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)

Alpha-2 interferon, produced in Escherichia coli using recombinant DNA techniques, was administered to 17 children with refractory acute lymphoblastic leukemia (ALL) in relapse, two children with TdT-positive, Philadelphia chromosome-positive chronic myelocytic leukemia (CML) in blast crisis, and one child with B cell (SIg+) non-Hodgkin's lymphoma (NHL) in a second extramedullary relapse. An initial 2-week intravenous (IV) phase of interferon was followed by a 3-month subcutaneous (SC) maintenance phase if patients had an objective response or disease stabilization without significant bleeding or infectious complications. When interferon dosages were escalated from 3 to 100 X 10(6) U/m2 in the first phase of therapy, there was rapid progression of disease in the first four patients treated, prompting a modification of the treatment plan. The last 16 patients enrolled received fixed dosages of interferon (ie, 10, 20, 30, and 50 X 10(6) U/m2 administered to four subjects each). One child with T cell ALL had an 11-month complete remission; the patient with lymphoma had a dramatic but brief response; three others (one CML and two ALL) showed disease stabilization for 3 to 6 months with a definite oncolytic effect in two of the three patients. The remaining 15 patients had progressive disease within 2 months and were removed from the study. Acute toxicity included a flu-like syndrome in all patients, increased serum transaminase levels in five, seizures in three (two cases temporally related to fever and one to a thrombocytopenic subarachnoid hemorrhage), and prolonged activated partial thromboplastin times in seven. This phase I-II trial of recombinant alpha-2 interferon demonstrated definite activity without dose-limiting toxicity.
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PMID:Phase I-II study of recombinant alpha-2 interferon against advanced leukemia and lymphoma in children. 345 76

Previously, we established that persistent upregulation of c-fos expression preceded kainic acid (KA)-induced neuronal death in mice. To discriminate between events that are products of the seizures elicited by KA and those that are specifically associated with its neurotoxic actions, we have examined the expression of cellular immediate-early genes (cIEGs) following KA or pentylenetetrazol (PTZ) treatment in c-fos-lacZ transgenic rats. While both chemoconvulsants elicit seizures, only KA causes selective neuronal death. Following treatment of transgenic rats with KA there was a protracted expression of Fos-lacZ that lasted for 2-3 d. In contrast, PTZ elicited a transient increase in the transgene product that lasted about 6 hr. Normally, Fos and Fos-lacZ were detected only in neuronal nuclei. However, 6 hr following kainic acid (but not PTZ) administration, beta-galactosidase activity appeared in the cytoplasm of neurons within vulnerable regions (as determined by the terminal transferase biotinylated-UTP nick end labeling (TUNEL) procedure). Like c-fos, transcripts for other cIEGs were elevated for longer periods in the KA-treated rat hippocampus. In addition, fra-1 and fra-2 were only induced in the KA-treated rat. These changes in mRNA levels were paralleled by a sustained increase in AP-1 DNA binding activity. Thus, quantitative and qualitative changes in AP-1 DNA binding complexes accompany neurotoxic cell death that are not observed following seizures.
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PMID:Kainic acid-induced neuronal death is associated with DNA damage and a unique immediate-early gene response in c-fos-lacZ transgenic rats. 779 Sep 8

Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
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PMID:Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. 929 28

Seizure-induced neuronal damage may involve both excitotoxic and apoptotic (programmed cell death) mechanisms. In the present study, we used an amygdala kindled seizure model to study whether apoptotic cell death occurs. To evaluate apoptosis, we counted the numbers of cells that had DNA fragments labeled at the 3' end with digoxigenin using terminal transferase (ApopTag, Oncor). Additionally, the expression of Bax and Bcl-2, two genes associated with apoptotic cell death, was also measured following kindled seizures. We found that the number of ApopTag-positive cells in the hippocampus increased 30.4% after one kindled seizure and 82.5% after 20 seizures compared to sham controls. The ApopTag-labeled cells could be mainly interneurons of the hippocampal formation, although additional studies are required. Preferential vulnerability of inhibitory interneurons is consistent with previous studies on seizure-induced cell loss. These results, coupled with our findings that the ratio of Bax/Bcl-2 expression is increased in the hippocampus by seizures, suggest that apoptosis of hippocampal interneurons may lead to dysinhibition in the hippocampus and increased seizure susceptibility.
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PMID:Apoptosis of hippocampal neurons after amygdala kindled seizures. 958 22

