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)

A small area of deep prepiriform cortex is uniquely susceptible to convulsant and anticonvulsant drugs in the rat. We have studied the pattern of expression of the non-constitutive stress protein (HSP72) following seizures induced by unilateral microinjection of bicuculline into this area. HSP was seen first in ipsilateral dorsal medial thalamus, amygdala and associated piriform cortex, and with more sustained seizures was seen bilaterally in these structures as well as in other projection sites. Neuronal cell death, as assessed by acid-fuchsin staining, occurred in the same brain regions. Frank necrosis was found in the ipsilateral piriform cortex with prolonged seizures. Behaviorally, the seizures induced are characteristic of involvement of the limbic system and, therefore, may be a model of human complex partial seizures.
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PMID:Distribution of HSP72 induction and neuronal death following limbic seizures. 137 69

Doctors who learned exclusively western medicine probably understand a priori Kampo (Japanese herbal) medicine merely as a kind of folk medicine which is not so effective and only a supplementary therapy to western medicine. We have been performing experiments on the mechanism of epileptogenesis mainly at the cellular level for a long time. During the research process, we unexpectedly encountered Kampo (Japanese herbal) medicine, and also performed research on the mechanism of action of a herbal mixture prescription, saiko-keishi-to-ka-shakuyaku (SK, TJ-960). Recently we discovered that SK acts to induce the best functional state of neurons and consequently intractable nervous symptoms disappear. SK has protective effects against neuron damage, normalizing effects on developmental defects of El mouse neurons, complete preventive effects on stress-induced increased c-fos and HSP 72 expression, complete suppression effects on the Reilly syndrome, complete normalizing effects on expression of the seizure-related gene, PTZ-17, and also, surprisingly, complete suppression effects on amyloid beta protein-induced neuron death. Such wide ranging effects which are preferable to functional maintenance and development of neurons can not be obtained by pure chemical drugs. These findings suggest that we should effectively use such ancient herbal prescriptions which show excellent preventive effects against neuron damage, enforcing action on natural healing forces and even regulatory action against adverse expression of genes, at least to prevent intractable nervous diseases, such as epilepsy, Alzheimer's disease and developmental defects of neurons during pregnancy and after birth. We should also create a future medicine, the 'third medicine', which is situated in a higher dimension than that of contemporary oriental and western medicines. For this purpose, it is necessary to perform research on the mechanism of action of Kampo (Japanese herbal) medicine.
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PMID:Nervous diseases and Kampo (Japanese herbal) medicine: a new paradigm of therapy against intractable nervous diseases. 910 54

The substantia nigra pars reticulata (SNpr) is recognized as an important modulator of seizures within the limbic system. We have investigated the effects of N-methyl-D-aspartate (NMDA) infusion into SNpr upon seizure-related neuronal injury (assessed by expression of the 72-kDa heat shock protein - HSP 72) induced by systemic kainic acid (KA) in rats. Three to four days following implantation of guide cannulae for drug administration into SNpr, KA (7 mg/kg) was injected intravenously to induce seizures. Bilateral intranigral infusion of NMDA (20 nmol) 15 min prior to KA injection, suppressed the expression of HSP 72 in the hippocampal CA1 region without affecting seizure duration. These results support the involvement of NMDA receptors within SNpr in modulating neuronal injury following KA-induced limbic seizures.
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PMID:Bilateral intranigral NMDA infusion suppresses neuronal injury without affecting the duration of kainic acid-induced seizures in rats. 971 67

