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)

NMDA receptor activation during status epilepticus (SE) has previously been shown to be required for epileptogenesis as well as the persistent upregulation of serum response factor (SRF) in the in vivo pilocarpine model of epilepsy. SRF is established as a regulator of the FosB gene which expresses FosB and DeltaFosB components of the AP-1 transcription factor complex. Therefore we investigated whether DeltaFosB expression and AP-1 DNA binding were also persistently elevated in pilocarpine-treated rats which chronically displayed spontaneous seizures. Using hippocampal nuclear extracts, DeltaFosB expression and AP-1 DNA binding were significantly elevated for up to one year in the epileptic animals. The expression of other fos and jun proteins was not persistently altered in epilepsy. Neuronal upregulation of DeltaFosB was correlated with regions of the brain that were involved in seizure generation and propagation. The increase in AP-1 DNA binding was shown to be dependent on NMDA receptor activation during SE. Hippocampal DeltaFosB immunostaining was seen predominately in the neuronal nuclei as opposed to other cell types. The data indicate that recurrent seizures which persistently occur in this model were not responsible for the increased DeltaFosB expression. Chronic DeltaFosB expression in epilepsy may be playing a role in the altered expression of other genes in this model and may be involved in some of the neuronal plasticity changes associated with epileptogenesis.
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PMID:Chronic DeltaFosB expression and increased AP-1 transcription factor binding are associated with the long term plasticity changes in epilepsy. 1092 51

Electroconvulsive therapy, which is used to treat refractory major depression in humans increases seizure threshold and decreases seizure duration. Moreover, the expression of brain derived neurotrophic factor induced by electroshocks (ECS) might protect hippocampal cells from death in patients suffering from depression. As temporal lobe epilepsy is linked to neuronal damage in the hippocampus, we tested the effect of repeated ECS on subsequent status epilepticus (SE) induced by lithium-pilocarpine and leading to cell death and temporal epilepsy in the rat. Eleven maximal ECS were applied via ear-clips to adult rats. The last one was applied 2 days before the induction of SE by lithium-pilocarpine. The rats were electroencephalographically recorded to study the SE characteristics. The rats treated with ECS before pilocarpine (ECS-pilo) developed partial limbic (score 2) and propagated seizures (score 5) with a longer latency than the rats that underwent SE alone (sham-pilo). Despite this delay in the initiation and propagation of the seizures, the same number of ECS- and sham-pilo rats developed SE with a similar characteristic pattern. The expression of c-Fos protein was down-regulated by repeated ECS in the amygdala and the cortex. In ECS-pilo rats, c-Fos expression was decreased in the piriform and entorhinal cortex and increased in the hilus of the dentate gyrus. Neuronal damage was identical in the forebrain areas of both groups, while it was worsened by ECS treatment in the substantia nigra pars reticulata, entorhinal and perirhinal cortices compared to sham-pilo rats. Finally, while 11 out of the 12 sham-pilo rats developed spontaneous recurrent seizures after a silent period of 40+/-27 days, only two out of the 10 ECS-pilo rats became epileptic, but after a prolonged latency of 106 and 151 days. One ECS-pilo rat developed electrographic infraclinical seizures and seven did not exhibit any seizures. Thus, the extensive neuronal damage occurring in the entorhinal and perirhinal cortices of the ECS-pilo rats seems to prevent the establishment of the hyperexcitable epileptic circuit.
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PMID:Electroshocks delay seizures and subsequent epileptogenesis but do not prevent neuronal damage in the lithium-pilocarpine model of epilepsy. 1099 2

Estimates of neuronal dropout for approximately 100 structures as defined by Paxinos-Watson were completed for brains of male Wistar albino rats between 1 and 50 days after status epilepticus was evoked by a single systemic injection of lithium and pilocarpine. Sample estimates of neuronal loss were strongly correlated with direct measures of cell density. The most extensive immediate damage occurred within the substantia nigra reticulata, CA1 field of the hippocampus, the piriform cortex and the reuniens and paratenial nuclei of the thalamus. Neuronal dropout continued in many other structures over a 50-day period. Structures that showed the greatest 2-deoxyglucose (2-DG) uptake during discrete seizures and waxing and waning seizures within the early stages of status epilepticus but the least 2-DG uptake at the time of late continuous spiking and fast spiking with pauses [Neuroscience 64 (1995) 1057, 1075] exhibited the most neuronal dropout. Relationships between the delay of injection of acepromazine (which facilitated survival) and the amount of damage suggested that the source of the process that results in permanent brain damage may originate within the region of the piriform cortices and its subcortices.
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PMID:Temporal changes in neuronal dropout following inductions of lithium/pilocarpine seizures in the rat. 1103 88

