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)

While it is clear that acute hippocampal injury or status epilepticus increases the production of new neurons in the adult dentate gyrus (DG), the effects of chronic epilepsy on dentate neurogenesis are unknown. We hypothesize that epileptogenic changes and spontaneous recurrent motor seizures (SRMS) that ensue after hippocampal injury or status epilepticus considerably decrease dentate neurogenesis. We addressed this issue by quantifying the number of cells that are positive for doublecortin (DCX, a marker of new neurons) in the DG of adult F344 rats at 16 days and 5 months after an intracerebroventricular kainic acid (ICV KA) administration or after graded intraperitoneal KA (IP KA) injections, models of temporal lobe epilepsy (TLE). At early post-KA administration, the injured hippocampus exhibited increased dentate neurogenesis in both models. Conversely, at 5 months post-KA administration, the chronically epileptic hippocampus demonstrated severely declined neurogenesis, which was associated with considerable SRMS in both KA models. Additionally, stem/progenitor cell proliferation factors, FGF-2 and IGF-1, were decreased in the chronically epileptic hippocampus. Interestingly, the overall decrease in neurogenesis and the extent of SRMS were greater in rats receiving IP KA than rats receiving ICV KA, suggesting that the extent of neurogenesis during chronic TLE exhibits an inverse relationship with SRMS. These results provide novel evidence that chronic TLE is associated with extremely declined dentate neurogenesis. As fraction of newly born neurons become GABA-ergic interneurons, declined neurogenesis may contribute to the increased seizure-susceptibility of the DG in chronic TLE. Likewise, the hippocampal-dependent learning and memory deficits observed in chronic TLE could be linked at least partially to the declined neurogenesis.
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PMID:Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. 1557 83

Previous studies showed that neurogenesis occurs in the dentate gyrus of the adult rodent. Recent evidence suggests that the resulting newly born neurons integrate into pre-existing hippocampal circuitry. Newly born neurons in the developing and adult dentate gyrus exhibit a transient basal dendrite. In adult pilocarpine-induced epileptic rats, basal dendrites persist and are ectopically located in the hilus where they receive synaptic input from mossy fiber axons. We hypothesize that these hilar basal dendrites are derived from newly born neurons that are born after the pilocarpine-induced seizures. To test this hypothesis, the length of basal dendrites from epileptic rats was compared with that from control rats using doublecortin immunocytochemistry, which labels newly born neurons and their processes for up to 3 weeks after their genesis. The data on hilar basal dendrites in pilocarpine animals indicate that those from newly born neurons are significantly longer than those found in the control rats. We also demonstrate that 20% of newly born neurons in the epileptic rat have a basal dendrite that enters the hilus at an angle greater than 30 degrees from its cell body as compared with <2% in the control rats. Lastly, we provide evidence that the hilar basal dendrites in the epileptic rats are adjacent to glial fibrillary acidic protein-labeled astrocytic processes in the hilus and suggest that an ectopic glial scaffold in the hilus is involved with the formation of hilar basal dendrites. In conclusion, the data show that newly born neurons from epileptic rats have longer hilar basal dendrites and their formation might relate to gliosis which occurs as a result of hilar neuronal cell loss after status epilepticus.
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PMID:Newly generated dentate granule cells from epileptic rats exhibit elongated hilar basal dendrites that align along GFAP-immunolabeled processes. 1634 54

Increased production of new neurons in the adult dentate gyrus (DG) by neural stem/progenitor cells (NSCs) following acute seizures or status epilepticus (SE) is a well known phenomenon. However, it is unknown whether NSCs in the aged DG have similar ability to upregulate neurogenesis in response to SE. We examined DG neurogenesis after the induction of continuous stages III-V seizures (SE) for over 4 h in both young adult (5-months old) and aged (24-months old) F344 rats. The seizures were induced through 2-4 graded intraperitoneal injections of the excitotoxin kainic acid (KA). Newly born cells in the DG were labeled via daily intraperitoneal injections of the 5'-bromodeoxyuridine (BrdU) for 12 days, which commenced shortly after the induction of SE in KA-treated rats. New cells and neurons in the subgranular zone (SGZ) and the granule cell layer (GCL) were analyzed at 24 h after the last BrdU injection using BrdU and doublecortin (DCX) immunostaining, BrdU-DCX and BrdU-NeuN dual immunofluorescence and confocal microscopy, and stereological cell counting. Status epilepticus enhanced the numbers of newly born cells (BrdU(+) cells) and neurons (DCX(+) neurons) in young adult rats. In contrast, similar seizures in aged rats, though greatly increased the number of newly born cells in the SGZ/GCL, failed to increase neurogenesis due to a greatly declined neuronal fate-choice decision of newly born cells. Only 9% of newly born cells in the SGZ/GCL differentiated into neurons in aged rats that underwent SE, in comparison to the 76% neuronal differentiation observed in age-matched control rats. Moreover, the number of newly born cells that migrate abnormally into the dentate hilus (i.e., ectopic granule cells) after SE in the aged hippocampus is 92% less than that observed in the young adult hippocampus after similar SE. Thus, SE fails to increase the addition of new granule cells to the GCL in the aged DG, despite a considerable upregulation in the production of new cells, and SE during old age leads to much fewer ectopic granule cells. These results have clinical relevance because earlier studies have implied that both increased and abnormal neurogenesis occurring after SE in young animals contributes to chronic epilepsy development.
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PMID:Status epilepticus during old age is not associated with enhanced hippocampal neurogenesis. 1849 29