Kainic acid-induced seizures in rats represent an established animal model for human temporal lobe epilepsy. However, it is well-known that behavioral responses to the systemic administration of kainic acid are inconsistent between animals. In this study, we examined the relationship between expression of genes, neuropathological damage, and behavioral changes (seizure intensity and body temperature) in rats after systemic administration of kainic acid. The considerable differences in the response to kainic acid-induced seizures were observed in rats after a single administration of kainic acid (12 mg/kg i.p.). There was no detection of the expression of heat shock protein hsp-70 mRNA and HSP-70 protein in brain of vehicle-treated controls and in animals exhibiting weak behavioral changes (stage 1-2). A moderate expression of hsp-70 mRNA was detected throughout all regions (the pyramidal cell layers of CA1-3 and dentate gyrus) of the hippocampus, the basolateral, lateral, central and medial amygdala, the piriform cortex, and the central medial thalamic nucleus of rats that developed moderate seizures (stage 3-4). Marked expression of hsp-70 mRNA was detected in the all regions (cingulate, parietal, somatosensory, insular, entorhinal, piriform cortices) of cerebral cortex and all regions of hippocampus, and the central medial thalamic nucleus of the rats that developed severe seizures (stage 4-5). In addition, marked HSP-70 immunoreactivity was detected in the pyramidal cell layers of CA1 and CA3 regions of hippocampus, all regions (cingulate, parietal, somatosensory, insular, piriform cortices) of cerebral cortex, and the striatum of rats that developed severe seizures (stage 4-5). Furthermore, a marked expression of cyclooxygenase-2 (COX-2) mRNA and brain-derived neurotrophic factor (BDNF) mRNA levels by kainic acid-induced behavioral seizures (stage 3-4 or stage 4-5) was detected in all hippocampal pyramidal cell layers, granule layers of dentate gyrus, piriform cortex, neocortex, and amygdala. The present study suggest that the behavioral changes (seizure intensity and body temperature) and neuropathological damage after systemic administration of kainic acid are inconsistent between animals, and that these behavioral changes (severity of kainic acid-induced limbic seizures) might be correlated with gene expression of hsp-70 mRNA, COX-2 mRNA, and BDNF mRNA in rat brain.
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PMID:Behavioral changes and expression of heat shock protein hsp-70 mRNA, brain-derived neurotrophic factor mRNA, and cyclooxygenase-2 mRNA in rat brain following seizures induced by systemic administration of kainic acid. 975 41

Kainate-induced seizures are widely studied as a model of human temporal lobe epilepsy due to behavioral and pathological similarities. While kainate-induced neuronal injury is well characterized in rats, relatively little data is available on the use of kainate and its consequences in mice. The growing availability of genetically altered mice has focused attention on the need for well characterized mouse seizure models in which the effects of specific genetic manipulations can be examined. We therefore examined the kainate dose-response relationship and the time-course of specific histopathological changes in C57/BL mice, a commonly used founder strain for transgenic technology. Seizures were induced in male C57/BL mice (kainate 10-40 mg/kg i.p.) and animals were sacrificed at various time-points after injection. Seizures were graded using a behavioral scale developed in our laboratory. Neuronal injury was assayed by examining DNA fragmentation using in situ nick translation histochemistry. In parallel experiments, we examined the expression an inducible member of the heat shock protein family, HSP-72, another putative marker of neuronal injury, using a monoclonal antibody. Seizure severity paralleled kainate dosage. At higher doses DNA fragmentation is seen mainly in hippocampus in area CA3, and variably in CA1, thalamus and amygdala within 24 h, is maximal within 72 h, and is largely gone by 7 days after administration of kainate. HSP-72 expression is also highly selective, occurring in limbic structures, and it evolves over a characteristic time-course. HSP-72 is expressed mainly in structures that also manifest DNA fragmentation. Using double-labeling techniques, however, we find essentially no overlap between neurons expressing HSP-72 and DNA fragmentation. These findings indicate that DNA fragmentation and HSP-72 expression are complementary markers of seizure-induced stress and injury, and support the notion that HSP-72 expression is neuroprotective following kainate-induced seizures.
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PMID:Neuronal stress and injury in C57/BL mice after systemic kainic acid administration. 981 46