The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces most of the features of human temporal lobe epilepsy. After having studied the metabolic changes occurring during the silent phase, in the present study, we explored the relationship between interictal metabolic changes and neuronal loss during the chronic phase following status epilepticus (SE) induced by Li-Pilo in 10-day-old (P10), 21-day-old (P21), and adult rats. Rats were observed and their EEG was recorded to detect the occurrence of spontaneous recurrent seizures (SRS). Local cerebral glucose utilization was measured during the interictal period of the chronic phase, between 2 and 7 months after SE, by the [(14)C]2-deoxyglucose method in rats subjected to SE at P10, P21, or as adults. Neuronal damage was assessed by cell counting on adjacent cresyl violet stained sections. When SE was induced at P10, rats did not become epileptic, did not develop lesions and cerebral glucose utilization was in the normal range 7 months later. When SE was induced in adult rats, they all became epileptic after a mean duration of 25 days and developed lesions in the forebrain limbic areas, which were hypometabolic during the interictal period of the chronic phase, 2 months after SE. When SE was induced in P21 rats, 24% developed SRS, and in 43% seizures could be triggered (TS) by handling, after a mean delay of 74 days in both cases. The remaining 33% did not become epileptic (NS). The three groups of P21 rats developed quite comparable lesions mainly in the hilus of the dentate gyrus, lateral thalamus, and entorhinal cortex; at 6 months after SE, the forebrain was hypometabolic in NS and TS rats while it was normo- to slightly hypermetabolic in SRS rats. These data show that interictal metabolic changes are age-dependent. Moreover, there is no obvious correlation, in this model, between interictal hypometabolism and neuronal loss, as reported previously in human temporal lobe epilepsy.
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PMID:Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat. 1116 11

Neuronal fibres of the hippocampal formation of normal and chronic epileptic rats were investigated by fluorescent tracing methods using the pilocarpine model of limbic epilepsy. Two months after onset of spontaneous limbic seizures, hippocampal slices were prepared and maintained in vitro for 10 h. Small crystals of fluorescent dye [fluorescein (fluoro-emerald) and tetramethylrhodamine (fluoro-ruby)] were applied to different hippocampal regions. The main findings were: (i) in control rats there was no supragranular labelling when the mossy fibre tract was stained in stratum radiatum of area CA3. However, in epileptic rats a fibre network in the inner molecular layer of the dentate gyrus was retrogradely labelled; (ii) a retrograde innervation of area CA3 by CA1 pyramidal cells was disclosed by labelling remote CA1 neurons after dye injection into the stratum radiatum of area CA3 in chronic epileptic rats; (iii) labelling of CA1 neurons apart from the injection site within area CA1 was observed in epileptic rats but not in control animals; and (iv), a subicular-hippocampal projection was present in pilocarpine-treated rats when the tracer was injected just below the stratum pyramidale of area CA1. The findings show that fibre rearrangement in distinct regions of the epileptic hippocampal formation can occur as an aftermath of pilocarpine-induced status epilepticus.
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PMID:Fluorescent tracer in pilocarpine-treated rats shows widespread aberrant hippocampal neuronal connectivity. 1148 52

Neuronal loss, gliosis and axonal sprouting in the hippocampal formation are characteristics of the syndrome of mesial temporal sclerosis (MTS). In the post-status epilepticus (SE) rat model of spontaneous seizures these features of the MTS syndrome can be reproduced. To get a global view of the changes in gene expression in the hippocampus we applied serial analysis of gene expression (SAGE) during the early phase of epileptogenesis (latent period), prior to the onset of the first spontaneous seizure. A total of 10 000 SAGE tags were analyzed per experimental group, resulting in 5053 (SE) and 5918 (control group) unique tags (genes), each representing a specific mRNA transcript. Of these, 92 genes were differentially expressed in the hippocampus of post-SE rats in comparison to controls. These genes appeared to be mainly associated with ribosomal proteins, protein processing, axonal growth and glial proliferation proteins. Verification of two of the differentially expressed genes by in situ hybridization confirmed the changes found by SAGE. Histological analysis of hippocampal sections obtained 8 days after SE showed extensive cell loss, mossy fibre sprouting and gliosis in hippocampal sub regions. This study identifies new high-abundant genes that may play an important role in post-SE epileptogenesis.
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PMID:Altered hippocampal gene expression prior to the onset of spontaneous seizures in the rat post-status epilepticus model. 1172 9