We have investigated the potential antiepileptic action of superoxide dismutase (SOD) activities in the brain of the epileptic mutant EL mouse. EL mice which experienced frequent seizures (EL[s]) had abnormally low levels of SOD isoenzyme activity in the hippocampal area. Once epileptogenicity was established in these animals, activity of cyanide-sensitive Cu,Zn-SOD was maintained at significantly lower levels than in control mice. However, cyanide-insensitive Mn-SOD activity was not different from non-epileptic controls. In EL mice which had not experienced seizure provoking stimulations and exhibited no seizures (EL[ns]) there was moderately lower levels of SOD isoenzyme activities compared to controls. In spite of the low level of Cu,Zn-SOD activity in EL[s] mice, the Cu,Zn-SOD protein content was high in the hippocampus of these animals, suggesting that inactive Cu,Zn-SOD might be induced during development. After allopurinol (ALP) was given orally to EL[s] mice, Cu,Zn-SOD activities increased dramatically in the hippocampus and seizure activity was decreased. Even after 48 h, when antiepileptic action of ALP was lost, the SOD activity was maintained at the high level associated with initial ALP administration. EL[s] mice also showed DNA fragmentation in the hippocampal CA1 region and the parietal cortex, detected with in situ terminal transferase-mediated dUTP nick labeling with the aid of alkaliphosphatase or peroxidase. The degree of DNA fragmentation was less severe in EL[ns] mice. We propose that abnormalities in region specific Cu,Zn-SOD isoenzyme activity might produce free radicals, leading to DNA fragmentations and cell loss. This might contribute to hippocampal epileptogenesis in EL mice.
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PMID:Antiepileptic effects of allopurinol on EL mice are associated with changes in SOD isoenzyme activities. 976 25

The basic helix-loop-helix transcription factor c-Myc is a potent trigger of programmed cell death when overexpressed during late oligodendrocyte development in transgenic mice. Here we provide evidence that c-Myc can act synergistically with the Pit, Oct, Unc homeodomain transcription factor Oct-6 to produce myelin disease pathogenesis in transgenic mice. More than 70% of c-myc/Oct-6 bitransgenic mice, obtained from crosses between phenotypically normal heterozygous mice of various My (c-Myc) and Oc (Oct-6) transgenic strains that express c-myc and oct-6 transgenes under transcriptional control of the myelin basic protein gene, developed severe neurological disturbances characterized by action tremors, recurrent seizures, and premature death. Affected bitransgenic mice exhibited multiple hypomyelinated lesions in the white matter that did not stain with myelin-specific antibodies against myelin basic protein, proteolipid protein, CNPase, and myelin-associated glycoprotein. The mice also exhibited a larger number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling positive cells in the white matter as well as ultrastructural evidence of glial cell death and astrogliosis. These observations indicate that the myelin lesions observed in the c-myc/oct-6 bitransgenic mice result from the untimely programmed cell death of oligodendroglia and that the c-myc and oct-6 transgenes act synergistically in producing the lesions.
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PMID:Oligodendrocyte programmed cell death and central myelination deficiency induced in transgenic mice by synergism between c-Myc and Oct-6. 1051 74