Japanese herbal medicine has long been considered as only supplementary therapy to Western medicine. However, we discovered that an herbal mixture, Saiko-keishi-to-ka shakuyaku (SK, TJ-960), showed regulatory function of gene expression such as increased expression of seizure-related gene PTZ-17, proto-oncogene c-fos and heat shock protein HSP 72. These results provide a scientific basis for an important ancient concept and usage of herbal mixtures as a "therapy against diseases which will be suffered in the future". Our results also give an adequate provide break-throughs for therapy and even prevention of intractable epilepsy, Alzheimer's disease, developmental disorders during pregnancy and the postnatal period, and also probably for prevention of metastasis or relapse of various cancers.
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PMID:Regulation of gene expression by herbal medicines--a new paradigm of gene therapy for multifocal abnormalities of genes. 1148 47

Cell signaling commanding death or survival in human epileptic hippocampus is difficult to trace because of the long interval between the beginning of symptoms and the sampling of damaged cerebral tissue for neuropathological examination. Intraperitoneal injection of the glutamate analogue kainic acid (KA) is a useful tool to analyze the effects of seizures and the excitotoxic damage in the rodent hippocampus. KA acts on NMDA and KA receptors, whereas it has little impact on AMPA receptors. Neurons of the hilus and CA3 neurons are primary targets of KA, although parvalbumin containing GABAergic neurons are less vulnerable than glutamatergic neurons. Immediate responses to KA are hsp 70 mRNA induction and HSP 70/72 protein expression, as well as c fos and c jun mRNA, and c Fos and c Jun protein expression in the hippocampus. Yet increased c Fos and c Jun expression is not a predictor of cell death or cell survival. In contrast, the tissular plasminogen activator (tPA) and the membrane Fas/Fas L signaling pathway probably have a role in facilitating cell death following KA injection. The involvement of other pathways remains controversial. Increased expression of the pro apoptotic Bax together with decreased Bcl 2 suggests Bax mediated apoptosis. Activation of the mitochondrial pathway includes leakage of citochrome c to the cytosol and activation of the caspase cascade leading to apoptosis. However, other studies have emphasized the limited expression of caspase 3, the main executioner of apoptosis, and the relevance of necrosis as the main form of cell death following KA excitotoxicity. Phosphorylation dependent activation of several kinases, including MAPK, p 38 and JNK/SAPK, and their substrates has been found in KA treated animals. Decreased CREBp expression is associated with cell death whereas increased ATF 2P and Elk 1P are associated with cell survival. Trophic factors probably do not play a significant role during the early stages of hippocanmpal damage but they are important in the remodeling of the granukle cells and the sprouting of mossy fibers to the molecular layer of the dentate gyrus. This abnormal regeneration, in turn, facilitates seizure recruitment and the chronic maintenance of convulsions.
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PMID:[Cell signaling in the epileptic hippocampus]. 1204 Apr 99

The intrahippocampal administration of 4-aminopyridine (4-AP) induces epileptic seizures and neurodegeneration, due probably to stimulation of glutamate release from synaptic terminals. We have studied the time course of the neurodegenerative changes produced by 4-AP, perfused through microdialysis cannulas in rat hippocampus, and correlated them with the expression of the inducible heat shock protein 70 (HSP70), detected immunocytochemically. Electroencephalographic seizure activity appeared immediately after the beginning of 4-AP perfusion. The first signs of histological neuronal damage were observed in CA1 and CA3 subfields of the perfused hippocampus 3 h after treatment and progressed until reaching a maximal neuronal loss at 24 h. In 4-AP-treated rats HSP70 was expressed mainly in neurons of the contralateral hippocampus, with a time course and cellular distribution very similar to the neurodegeneration observed in the perfused hippocampus, but no neuronal damage was observed. The N-methyl-D-aspartate (NMDA) receptor antagonists MK-801 and (3-phosphonopropyl)-piperazine-2-carboxylic acid prevented the seizures, the neurodegeneration and the expression of HSP70. These data demonstrate that the 4-AP-induced release of endogenous glutamate overactivates NMDA receptors in the perfused hippocampus and that the resulting neuronal hyperexcitability propagates to the contralateral hippocampus, generating a glutamate-mediated neuronal stress sufficient to induce the expression of HSP70 but not to produce neurodegeneration. These findings provide a useful model for investigating the relationships between neuronal hyperexcitation, neurodegeneration and the role of HSP expression.
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PMID:Expression of heat shock protein 70 induced by 4-aminopyridine through glutamate-mediated excitotoxic stress in rat hippocampus in vivo. 1294 78

