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)

Status epilepticus (StE) in immature rats causes long-term functional impairment. Whether this is associated with structural alterations remains controversial. The present study was designed to test the hypothesis that StE at an early age results in neuronal loss. StE was induced with lithium-pilocarpine in 12-d-old rats, and the presence of neuronal damage was investigated in the brain from 12 hr up to 1 week later using silver and Fluoro-Jade B staining techniques. Analysis of the sections indicated consistent neuronal damage in the central and lateral segments of the mediodorsal nucleus of the thalamus, which was confirmed using adjacent cresyl violet-stained preparations. The mechanism of thalamic damage (necrosis vs apoptosis) was investigated further using TUNEL, immunohistochemistry for caspase-3 and cytochrome c, and electron microscopy. Activated microglia were detected using OX-42 immunohistochemistry. The presence of silver and Fluoro-Jade B-positive degenerating neurons in the mediodorsal thalamic nucleus was associated with the appearance of OX-42-immunopositive activated microglia but not with the expression of markers of programmed cell death, caspase-3, or cytochrome c. Electron microscopy revealed necrosis of the ultrastructure of damaged neurons, providing further evidence that the mechanism of StE-induced damage in the mediodorsal thalamic nucleus at postnatal day 12 is necrosis rather than apoptosis. Finally, these data together with previously described functions of the medial and lateral segments of the mediodorsal thalamic nucleus suggest that some functions, such as adaptation to novelty, might become compromised after StE early in development.
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PMID:Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. 1133 88

Status epilepticus (SE) increases neurogenesis in the subgranular zone (SGZ) of the adult dentate gyrus, but many of the newborn cells die, partly through caspase-induced apoptosis. Here we provide immunohistochemical evidence indicating that the caspase-evoked death of the new neurons involves the mitochondrial but not the death-receptor-mediated pathway. Cytochrome c released from mitochondria was found in a subset of progenitor cell progeny, while Fas ligand and tumor necrosis factor 1 receptor-associated domain as well as the mitochondria-related, caspase-independent apoptosis-inducing factor were not detected. We also show that additional seizures, induced at different stages during neuronal differentiation of progenitor cell progeny following SE, neither potentiate cell death mechanisms in the SGZ nor compromise the survival of the new cells. Thus, we found similar expression of cytochrome c, active caspase-3, caspase-cleaved PARP, and TUNEL/Hoechst-positive DNA fragmentation, as well as numbers of new cells in the SGZ in rats exposed to additional seizures at days 6 and 7 or days 33 and 34 following SE as in control animals only subjected to SE. We propose that the degree of survival of newly generated neurons is determined primarily by the initial SE insult and the ensuing pathology in the tissue environment, whereas spontaneous seizures play a minor role.
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PMID:Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival. 1467 67

We examined the mechanism of neuronal necrosis induced by hypoxia in dentate gyrus cultures or by status epilepticus (SE) in adult mice. Our observations showed that hypoxic necrosis can be an active process starting with early mitochondrial swelling and loss of the mitochondrial membrane potential, followed by cytochrome c release and caspase-9-dependent activation of caspase-3. This sequence of events (or program) was independent of protein synthesis and may be induced by energy failure and/or calcium overloading of mitochondria. We called this form of necrosis "programmed necrosis." After SE in adult mice, CA1 and CA3 pyramidal neurons displayed a necrotic morphology, associated with caspase-3 immunoreactivity and with double-stranded DNA breaks, suggesting that "programmed necrosis" may be involved in SE-induced neuronal loss.
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PMID:Programmed neuronal necrosis and status epilepticus. 1598 52

Status epilepticus results in preferential neuronal cell loss in the hippocampus. We evaluated the hypothesis that the repertoire of intracellular events in the vulnerable hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus entails upregulation of nitric oxide synthase II (NOS II), followed by the release of mitochondrial cytochrome c that triggers the cytosolic caspase-3 cascade, leading to apoptotic cell death. In Sprague-Dawley rats, significant and temporally correlated upregulation of NOS II (3-24h), but not NOS I or II expression, enhanced cytosolic translocation of cytochrome c (days 1 and 3), augmented activated caspase-3 in cytosol (days 1, 3 and 7) and DNA fragmentation (days 1, 3 and 7) was detected bilaterally in the hippocampal CA3 subfield after elicitation of sustained seizure activity by microinjection of kainic acid into the unilateral CA3 subfield. Application bilaterally into the hippocampal CA3 subfield of a selective NOS II inhibitor, S-methylisothiourea, significantly blunted these apoptotic events; a selective NOS I inhibitor, N(omega)-propyl-l-arginine or a potent NOS III inhibitor, N(5)-(1-iminoethyl)-l-ornithine was ineffective. We conclude that upregulation of NOS II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following the induction of experimental temporal lobe status epilepticus.
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PMID:Upregulation of nitric oxide synthase II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following induction of experimental temporal lobe status epilepticus in the rat. 1733 42

