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)

Changes in the histological morphology of the caudate-putamen (CPu) were determined after a high-dose methamphetamine (METH) exposure in an effort to elucidate whether BBB disruption plays a role in CPu neurotoxicity. This was accomplished by evaluating the tyrosine hydroxylase immunoreactivity (TH-IR), isolectin B4 reactivity, Black Gold II (BG-II) and Fluoro-Jade C (FJ-C) staining, and immunoreactivity to mouse immunoglobulin G (IgG-IR) in adult male mice at 90-min, 4-h, 12-h, 1-day, and 3-day post-METH exposure. The IgG-IR indicated that the BBB was only modestly altered in the CPu at time points after neurodegeneration occurred and dependent on hyperthermia and status epilepticus. The modest CPu IgG-IR changes observed in the perivascular areas indicated that immunoglobulins were present on some CPu microglia 1 day or more after METH. The first signs of CPu damage were swellings in the TH-IR axons, myelin damage, and a few degenerating neurons at 4-h post-METH. The loss of TH-IR was dependent on hyperthermia but not seizures or CPu neurodegeneration, and the TH-IR was virtually absent throughout the CPu within 12 h. Surprisingly, signs of FJ-C labeling (degenerating) axons in the CPu were seen only in the regions of pronounced somatic neurodegeneration and independent of TH-IR loss. Microglial activation did not occur until 1 day or more post-METH. In summary, a major BBB disruption within the CPu does not directly contribute to neurotoxicity in this single high-dose METH exposure. However, seizure activity produced or exacerbated by amygdalar BBB disruption can significantly increase CPu somatic neurodegeneration (but not affect dopamine (DA) terminal damage). The time course of microglial activation indicates a response to the neurodegeneration, myelin damage, and/or damaged DA terminals after loss of TH-IR.
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PMID:Neurotoxic-related changes in tyrosine hydroxylase, microglia, myelin, and the blood-brain barrier in the caudate-putamen from acute methamphetamine exposure. 1808 Nov 84

Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (10 mg/kg) intraperitoneally and killed 24 h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labeling in the CA1 and CA3 areas of the hippocampus in the rats that received kainic acid, when compared with saline-treated rats. Immunohistochemistry and western blot analysis for the calpain-derived breakdown products of spectrin showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
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PMID:Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus. 1808 74

We tested a hypothesis that manganese enhanced magnetic resonance imaging (MEMRI) after systemic injection of MnCl(2) could detect axonal sprouting in the hippocampus following kainate (KA) induced status epilepticus (SE). MEMRI was performed at 3 h, 25 h, 4 days, and 2 months post-SE. To assess the contribution of various cellular alterations that occur in parallel with sprouting to the MEMRI signal, we sacrificed animals for histology at 4 days and 2 months post-SE. Neurodegeneration was assessed from thionin and Fluoro-Jade B stained preparations, astrogliosis from GFAP (glial fibrillary acidic protein) and microgliosis from Ox-42 immunostained preparations. Sprouting of granule cells axons (mossy fibers) in the dentate gyrus was analyzed from Timm stained sections. Occurrence of spontaneous epileptic seizures was analyzed at 2 months post-SE using continuous video-EEG monitoring. Integrity of the blood-brain barrier (BBB) was studied using Gd-enhanced MRI. We found abnormal MEMRI hyperintensity in the CA1 and the dentate gyrus at 2 months post-SE but not at earlier time points. Based on histologic analysis of individual animals with MEMRI hyperintensity, hippocampal MEMRI changes could be attributed to increasing axonal density rather than to neurodegeneration, astrogliosis, or microgliosis. Moreover, MEMRI contrast was not affected by seizure activity, and we could not detect any leakage of the BBB that could have explained the observed MEMRI hyperintensity. Present data show that systemic MEMRI can reveal axonal sprouting, and thus, can potentially serve as a marker for neuroplasticity in preclinical studies.
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PMID:Manganese enhanced MRI detects mossy fiber sprouting rather than neurodegeneration, gliosis or seizure-activity in the epileptic rat hippocampus. 1832 32