The results of several studies have contributed to the hypothesis that BDNF promotes seizure activity, particularly in adult hippocampus. To test this hypothesis, BDNF, vehicle (phosphate-buffered saline, PBS), or albumin was infused directly into the hippocampus for 2 weeks using osmotic minipumps. Rats were examined behaviorally, electrophysiologically, and anatomically. An additional group was tested for sensitivity to the convulsant pilocarpine. Spontaneous behavioral seizures were observed in BDNF-infused rats (8/32; 25%) but not in controls (0/20; 0%). In a subset of six animals (three BDNF, three albumin), blind electrophysiological analysis of scalp recordings contralateral to the infused hippocampus demonstrated abnormalities in all BDNF rats; but not controls. Neuronal loss in BDNF-treated rats was not detected relative to PBS- or albumin-treated animals, but immunocytochemical markers showed a pattern of expression in BDNF-treated rats that was similar to rats with experimentally induced seizures. Thus, BDNF-infused rats had increased expression of NPY in hilar neurons of the dentate gyrus relative to control rats. NPY and BDNF expression was increased in the mossy fiber axons of dentate gyrus granule cells relative to controls. The increase in NPY and BDNF expression in BDNF-treated rats was bilateral and occurred throughout the septotemporal axis of the hippocampus. Mossy fiber sprouting occurred in five BDNF-treated rats but no controls. In another group of infused rats that was tested for seizure sensitivity to the convulsant pilocarpine, BDNF-infused rats had a shorter latency to status epilepticus than PBS-infused rats. In addition, the progression from normal behavior to severe seizures was faster in BDNF-treated rats. These data support the hypothesis that intrahippocampal BDNF infusion can facilitate, and potentially initiate, seizure activity in adult hippocampus.
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PMID:Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. 1192 62

Neuronal precursors in the adult rodent forebrain subventricular zone (SVZ) proliferate, migrate to the olfactory bulb in a restricted pathway known as the rostral migratory stream (RMS), and differentiate into neurons. The effects of injury on this neurogenic region of the mature brain are poorly understood. To determine whether seizure-induced injury modulates SVZ neurogenesis, we induced status epilepticus (SE) in adult rats by systemic chemoconvulsant administration and examined patterns of neuronal precursor proliferation and migration in the SVZ-olfactory bulb pathway. Within 1-2 weeks after pilocarpine-induced SE, bromodeoxyuridine (BrdU) labeling and Nissl staining increased in the rostral forebrain SVZ. These changes were associated with an increase in cells expressing antigenic markers of SVZ neuroblasts 2-3 weeks after prolonged seizures. At these same time points the RMS expanded and contained more proliferating cells and immature neurons. BrdU labeling and stereotactic injections of retroviral reporters into the SVZ showed that prolonged seizures also increased neuroblast migration to the olfactory bulb and induced a portion of the neuronal precursors to exit the RMS prematurely. These findings indicate that SE expands the SVZ neuroblast population and alters neuronal precursor migration in the adult rat forebrain. Identification of the mechanisms underlying the response of neural progenitors to seizure-induced injury may help to advance brain regenerative therapies by using either transplanted or endogenous neural precursor cells.
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PMID:Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway. 1194 19

Neuronal nitric oxide synthase (nNOS) is a constitutively expressed and calcium-dependent enzyme. Despite predominantly expressed in neurons, nNOS has been also found in astrocytes, although at lower expression levels. We have studied the regulation of nNOS expression in cultured rat astrocytes from cortex and spinal cord by Western blotting and immunocytochemistry. nNOS was not detectable in cultured astrocytes grown in serum-containing medium (SCM), but was highly expressed after serum deprivation. Accordingly, calcium-dependent NOS activity and both intracellular nitrite levels and nitrotyrosine immunoreactivity after glutamate stimulation were higher in serum-deprived astrocytes than in cells grown in SCM. Serum deprivation induced a modification of astrocytes morphology, from flat to stellate. nNOS up-regulation was also observed in reactive astrocytes of rat hippocampi after electrically induced status epilepticus, as demonstrated by double-labeling experiments. Thus, nNOS upregulation occurs in both in vitro stellate and in vivo reactive astrocytes, suggesting a possible involvement of glial nNOS in neurological diseases characterized by reactive gliosis.
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PMID:Upregulation of neuronal nitric oxide synthase in in vitro stellate astrocytes and in vivo reactive astrocytes after electrically induced status epilepticus. 1267 51

Lithium-pilocarpine-induced status epilepticus (SE) leads to the genesis of massive neuronal loss in adult rats and to a lesser extent in P21 rats. Neuronal damage occurs mainly via a process of necrosis in limbic forebrain, cerebral cortex, thalamus, and substantia nigra. It is not known, however, whether damage is the result of local excitotoxic hyperactivity or if leakage at the blood-brain barrier (BBB) could participate in the damaging process. Therefore, we investigated the permeability of the BBB in adult and P21 rats using [alpha-(14)C]aminoisobutyric acid, which does not cross an intact BBB, at 90 min after the onset of SE. At both ages, BBB opening occurred both in structures that will undergo damage (thalamus, septum, amygdala) and structures that will not be injured (globus pallidus, hypothalamus). In addition, neuronal damage occurs in the absence of increased BBB permeability in hippocampus, entorhinal cortex, and substantia nigra. Moreover, the increase in the intensity and distribution of BBB permeability changes is age-related, suggesting a differential activation of seizure circuits in adult and P21 rats. In summary, there is no clear correlation between the anatomical distribution of BBB opening and the occurrence of neuronal damage which, in this model, appears to rather depend on excitotoxic mechanisms due to major neuronal hyperexcitability.
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PMID:In the lithium-pilocarpine model of epilepsy, brain lesions are not linked to changes in blood-brain barrier permeability: an autoradiographic study in adult and developing rats. 1289 47


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