active p17 subunit, active caspase-3 immunoreactivity, and a 25-fold increase in caspase-3-like activity. Six hours after SE, necrotic neurons by electron-microscopic examination in hippocampus, amygdala and piriform, entorhinal and frontal cortices showed no TUNEL and no DNA laddering. Twenty-four hours after seizures, most necrotic neurons were negative for TUNEL, some were positive, but all regions showed DNA laddering. However, 6 and 24 h after seizures, active caspase-3 immunoreactivity was negative, caspase-3-like activity did not increase, and western blot analysis failed to show the p17 subunit. In addition, 24 h after seizures,microdialytic perfusion of carbobenzoxy-valyl-alanyl-aspartyl (O-methylester) fluoromethylketone was not neuroprotective. Thus, caspase-3 is not activated in brain regions with seizure-induced neuronal necrosis with DNA laddering. Either caspase-activated DNase is activated by another enzyme, or a caspase-independent DNase is responsible for the DNA cleavage.
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PMID:Caspase-3 is not activated in seizure-induced neuronal necrosis with internucleosomal DNA cleavage. 1235 47

Apoptotic cell death induced by kainic acid (KA) in cultures of rat cerebellar granule cells (CGC) and in different brain regions of Wistar rat pups on postnatal day 21 (P21) was studied. In vitro, KA (100-500 microM) induced a concentration-dependent loss of cell viability in MTT assay and cell death had apoptotic morphology as studied by chromatin staining with propidium iodide (PI). In vivo, twenty-four hours after induction of status epilepticus (SE) by an intraperitoneal KA injection (5 mg/kg) we quantified apoptotic cells in hippocampus (CA1 and CA3), parietal cortex and cerebellum using PI staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) technique. We report that dantrolene, a specific ryanodine receptor antagonist, was able to significantly reduce the apoptotic cell death in CGC cultures and in hyppocampal CA1 and parietal cortex regions. Our finding can be valuable for neuroprotective therapy strategies in patients with repeated generalized seizures or status epilepticus.
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PMID:Dantrolene protects neurons against kainic acid induced apoptosis in vitro and in vivo. 1261 40

Seizures increase dentate granule cell proliferation in adult rats but decrease proliferation in young pups. The particular period and number of perinatal seizures required to cause newborn granule cell suppression in development are unknown. Therefore, we examined cell proliferation with bromodeoxyuridine (BrdU) immunohistochemistry during the peak of neurogenesis (e.g., P6 and P9) and at later postnatal ages (e.g., P13, P20, or P30) following single and multiple episodes of perinatal status epilepticus induced by kainate (KA). Because an inverse relationship exists between glucocorticosteroids (CORT) levels and granule cell proliferation, plasma CORT levels and electroencephalographic (EEG) activity were simultaneously monitored to elucidate underlying mechanisms that inhibit cell proliferation. In control animals, the number of BrdU-labeled cells increased then declined with maturation. After 1x KA or 2x KA administered on P6 and P9, the numbers of BrdU-labeled cells were not different from age-matched controls. However, rat pups with 3x KA (on P6, P9, and P13) had marked suppression of BrdU-labeled cells 48-72 h after the last seizure (43 +/- 6.5% of control). Cell proliferation was also significantly inhibited on P20 after 2x KA (to 56 +/- 6.9%) or 3x KA (to 54 +/- 7.9%) and on P30 with 3x KA (to 74.5 +/- 8.2% of age-matched controls). Cell death was not apparent as chromatin stains showed increased basophilia of only inner cells lining the granule cell layers, in the absence of eosinophilia, argyrophilia, or terminal deoxynucleotidyl dUTP nick endlabeling (TUNEL) labeling at times examined. In P13 pups with 3x KA, electron microscopy revealed an increased number of immature granule cells and putative stem cells with irregular shape, condensed cytoplasm, and electron dense nuclei, and they were also BrdU positive. The EEG showed no relationship between neurogenesis and duration of high-synchronous ictal activity. However, endocrine studies showed a correlation with BrdU number and age, sustained increases in circulating CORT levels following 1x KA on P6 (0.7 +/- 0.1 to 2.40 +/- 0.86 microg/dl), and cumulative increases that exceeded 10 microg/dl at 4-8 h after 3x KA on P13 or P20. In conclusion, a history of only one or two perinatal seizure(s) can suppress neurogenesis if a second or third seizure recurs after a critical developmental period associated with a marked surge in CORT. During the first 2 weeks of postnatal life sustained increases in postictal circulating CORT levels but not duration or intensity of ictal activity has long-term consequences on neurogenesis. The occurrence of an increased proportion of immature granule cells and putative stem cells with irregular morphology in the absence of neurodegeneration suggests that progenitors may not differentiate properly and remain in an immature state.
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PMID:Suppression of hippocampal neurogenesis is associated with developmental stage, number of perinatal seizure episodes, and glucocorticosteroid level. 1463 92

