| 1. |
- Bengzon, Johan, et al.
(författare)
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Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
- 1997
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 94:19, s. 10432-10437
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 2. |
- Ekdahl, Christine T, et al.
(författare)
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Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus
- 2001
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 14:6, s. 937-945
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Tidskriftsartikel (refereegranskat)abstract
- The dentate gyrus (DG) is one of the few regions in the brain that continues to produce new neurons throughout adulthood. Seizures not only increase neurogenesis, but also lead to death of DG neurons. We investigated the relationship between cell death and neurogenesis following seizures in the DG of adult rats by blocking caspases, which are key components of apoptotic cell death. Multiple intracerebroventricular infusions of caspase inhibitors (pancaspase inhibitor zVADfmk, and caspase 3 and 9 inhibitor) prior to, just after, 1 day after, and 1 week following 2 h of lithium-pilocarpine-induced status epilepticus reduced the number of terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelled (TUNEL) cells and increased the number of bromodeoxyuridine (BrdU) -stained proliferated cells in the subgranular zone at 1 week. The caspase inhibitor-treated group did not differ from control at 2 days or 5 weeks following the epileptic insult. Our findings suggest that caspases modulate seizure-induced neurogenesis in the DG, probably by regulating apoptosis of newly born neurons, and that this action can be suppressed transiently by caspase inhibitors. Furthermore, although previous studies have indicated that increased neuronal death can trigger neurogenesis, we show here that reduction in apoptotic death may be associated with increased neurogenesis.
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| 3. |
- Elmer, Eskil, et al.
(författare)
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Delayed kindling development after rapidly recurring seizures: relation to mossy fiber sprouting and neurotrophin, GAP-43 and dynorphin gene expression
- 1996
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 712:1, s. 19-34
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Tidskriftsartikel (refereegranskat)abstract
- Development of kindling and mossy fiber sprouting, and changes of gene expression were studied after 40 seizures produced during about 3 h by electrical stimulation every 5 min in the ventral hippocampus. As assessed by 5 test stimulations, enhanced responsiveness was present already after 6-24 h but from 1 week post-seizure increased gradually up to 4 weeks without additional stimuli. Sprouting of mossy fibers in the dentate gyrus was demonstrated only at 4 weeks with Timm's staining. In situ hybridization showed a transient increase (maximum at 2 h) of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), TrkB and TrkC mRNA levels and reduction (maximum at 12-24 h) of neurotrophin-3 (NT-3) mRNA expression in dentate granule cells after the seizures. In addition, BDNF mRNA levels were elevated in CA1 and CA3 regions, amygdala and piriform cortex. Marked increases of mRNA for growth-associated protein (GAP-43), with maximum expression at 12-24 h, were observed in dentate granule cells and in amygdala-piriform cortex. Dynorphin mRNA levels showed biphasic changes in dentate granule cells with an increase at 2 h followed by a decrease at 24 h. No long-term alterations of gene expression were observed. These findings indicate that increased responsiveness develops rapidly after recurring seizures but that the kindled state is reached gradually in about 4 weeks. Mossy fiber sprouting occurs in parallel to epileptogenesis and may play a causative role. Short-term changes of neurotrophin and Trk, GAP-43 and dynorphin mRNA levels and the assumed alterations of the corresponding proteins could trigger structural rearrangements underlying kindling but might also contribute to the initial increase of seizure susceptibility.
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| 4. |
- Elmer, Eskil, et al.
(författare)
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Dynamic changes of brain-derived neurotrophic factor protein levels in the rat forebrain after single and recurring kindling-induced seizures
- 1998
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Ingår i: Neuroscience. - 1873-7544. ; 83:2, s. 351-362
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Tidskriftsartikel (refereegranskat)abstract
- Regional levels of brain-derived neurotrophic factor protein were measured in the rat brain using enzyme immunoassay following seizures evoked by hippocampal kindling stimulations. One stimulation, which induced a brief, single episode of epileptiform activity in hippocampus and piriform cortex but not in parietal cortex or striatum, gave rise to a transient increase of brain-derived neurotrophic factor levels in dentate gyrus and CA3 region and a decrease in piriform cortex. After 40 rapidly recurring seizures, with epileptiform activity also involving parietal cortex and striatum, increases were observed in dentate gyrus, CA3 and CA1 regions, piriform cortex and striatum. Maximum levels were reached at 2-24 h and brain-derived neurotrophic factor then returned to baseline except in dentate gyrus, where elevated protein content was sustained for four days. The differential regulation of brain-derived neurotrophic factor protein levels in various forebrain structures, which only partly correlates to messenger RNA changes, could indicate regional differences in protein release, antero- or retrograde transport, or brain-derived neurotrophic factor promotor activation. The dynamic changes of brain-derived neurotrophic factor levels in regions involved in the generation and spread of seizure activity may regulate excitability and trigger plastic responses in the post-seizure period.