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

The mechanism of status epilepticus-induced neuronal death in the immature brain is not fully understood. In the present study, we examined the contribution of caspases in our lithium-pilocarpine model of status epilepticus in 14 days old rat pups. In CA1, upregulation of caspase-8, but not caspase-9, preceded caspase-3 activation in morphologically necrotic cells. Pretreatment with a pan-caspase inhibitor provided neuroprotection, showing that caspase activation was not an epiphenomenon but contributed to neuronal necrosis. By contrast, upregulation of active caspase-9 and caspase-3, but not caspase-8, was detected in apoptotic dentate gyrus neurons, which were immunoreactive for doublecortin and calbindin-negative, two features of immature neurons. These results suggest that, in cells which are aligned in series as parts of the same excitatory hippocampal circuit, the same seizures induce neuronal death through different mechanisms. The regional level of neuronal maturity may be a determining factor in the execution of a specific death program.
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PMID:Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage. 1987 60

Angiogenesis and blood-brain-barrier (BBB) damage have been proposed to contribute to epileptogenesis and/or ictogenesis in experimental and human epilepsy. We tested a hypothesis that after brain injury angiogenesis occurs in the most damaged hippocampal areas with the highest need of tissue repair, and associates with formation of epileptogenic neuronal networks. We induced status epilepticus (SE) with pilocarpine in adult rats, and investigated endothelial cell proliferation (BrdU and rat endothelial cell antigen-1 (RECA-1) double-labeling), vessel length (unbiased stereology), thrombocyte aggregation (thrombocyte immunostaining), neurodegeneration (Nissl staining), neurogenesis (doublecortin (DCX) immunohistochemistry), and mossy fiber sprouting (Timm staining) in the hippocampus at different time points post-SE. As functional measures we determined BBB leakage (quantified immunoglobulin G (IgG) immunostaining), and hippocampal blood volume (CBV) and flow (CBF) in vivo (magnetic resonance imaging, MRI). The total length of hippocampal blood vessels was decreased by 17% at 2 d after status epilepticus (SE) induced by pilocarpine in adult rats (P<0.05 as compared to controls) which was not accompanied by alterations in hippocampal blood volume (BV) and flow (BF). Number of proliferating endothelial cells peaked at 4 d post-SE and correlated with an increase in vessel length (r=0.900, P<0.05). Vessels length had recovered to control level or even higher at 2 wk post-SE, angiogenesis being most prominent in the CA3 (128% as compared to that in controls, P<0.05), and was associated with increased BV (178% as compared to that in controls, P<0.05). Enlargement of vessel diameter in the hippocampal fissure was associated with thrombocyte aggregation in distal capillaries. BBB was most leaky during the first 4 d post-SE and increased IgG extravasation was observed for 60 d. Our data show that magnitude of endothelial cell proliferation is not associated with severity of acute post-SE neurodegeneration or formation of abnormal neuronal network. This encourages identification of molecular targets that initiate and maintain specific aspects of tissue reorganization, including preservation and proliferation of endothelial cells to reduce the risk of epileptogenesis and enhance recovery after brain injury.
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PMID:Vascular changes in epilepsy: functional consequences and association with network plasticity in pilocarpine-induced experimental epilepsy. 2000 12