Experimentally evoked seizures can activate the intrinsic mitochondrial cell death pathway, components of which are modulated in the hippocampus of patients with temporal lobe epilepsy. Bcl-2 family proteins are critical regulators of mitochondrial dysfunction, but their significance in this setting remains primarily untested. Presently, we investigated the mitochondrial pathway and role of anti-apoptotic Bcl-2 proteins using a mouse model of seizure-induced neuronal death. Status epilepticus was evoked in mice by intra-amygdala kainic acid, causing cytochrome c release, processing of caspases 9 and 7, and death of ipsilateral hippocampal pyramidal neurons. Seizures caused a rapid decline in hippocampal Bcl-w levels not seen for either Bcl-2 or Bcl-xl. To test whether endogenous Bcl-w was functionally significant for neuronal survival, we investigated hippocampal injury after seizures in Bcl-w-deficient mice. Seizures induced significantly more hippocampal CA3 neuronal loss and DNA fragmentation in Bcl-w-deficient mice compared with wild-type mice. Quantitative electroencephalography analysis also revealed that Bcl-w-deficient mice display a neurophysiological phenotype whereby there was earlier polyspike seizure onset. Finally, we detected higher levels of Bcl-w in hippocampus from temporal lobe epilepsy patients compared with autopsy controls. These data identify Bcl-w as an endogenous neuroprotectant that may have seizure-suppressive functions.
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PMID:Bcl-w protects hippocampus during experimental status epilepticus. 1770 91

Status epilepticus (SE) is a severe clinical manifestation of epilepsy which causes brain damage. The pathological process and underlying mechanisms involved in the programmed cell death (PCD) are still not fully clear. In the current study, rats were induced SE by lithium-pilocarpine administration. Our data showed hippocampal neurons death appeared at 6h after SE and sustained for 7 days. By blotting the activation of mu-calpain and its specific cleavage of nonerythroid alpha-spectrin (alphaSpII) (145 kDa) was evident at 1 and 3 days after SE, which coincided with Bid activation, apoptosis inducing factor (AIF) translocation and cytochrome c release from mitochondria, whereas, activated caspase-3 and caspase-3-specific fragments of alphaSpII (120 kDa) predominantly appeared at 5 and 7 days after SE. Moreover, MDL-28170, a calpain inhibitor, partially rescued the neuron death and attenuated the expression of activated mu-calpain, cleavage of Bid (15 kDa), AIF translocation and cytochrome c release. Taken together, our study indicated that mu-calpain mediated hippocampal neuron PCD is prior to caspase-3 activation. It functioned via translocation of Bid, AIF and cytochrome c release.
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PMID:Mu-calpain mediates hippocampal neuron death in rats after lithium-pilocarpine-induced status epilepticus. 1905 71

Prolonged seizures activate members of the Bcl-2 homology domain 3-only sub-group of the Bcl-2 protein family, which are essential for initiation of apoptosis signaling. Bid is a potent pro-apoptotic Bcl-2 homology domain 3-only protein, which upon proteolytic activation translocates to mitochondria to promote activation of the Bax/Bak sub-group of the pro-apoptotic Bcl-2 family and thereby contributes to release of apoptogenic molecules, such as cytochrome c and possibly apoptosis-inducing factor (AIF). Bid-deficient mice have been reported to show reduced lesion volumes after ischemia and trauma in vivo but a causal role for Bid in the setting of seizure-induced neuronal death has not been investigated. In this study, we studied Bid activation following status epilepticus in mice and compared hippocampal damage between wild-type and Bid-deficient animals. Full-length Bid was detected in normal mouse hippocampus and the cleaved (activated) p15 fragment of Bid was detected shortly after status epilepticus. Bid-deficient mice underwent equivalent electrographic seizure responses during status epilepticus as wild-type animals. Hippocampal counts of degenerating neurons and surviving neuron-specific nuclear protein-positive cells were not significantly different between wild-type and Bid-deficient mice. Additionally, nuclear translocation of AIF was not reduced in Bid-deficient compared with wild-type animals subjected to status epilepticus. The present study demonstrates that AIF is not dependent on Bid for mitochondrial release and nuclear import in this model and that while Bid is cleaved during seizure-induced neuronal death, it may be functionally redundant or even not essential.
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PMID:BH3-only protein Bid is dispensable for seizure-induced neuronal death and the associated nuclear accumulation of apoptosis-inducing factor. 2064 70