The molecular basis of neuronal circuit reorganization during epileptogenesis is poorly understood. Such data are, however, critical for the search of new targets for the prevention of epileptogenesis. Here, we extended our previous studies on caspases in epileptogenesis by investigating the expression and activity of caspase 6 at different phases of the epileptic process in rats. Epileptogenesis was triggered by kainate-induced status epilepticus (SE) under video-electroencephalography-monitoring. Caspase 6 activity was measured fluorometrically in the hippocampus 8 h, 24 h, 48 h, 1 week, and 4 weeks after SE. Caspase 6 expression was examined using Western blot and immunohistochemistry. Our data demonstrated that the SE-induced increase in the expression of cleaved caspase 6 and its intraneuronal localization were dependent on the time delay from SE induction. Double-labeling with a neuronal marker, NeuN, indicated that within the first 48 h, caspase 6 immunoreactivity was present both in the hippocampal pyramidal cells and hilar neurons, some of which were also terminal transferase dUTP-end labeling-positive. This was coincident with a transient 18-fold increase in caspase 6 enzymatic activity. At the 1-week and 4-week time points, elevated caspase 6 immunoreactivity was detected in the dendritic processes and neuropil. These findings indicate that caspase 6 expression remains elevated long after the occurrence of acute cell death during epileptogenesis and epilepsy. Further, caspase 6 protein is not exclusively located in the somata of neurons, but also in dendrites. These data suggest that caspase 6 has functions other than execution of programmed cell death in epileptogenic hippocampus.
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PMID:Caspase 6 expression in the rat hippocampus during epileptogenesis and epilepsy. 1574 43

Induction of status epilepticus (SE) with kainic acid results in a large reorganization of neuronal brain circuits, a phenomenon that has been studied primarily in the hippocampus. The neurotrophin BDNF, by acting through its receptor TrkB, has been implicated in such reorganization. In the present work we investigated, by Western blot and immunohistochemistry, whether regional changes of TrkB expression within the rat brain cortex are correlated with altered neuronal morphology and/or with apoptotic cell death. We found that the full-length TrkB protein decreased within the cortex when measured 24 h to 1 week after induction of SE. Analysis by immunohistochemistry revealed that TrkB staining diminished within layer V of the retrosplenial granular b (RSGb) and motor cortices, but not within the auditory cortex. In layer II/III, differential changes were also observed: TrkB decreased in the motor cortex, did not change within the RSGb but increased within the auditory cortex. Reduced TrkB was associated with dendritic atrophy and decreased spine density in pyramidal neurons within layer V of the RSGb. No correlation was observed between regional and cellular changes of TrkB protein and apoptosis, measured by the TdT-mediated dUTP nick end labeling (TUNEL) method. The global decrease of TrkB within the neocortex and the associated dendritic atrophy may counteract seizure propagation in the epileptic brain but may also underlie cognitive impairment after seizures.
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PMID:Status epilepticus induces region-specific changes in dendritic spines, dendritic length and TrkB protein content of rat brain cortex. 1739 6

Status epilepticus (SE) is a grave condition in which the brain undergoes lasting seizures which can lead to neuronal loss. Our previous study suggested that preconditioning with erythropoietin (Epo) suppressed neuronal apoptosis in hippocampus of rats following SE in vivo by inhibiting caspase-3. In this study, we investigated the mechanisms by which Epo preconditioning may exert its anti-apoptotic effects using a lithium-pilocarpine induced SE model in rats. The effects of Epo on neuronal cell death were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and the role of the Bcl-2 protein family, which have been shown to be anti- (Bcl-2, Bcl-w) or pro- (Bid, Bim) apoptotic, was examined with immunofluorescence. We found Epo preconditioning decreased the total number of TUNEL, Bim and Bid positive cells, but increased the total number of Bcl-w and Bcl-2 positive cells. These results suggest that systemic Epo pretreatment protects neurons in an acute phase of SE and may result in further suppression of neuronal apoptosis in hippocampus by regulating the balance between pro- and anti-apoptotic Bcl-2 family proteins.
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PMID:Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. 1769 Dec 21

Selective neuronal loss is closely associated with cognitive impairments that occur following status epilepticus (SE). Our previous study suggested that erythropoietin (Epo) pre-treatment suppressed hippocampal neuronal death in rats after 1 h of SE convulsions. However, the underlying protective mechanism remained unclear. In the present study, we investigated the anti-apoptotic mechanism of Epo pre-treatment in the hippocampus using Li-pilocarpine-induced SE in rats. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed to detect apoptosis and the Morris water maze was employed to assess spatial learning ability and to analyze the protective effects of Epo. Levels of Bcl-2 family (Bid, Bcl-2 and Bax) markers were examined via Western blot and immunofluorescence. We found that Epo pre-treatment prevented SE-induced cognitive impairments. The protection and cognitive effects were associated with higher levels of Bcl-2 and lower levels of Bax. The present results suggest that systemic Epo pre-treatment can confer neuroprotection following SE, and may provide novel insights into pathogenesis and treatment following SE injury.
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PMID:Erythropoietin pre-treatment prevents cognitive impairments following status epilepticus in rats. 1949 15


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