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

Treatment of male Sprague-Dawley rats with kainic acid (10 mg/kg, i.p.) triggered limbic seizures in 60% of the animals starting within 30 min and lasting for about 6 h. Cyclooxygenase-2 (COX-2) mRNA was strongly induced in the pyramidal cells of the hippocampus, in the amygdala and the piriform cortex after 8 h, as shown by in situ hybridization, and returned to control levels after 72 h. At this time marked cell loss occurred in the CA1-CA3 areas of the hippocampus. We hypothesize that rofecoxib, a selective COX-2 inhibitor, might abbreviate the late neurotoxicity, possibly associated with COX-2 induction. Animals which developed seizures were treated for 3 days with rofecoxib (10 mg/kg, i.p., n = 12) starting 6 or 8 h after kainic acid injection. Histological staining of viable cells confirmed that rofecoxib treatment selectively diminished cell loss in the hippocampus. The TdT-mediated dUTP nick end labelling (TUNEL) technique was used to estimate delayed cell death. Abundant TUNEL-positive cells were detected in seizure rats 72 h after kainic acid injection in pyramidal cells of the hippocampus (CA1-CA3), in cells of the thalamus, the amygdala and the piriform cortex. Treatment with rofecoxib selectively and significantly (P < 0.05) attenuated the number of TUNEL-positive cells in the hippocampus, whereas the cells of the thalamus, amygdala and piriform cortex were not protected. Therefore we conclude that COX-2 might contribute to cell death of pyramidal cells of the hippocampus as a consequence of limbic seizures.
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PMID:The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. 1116 65

Kainate-induced seizures result in hippocampal neurodegeneration and spatial learning deficits in rodents. Previous studies show that rofecoxib, a selective cyclooxygenase-2 inhibitor, protects against kainate-induced hippocampal cell death 3 days after seizures. Our aim was to determine whether rofecoxib attenuates visuospatial learning deficits and late neuronal death after kainate-induced seizures. Seizures were induced in Sprague-Dawley rats with kainic acid (10 mg/kg, i.p.). Eight hours later, animals received rofecoxib (10 mg/kg; n = 15) or vehicle (dimethylsulfoxide, n = 11). Animals were then treated daily for additional 2 or 9 days. Visuospatial learning was assessed in the Morris water maze (MWM) on days 5-9 after seizures. Seizure animals learned the MWM task significantly slower than non-seizure controls, but seizure animals showed higher swim speed (P < 0.05). Seizure animals receiving rofecoxib for 2 days showed no significant improvement in acquisition of the task compared to the vehicle group, even though mean latencies in the rofecoxib group were shorter from the third trial day onwards. This tendency was lost when rofecoxib was given for 9 days. TdT-mediated dUTP nick end labelling showed cell death in limbic structures 9 days after seizures. The time course of kainate-induced hippocampal cell death might be delayed by rofecoxib treatment, as the attenuation of cell death observed 3 days after seizures was no longer present after 9 days. We conclude that even though increasing evidence points to an injurious role of cyclooxygenase-2 products in acute brain injury processes, rofecoxib treatment failed to attenuate seizure-induced visuospatial learning deficits and the late phase of hippocampal neurodegeneration.
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PMID:Assessment of the effects of the cyclooxygenase-2 inhibitor rofecoxib on visuospatial learning and hippocampal cell death following kainate-induced seizures in the rat. 1626 51

Although minocycline has been generally thought to have neuroprotective properties, the neuroprotective role of minocycline has not been investigated in the animal model of epilepsy. In this study, we investigated whether minocycline is neuroprotective against kainic acid (KA)-induced cell death through the caspase-dependent or -independent mitochondrial apoptotic pathways. Adult male ICR mice were subjected to seizures by intrahippocampal KA injection with vehicle or with minocycline. For cell death analysis, TdT-mediated dUTP-biotin nick end labeling and cresyl-violet staining were performed. Western blot analysis and immunofluorescent staining for cytochrome c and apoptosis-inducing factor (AIF) were performed. Cell death was reduced in minocycline-treated mice. Cytosolic translocation of cytochrome c and subsequent activation of caspase-3 were diminished by minocycline treatment. AIF nuclear translocation and subsequent large-scale DNA fragmentation were also reduced in minocycline-treated mice. Thus, this study suggests that minocycline inhibits both caspase-dependent and -independent apoptotic pathways and may be neuroprotective against hippocampal damage after KA treatment.
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PMID:Minocycline inhibits caspase-dependent and -independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. 1646 40


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