Actin-depolymerizing factor (ADF)/cofilin is a small cytoskeletal protein that is a stimulus-responsive mediator of actin dynamics. ADF/cofilin also translocates into mitochondria and nuclei in response to apoptotic stimuli for cytochrome c release. These ADF/cofilin translocations are negatively regulated by phosphorylation. Recently, it has been reported that pyridoxal-5'-phosphate (PLP) phosphatase/chronophin (PLPP/CIN) regulates phosphorylation of ADF/cofilin levels. Therefore, we investigated whether PLPP/CIN contributes to apoptosis-like events via modulation of ADF/cofilin phosphorylation following status epilepticus (SE). In the present study, apoptosis-like astroglial damages were detected in the dentate gyrus after SE. Upregulation of ADF/cofilin and PLPP/CIN expression in the cytoplasm and nucleus were accompanied by apoptosis-like events. PLPP/CIN level showed a direct proportionality to nuclear translocation of ADF/cofilin. Moreover, nuclear accumulation of apoptosis-inducing factor was simultaneously observed with that of ADF/cofilin. Tat-PLPP/CIN pretreatment accelerated astroglial apoptosis-like degeneration following SE, although Tat-PLPP/CIN transduction alone could not induce apoptosis or necrosis in astrocytes. Therefore, our findings suggest that nuclear accumulation of ADF/cofilin itself may not induce apoptogenic events, but may play a synergic role in apoptosis-like astroglial loss following SE.
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PMID:Pyridoxal-5'-phosphate phosphatase/chronophin induces astroglial apoptosis via actin-depolymerizing factor/cofilin system in the rat brain following status epilepticus. 2073 71

The ketogenic diet (KD) is effective in the treatment of refractory epilepsy, yet the molecular mechanisms underlying its antiepileptic effects have not been determined. There is increasing evidence that neuronal cell death induced by seizures via mitochondrial pathway and seizures can lead to mitochondrial release of cytochrome c, and we have shown previously that translocation of Smac/DIABLO into the cytosol play a role in the brain damage in a model of limbic seizure. In the present study, we explored the neuroprotective effect of KD in C57BL/6 mice with seizures induced by kainic acid (KA). Status epilepticus triggered by intra-amygdaloid microinjection of KA lead to neuronal death in the selective ipsilateral CA3 subfield of the hippocampus and mitochondrial release of Smac/DIABLO and cytochrome c. We found that KD significantly decreased neuronal death in the ipsilateral CA3 at 24h after KA-induced seizures. Furthermore, KD reduced Smac/DIABLO and cytochrome c release from mitochondria, attenuated activation of casepase-9 and caspase-3 following seizures. These results demonstrate that the neuroprotective effect of KD against brain injury induced by limbic seizures, at least partially, is associated with inhibition of mitochondrial release of Smac/DIABLO and cytochrome c.
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PMID:Ketogenic diet reduces Smac/Diablo and cytochrome c release and attenuates neuronal death in a mouse model of limbic epilepsy. 2279 83

The mitochondrial calcium uniporter (MCU) is reportedly involved in oxidative stress, apoptosis, and many neurological diseases. However, the role of the MCU in epilepsy remains unknown. In this study, we found that the MCU inhibitor Ru360 significantly attenuated neuronal death and exerted an anti-apoptotic effect on rat hippocampal neurons after pilocarpine-induced status epilepticus (SE), while the MCU activator spermine increased seizure-induced neuronal death and apoptosis. In addition, Ru360 decreased the level of seizure-induced reactive oxygen species (ROS) in mitochondria isolated from rat hippocampi. Moreover, Ru360 restored the altered mitochondrial membrane potential and cytochrome c (CytC) release in epileptic hippocampi. However, spermine treatment exerted an opposite effect on seizure-induced ROS production and mitochondrial membrane potential alteration and CytC release compared with Ru360 treatment. Altogether, the findings of this study suggest that MCU inhibition exerts a neuroprotective effect on seizure-induced brain injury possibly through the mitochondria/ROS/CytC pathway.
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PMID:Role of the Mitochondrial Calcium Uniporter in Rat Hippocampal Neuronal Death After Pilocarpine-Induced Status Epilepticus. 2614 31


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