In neuronal cultures it has been demonstrated that neurotrophins can elicit neuronal death through the p75 neurotrophic receptor (p75ntr) in the absence of concomitant Trk signaling. However, it was suggested that p75ntr induces neuronal death after status epilepticus (SE) in neuronal populations that express relatively high quantities of tropomyosin receptor kinase B (TrkB). Here, using Western blot and immunohistochemistry analyses in the hippocampus, we found that 3-h SE caused a remarkable decrease in TrkB expression and phosphorylation, and a significant increase in p75ntr. TrkB modification occurs before the overexpression of the tumor suppressor protein p53, accompanies the cell damage taking place in the dentate gyrus, and precedes the CA1 neuronal injury as assessed by Fluoro-Jade B and Nissl staining. Co-immunoprecipitation of brain-derived neurotrophic factor (BDNF) or its immature form proBDNF showed increased interaction with p75ntr after its binding to TrkB was reduced. Interestingly, proBDNF also increases its binding with p75ntr after seizures that do not cause neuronal death (animals injected with pilocarpine that fail to enter SE). However, in those animals, TrkB protein levels remained unchanged and its phosphorylation increased. Our results indicate an intrinsic capacity of neurons in vivo to modify final neurotrophin output by changing the proportion of their receptors' expression and the receptors' interaction with their ligands. These early events support the idea that neurotrophins may be involved in the induction of neuronal death in vivo under pathological conditions.
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PMID:Status epilepticus induces a TrkB to p75 neurotrophin receptor switch and increases brain-derived neurotrophic factor interaction with p75 neurotrophin receptor: an initial event in neuronal injury induction. 1851 Dec 10

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

Pilocarpine-induced status epilepticus (SE) mimics many features of temporal lobe epilepsy and is a useful model to study neural changes that result from prolonged seizure activity. In this study, distribution of the anti-adhesive extracellular matrix protein SC1 was examined in the rat hippocampus following SE. Western blotting showed decreased levels of SC1 protein in the week following SE. Immunohistochemistry demonstrated that the decrease in overall SC1 protein levels was reflected by a reduction of SC1 signal in granule cells of the dentate gyrus. Interestingly, levels of SC1 protein in neurons of the seizure-resistant CA2 sector of the hippocampus did not change throughout the seizure time course. However, at 1 day post-SE, a subset of neurons of the hippocampal CA1, CA3, and hilar regions, which are noted for extensive neuronal degeneration after SE, exhibited a transient increase in SC1 signal. Neurons exhibiting enhanced SC1 signal were not detected at 7 days post-SE. The cellular stress response was also examined. A prominent induction of heat-shock protein (Hsp70) and Hsp27 was detected following SE, while levels of constitutively expressed Hsp40, Hsp90, Hsp110, and Hsc70 showed little change at the time points examined. The subset of neurons that demonstrated a transient increase in SC1 colocalized with the cellular stress marker Hsp70, the degeneration marker Fluoro-Jade B, and the neuron activity marker activity-regulated cytoskeleton-associated protein (Arc). Taken together, these findings suggest that SC1 may be a component of the 'matrix response' involved in remodeling events associated with neuronal degeneration following neural injury.
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PMID:Extracellular matrix protein SC1/hevin in the hippocampus following pilocarpine-induced status epilepticus. 1880 51

Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at alpha1- but is a high efficacy positive allosteric modulator at alpha5-containing GABA(A) receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5 mg/kg or a higher dose of diazepam is required to produce similar protective effects. These finding suggests that imidazenil, a non-sedating anticonvulsant BZ ligand, is a more potent, effective, and safer drug than diazepam in protecting rats from DFP-induced seizures and the associated neuronal damage and/or ongoing neuronal degeneration.
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PMID:Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage. 1911 86