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| 5. |
- Elmer, Eskil, et al.
(författare)
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Epileptogenesis induced by rapidly recurring seizures in genetically fast- but not slow-kindling rats
- 1998
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Ingår i: Brain Research. - 1872-6240. ; 789:1, s. 111-117
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Tidskriftsartikel (refereegranskat)abstract
- A brief period of rapidly recurring hippocampal seizures can lead to the progressive development of a permanent increase of seizure susceptibility over several weeks, so-called 'delayed kindling'. We have analyzed seizure parameters critical for the induction of delayed kindling in two strains of rats characterized by fast and slow rates of traditional kindling, respectively. Forty seizures were produced during about 3 h by electrical kindling stimulations every 5 min in the ventral hippocampus. The fast rats displayed several generalized convulsions and had long periods of epileptiform activity, whereas the slow animals only exhibited brief, focal seizures. Changes in excitability were determined after 4 weeks using five test stimulations, and 2 weeks later by subjecting all animals to traditional hippocampal kindling. The fast rats showed clearly enhanced responsiveness at these time points, whereas no evidence of permanently increased seizure susceptibility was obtained in the slow rats. Our data indicate that the long-lasting stimulus-evoked seizures are mainly responsible for inducing delayed kindling, whereas the number of seizure events or generalized convulsions, and the total duration of epileptiform activity are less important. We hypothesize that long seizure episodes may be necessary to trigger the cascade of gene changes regulating the development of epilepsy.
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| 6. |
- Elmer, Eskil, et al.
(författare)
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Mossy fibre sprouting: evidence against a facilitatory role in epileptogenesis
- 1997
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Ingår i: NeuroReport. - 1473-558X. ; 8:5, s. 1193-1196
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Tidskriftsartikel (refereegranskat)abstract
- Sprouting of mossy fibres from dentate granule cells occurs in several animal models of epilepsy and in epileptic humans. Mossy fibre sprouting might contribute to epileptogenesis but also could be a compensatory, inhibitory response. We analysed mossy fibre sprouting in the supragranular zone of the dentate gyrus using Timm's histochemical method in genetically fast and slow kindling rats. Before the start of amygdala kindling, the slow rats showed higher Timm's staining scores than did the fast kindlers. No increase of mossy fibre density was observed when the animals were stimulated until either the fast or the slow rats had reached the fully kindled state. Our data argue against the hypothesis that mossy fibre sprouting facilitates epileptogenesis.
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| 7. |
- Elmer, Eskil, et al.
(författare)
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Regulation of neuronal nitric oxide synthase mRNA levels in rat brain by seizure activity
- 1996
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Ingår i: NeuroReport. - 1473-558X. ; 7:7, s. 1335-1335
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of neuronal nitric oxide synthase (NOS) mRNA levels during kindling epileptogenesis in the rat brain was investigated using in situ hybridization. Following 40 rapidly recurring seizures evoked by hippocampal stimulations, NOS mRNA expression decreased by 56% in the dentate granule cell layer (maximum at 2 h) and increased by 420,105 and 1260% in the CA1 and CA3 pyramidal layers and piriform cortex, respectively (maximum at 12-24 h). Gene expression had returned to control levels after one week. The presumed alterations of nitric oxide production, following the changes in NOS mRNA shown here, may modulate synaptic function during kindling development, and could influence neuronal vulnerability after epileptic insults.
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| 8. |
- Elmer, Eskil, et al.