Lamotrigine (LTG) and topiramate (TPM), two of the most commonly used new-generation antiepileptic drugs (AEDs), have been shown to produce no adverse and impaired cognitive effects in patients with epilepsy, respectively. As seizure-induced neurogenesis might contribute to cognitive deficits that are associated with status epilepticus (SE), we examined whether these two drugs produce differential effects on seizure-induced neurogenesis in the hippocampus of adult rats. Lithium pilocarpine model was used to mimic human temporal-lobe epilepsy. Five hours after SE, LTG and TPM were administered intragastrically twice daily throughout the entire length of the experiment with total daily dose of 20 and 80 mg/kg, respectively. The hippocampal neurogenesis was examined using 5-bromodeoxyuridine and doublecortin immunohistochemistry. Both LTG and TPM treatments significantly inhibited seizure-induced proliferation of neural progenitors in the hippocampus, but did not affect the neuronal differentiation of newborn cells. Long-term treatment with both AEDs decreased the number of spontaneous recurrent seizures after SE and alleviated chronic seizure-induced neuronal injury in the dentate hilus. Eventually, TPM significantly increased the number of newborn neurons in the dentate granular cell layer after seizures likely by promoting the survival of newborn neurons. In contrast, LTG treatment significantly reduced the number of ectopic hilar newborn neurons after seizures. Neither of them prevented the formation of hilar basal dendrites of newborn neurons in the epileptic hippocampus. These results indicate that TPM but not LTG promotes aberrant neuron regeneration in the hippocampus after SE, which might be partially related to their differential effects on cognitive function.
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PMID:Effects of lamotrigine and topiramate on hippocampal neurogenesis in experimental temporal-lobe epilepsy. 2002 52

Expression of urokinase-type plasminogen activator (uPA) is increased after brain injury, suggesting that, like in cancer tissue, uPA plays roles in brain remodeling. Here we injured brain with intrahippocampal kainic acid (KA) injection in adult Wt and uPA-/- mice. At 20 days post-injury, uPA-/- mice had more severe loss of contralateral pyramidal (p<0.05) and hilar neurons (p<0.05) than Wt mice. The number of doublecortin (DCX)-positive newly born neurons was also reduced in uPA-/- mice as compared to Wt (p<0.01). No difference was observed in granule cell dispersion or distribution of DCX-positive neurons in the dentate gyrus. uPA deficiency did not affect the total length of hippocampal blood vessels or vessel density. No differences were observed in the severity of status epilepticus or consequent epilepsy between the genotypes. These data indicate that uPA deficiency can unfavorably modulate both delayed neurodegeneration and neurogenesis but has little effect on post-injury neuronal migration and vascular density. Our results favor the idea that elevated uPA during the post-injury phase is neuroprotective.
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PMID:Urokinase-type plasminogen activator regulates neurodegeneration and neurogenesis but not vascular changes in the mouse hippocampus after status epilepticus. 2002 72

Modulation of the neural cell adhesion molecule by the attachment of polysialic acid residues through the polysialyl-transferase, ST8SiaIV, regulates neuronal plasticity and affects cellular alterations in the epileptic brain. Here, we determined the impact of ST8SiaIV deficiency on the pathophysiological consequences of status epilepticus (SE). ST8SiaIV deficiency reduced the latency to SE induction and increased SE-mediated mortality. Analysis of the doublecortin expression showed a reduced number of neuroblasts as a long-term consequence of SE in ST8SiaIV knockouts. Testing in a battery of different behavioral paradigms indicated that loss of ST8SiaIV affects the long-term behavioral consequences. In summary, the data suggest that the polysialic acid-neural cell adhesion molecule system is a putative target for the modulation of pathophysiological events and affects psychiatric comorbidities in epilepsies.
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PMID:Polysialic acid affects pathophysiological consequences of status epilepticus. 2035 97

Status epilepticus in the immature brain induces neuronal injury in the hippocampal formation, but the mode and mechanism of death are poorly understood. Our laboratory has recently investigated the role of caspase-3, -8, and -9 in neuronal injury, using a lithium-pilocarpine model of status epilepticus in 2-week-old rat pups. Our results showed that dying neurons in the dentate gyrus and CA1-subiculum area do not share the same mechanism of death. In CA1-subiculum, caspase-8 upregulation preceded caspase-3 activation in morphologically necrotic neurons. The pan-caspase inhibitor Q-VD-OPH reduced CA1 damage, showing that caspases contribute to status epilepticus-induced necrosis. In the dentate gyrus, dying neurons were caspase-9 and -3 immunoreactive and morphologically apoptotic. It is not clear why the same seizures cause different types of cell death in neurons that are connected in series along the same hippocampal circuit, but the apoptotic dentate neurons express doublecortin, and do not express calbindin-D28k, suggesting that their immaturity may be a factor in producing an apoptotic mode of death.
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PMID:Distinct caspase pathways mediate necrosis and apoptosis in subpopulations of hippocampal neurons after status epilepticus. 2061 2


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