Apart from the essential role of 1alpha,25-dihydroxyvitamin D3 in calcium and phosphorus metabolism, this compound and its analogs are involved in regulating the functions of the central nervous and immune systems. Active forms of vitamin D3 have been reported to stimulate neurotrophin gene expression and to prevent neuronal damage against a variety of insults. In the present study, we evaluated the effects of PRI-2191-a low-calcemic analog of 1alpha,25-dihydroxyvitamin D3 (50 ng/kg i.p., once daily for 8 days) on seizure-related neuronal degeneration, changes in some brain gene expression and immune system activity. Seizures were induced by pilocarpine (400 mg/kg; i.p.) administration. An in situ hybridization study showed that the pilocarpine-induced seizures led to time-dependent changes in the brain-derived neurotrophic factor (BDNF), heat shock protein 70 (HSP-70) and prepro-thyreoliberin (prepro-TRH) gene expression in several cortical and hippocampal regions. The maximal induction of gene expression was 3 h for BDNF and 24 h for HSP-70 and prepro-TRH; however, only in the case of prepro-TRH that effect was long-lasting. PRI-2191 alone had no effect on gene expression, but it enhanced the seizure-evoked expression of HSP-70, had an opposite effect on BDNF mRNA level and did not affect prepro-TRH mRNA level. Moreover, PRI-2191 had a moderate inhibitory effect on the seizure-related hippocampal damage in the CA1 field only. An immunological study revealed that PRI-2191 reversed the seizure-induced decrease in the proliferative activity of splenocytes and their ability to produce interferon-gamma. Summing up, the present study demonstrated that subchronic administration of PRI-2191 significantly modulated the seizure-related changes in both the brain and the peripheral immune system of rats.
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PMID:Effects of PRI-2191--a low-calcemic analog of 1,25-dihydroxyvitamin D3 on the seizure-induced changes in brain gene expression and immune system activity in the rat. 1578 Oct 40

Heat shock protein-27 (HSP-27) is an inducible stress response protein. It inhibits apoptotic cell death and is a reliable marker for oxidative stress. We studied the induction of HSP-27 in rat brains on days 1, 4 and 14 after repeated, pentylenetetrazole (PTZ)-induced seizures using immunohistochemisty. Saline treated control rats showed no induction of HSP-27. HSP-27 reactive astrocytes were rarely seen 1 or 4 days after PTZ injection. When present, single astrocytes were located in the cortex and/or the hippocampus. After 14 days PTZ treatment, a bilateral distribution of HSP-27 immunoreactive glia was present in piriform and entorhinal cortices and in the dentate gyrus of most brains. Rats with most intense HSP-27 upregulation showed HSP-27 in amygdala and thalamic nuclei. Astrocytes associated with blood vessels presented strongest HSP-27 staining, but did not show upregulation of gial fibrillary acidic protein and none responded with HSP-47 expression. Additionally, HSP-27 immunoreactivity increased in the endothelial cells of blood vessels in the affected brain regions, although no neuronal induction occurred. Contrastingly, a subconvulsive dose of the glutamine synthetase inhibitor L-methionine sulfoxime, which acts directly on astrocytes, resulted in a rapid, homogeneous astrocyte-specific HSP-27 upregulation within 24 h. Thus, repeated PTZ-induced seizure activity elicits a focal "heat shock" response in endothelial cells and astrocytes of selected cerebral regions indicating that expression of HSP-27 occurred in a seizure-dependent manner within the affected cerebral circuitries. Therefore, this PTZ-model of repeated seizure activity exhibited a cortical pattern of HSP-27 expression which is most comparable to that known from patients with epilepsy.
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PMID:Bilateral, vascular and perivascular glial upregulation of heat shock protein-27 after repeated epileptic seizures. 1592 84


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