(författare)
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Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice
- 1997
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 145:1, s. 93-103
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Tidskriftsartikel (refereegranskat)abstract
- In the kindling model of epilepsy, repeated electrical stimulations lead to progressive and permanent intensification of seizure activity. We find that the development of amygdala kindling is markedly retarded in mice heterozygous for a deletion of the neurotrophin-3 (NT-3) gene (NT-3+/- mice). These mice did not reach the fully kindled state (3rd grade 5 seizure) until after 28 +/- 4 days of stimulation compared to 17 +/- 2 days in the wild-type animals. The deficit in the NT-3+/- mice reflected dampening of the progression from focal to generalized seizures. The number of stimulations required to evoke focal (grade 1 and 2) seizures did not differ between the groups, but the NT-3 mutants spent a considerably longer period of time (13 +/- 3 days) than wild-type mice (2 +/- 1 days) in grade 2 seizures. As assessed by test stimulation 4-12 weeks after the 10th grade 5 seizure, kindling was maintained in the NT-3 mutants. In situ hybridization showed 30% reduction of basal NT-3 mRNA levels and lack of upregulation of TrkC mRNA expression at 2 h after a generalized seizure in dentate granule cells of the NT-3+/- mice, whereas the seizure-evoked increase in brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels was enhanced. These results indicate that endogenous NT-3 levels can influence the rate of epileptogenesis, and suggest a link between NT-3 and BDNF gene regulation in dentate granule cells.
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| 9. |
- Elmér, Olle, et al.
(författare)
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Prevention of posttraumatic pulmonary platelet trapping by portacaval transposition
- 1988
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Ingår i: The American Journal of Surgery. - 1879-1883. ; 155:2, s. 289-292
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Tidskriftsartikel (refereegranskat)abstract
- Significant soft-tissue trauma induces platelet activation, aggregation, and sequestration in the lungs. This pulmonary trapping is due either to the size of the platelet aggregates or to changes in the pulmonary microvasculature. To evaluate which one of these mechanisms is responsible for the trapping, we performed portacaval transposition in one group of pigs, making the liver the first receiving capillary bed for blood from the trauma sites in the lower extremities. One week after the operation, the platelets were labeled with indium oxine and reinfused, and the operated animals and a group of six control animals were subjected to standardized soft-tissue trauma to the lower extremities. Sequestration of platelets in the lungs and in the liver was registered dynamically before and for 90 minutes after the trauma. Soft-tissue trauma induced platelet sequestration in the liver in the operated group (p less than 0.01) and in the lungs in the control group (p less than 0.01). Trapping was paralleled by a decrease in the number of circulating platelets. This study has indicated that posttraumatic pulmonary platelet trapping is caused by platelet activation at the trauma sites and not by changes in the pulmonary microvasculature.
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| 10. |
- Ferencz, Istvan, et al.
(författare)
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Effects of cholinergic denervation on seizure development and neurotrophin messenger RNA regulation in rapid hippocampal kindling
- 1997
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Ingår i: Neuroscience. - 1873-7544. ; 80:2, s. 389-399
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Tidskriftsartikel (refereegranskat)abstract
- Intraventricular 192 IgG-saporin was used to induce a selective lesion of basal forebrain cholinergic neurons in rats. When subjected to 40 rapid hippocampal kindling stimulations with 5-min intervals, these animals exhibited increased number of generalized seizures and a higher mean seizure grade in response to the first five stimulations, and required fewer stimuli to develop focal behavioural seizures, as compared to non-lesioned rats. In contrast, both groups showed similarly enhanced responsiveness when test stimulated four weeks later. Using in situ hybridization, cholinergic denervation was found to cause a significant decrease of basal brain-derived neurotrophic factor messenger RNA levels in the hippocampal formation and piriform cortex, whereas gene expression for nerve growth factor, neurotrophin-3, and TrkB and TrkC was unchanged. Four weeks after rapid kindling stimulations, basal levels of brain-derived neurotrophic factor messenger RNA in the dentate granule cells were restored to normal in the lesioned rats, whereas neurotrophin-3 messenger RNA levels were decreased. No differences in the seizure-evoked levels of neurotrophin and Trk messenger RNAs were detected, except in the dentate granule cell layer, which had significantly higher brain-derived neurotrophic factor messenger RNA expression in the lesioned animals at 2 h. In conclusion, the basal forebrain cholinergic system (i) dampens the severity of recurring seizures induced by rapid hippocampal kindling stimulations, but has no effect on the subsequent delayed phase of epileptogenesis; and (ii) exerts a tonic stimulation of basal brain-derived neurotrophic factor messenger RNA levels in the hippocampal formation and piriform cortex. The findings also indicate that the cholinergic lesion does not affect neurotrophin and Trk gene expression after recurring seizures, and that the kindling process leads to long-term changes in basal brain-derived neurotrophic factor and neurotrophin-3 messenger RNA levels in the denervated animals.
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