Since there is limited information in the literature, the purpose of this study was to investigate clinical signs, morphology, and temporal progression of lesions from Days 3 to 168 in a kainic acid (KA)-induced Fischer-344 (F-344) rat model of mesial temporal lobe epilepsy (MTLE). Following a single KA subcutaneous dose of 9 mg/kg to young adult male rats, 95% survived, 93% exhibited status epilepticus, and 80% eventually developed spontaneous motor seizures. Histopathology included hematoxylin and eosin (H&E), autofluorescence, Fluoro-Jade B, Timm's, ED-1/CD68, GFAP, doublecortin, and Ki-67. Neuronal degeneration occurred on Day 3 in the hippocampal CA1, CA3, and dentate hilar regions; amyg-daloid and thalamic nuclei; and frontoparietotemporal, entorhinal and piriform cortices. Degeneration severity peaked on Day 6 and decreased progressively until Day 168. Aberrant mossy fiber (MF) sprouting was present in the inner molecular layer of dentate gyrus on Days 6-168. Microliosis and astrogliosis peaked on Day 28 and generally colocalized with the distribution of neuronal degeneration. Important correlates to human MTLE included induction of spontaneous seizures, more severe neuronal damage of CA1 than CA3 (in contrast to other animal models but similar to humans), hilar neuronal loss, activated microgliosis and astrogliosis, aberrant MF sprouting, and dentate granule cell neurogenesis. Aberrant MF sprouting prior to spontaneous motor seizures and reduced seizure frequency with a decrease in aberrant MF sprouting support the hypothesis that MF sprouts are necessary for spontaneous seizure generation and maintenance.
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PMID:Temporal profile of clinical signs and histopathologic changes in an F-344 rat model of kainic acid-induced mesial temporal lobe epilepsy. 1912 89

An episode of status epilepticus (SE), if left untreated, can lead to death, or brain damage with long-term neurological consequences, including the development of epilepsy. The most common first-line treatment of SE is administration of benzodiazepines (BZs). However, the efficacy of BZs in terminating seizures is reduced with time after the onset of SE; this is accompanied by a reduced efficacy in protecting the hippocampus against neuronal damage, and is associated with impaired function and internalization of hippocampal GABA(A) receptors. In the present study, using Fluoro-Jade C staining, we found that administration of diazepam to rats at 3 h after the onset of kainic acid-induced SE, at a dose sufficient to terminate SE, had no protective effect on the hippocampus, but produced a significant reduction in neuronal degeneration in the amygdala, piriform cortex, and endopiriform nucleus, examined on days 7-9 after SE. Thus, in contrast to the hippocampus, the amygdala and other limbic structures are responsive to neuroprotection by BZs after prolonged SE, suggesting that GABA(A) receptors are not significantly altered in these structures during SE.
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PMID:Diazepam administration after prolonged status epilepticus reduces neurodegeneration in the amygdala but not in the hippocampus during epileptogenesis. 1912 42

An acute brain insult such as traumatic head/brain injury, stroke, or an episode of status epilepticus can trigger epileptogenesis, which, after a latent, seizure-free period, leads to epilepsy. The discovery of effective pharmacological interventions that can prevent the development of epilepsy requires knowledge of the alterations that occur during epileptogenesis in brain regions that play a central role in the induction and expression of epilepsy. In the present study, we investigated pathological alterations in GABAergic interneurons in the rat basolateral amygdala (BLA), and the functional impact of these alterations on inhibitory synaptic transmission, on days 7 to 10 after status epilepticus induced by kainic acid. Using design-based stereology combined with glutamic acid decarboxylase (GAD) 67 immunohistochemistry, we found a more extensive loss of GABAergic interneurons compared to the loss of principal cells. Fluoro-Jade C staining showed that neuronal degeneration was still ongoing. These alterations were accompanied by an increase in the levels of GAD and the alpha1 subunit of the GABA(A) receptor, and a reduction in the GluK1 (previously known as GluR5) subunit, as determined by Western blots. Whole-cell recordings from BLA pyramidal neurons showed a significant reduction in the frequency and amplitude of action potential-dependent spontaneous inhibitory postsynaptic currents (IPSCs), a reduced frequency but not amplitude of miniature IPSCs, and impairment in the modulation of IPSCs via GluK1-containing kainate receptors (GluK1Rs). Thus, in the BLA, GABAergic interneurons are more vulnerable to seizure-induced damage than principal cells. Surviving interneurons increase their expression of GAD and the alpha1 GABA(A) receptor subunit, but this does not compensate for the interneuronal loss; the result is a dramatic reduction of tonic inhibition in the BLA circuitry. As activation of GluK1Rs by ambient levels of glutamate facilitates GABA release, the reduced level and function of these receptors may contribute to the reduction of tonic inhibitory activity. These alterations at a relatively early stage of epileptogenesis may facilitate the progress towards the development of epilepsy.
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PMID:Pathological alterations in GABAergic interneurons and reduced tonic inhibition in the basolateral amygdala during epileptogenesis. 1954 Mar 12


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