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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seizure-induced neuronal death may be under the control of the caspase family of cell death proteases. We examined the role of caspase-2 in a model of focally evoked limbic seizures with continuous EEG recording. Seizures were elicited by microinjection of kainic acid into the amygdala of the rat and terminated after 40 min by diazepam. Caspase-2 was constitutively present in brain, mostly within neurons, and was detected in both cytoplasm and nucleus. Cleaved caspase-2 (12 kDa) was detected immediately following seizure termination within injured ipsilateral hippocampus, contiguous with increased Val-Asp-Val-Ala-Asp (VDVADase) activity, a putative measure of activated caspase-2. Expression of receptor interacting protein (RIP)-associated Ich-1-homologous protein with death domain (RAIDD) was increased following seizures, whereas expression of RIP and tumor necrosis factor receptor associated protein with death domain (TRADD), other components thought to be linked to the caspase-2 activation and signaling mechanism, were unchanged. Intracerebroventricular administration of z-VDVAD-fluoromethyl ketone blocked seizure-induced caspase-2 activity but did not alter caspase-8 activity and failed to affect DNA fragmentation or neuronal death. These data support activation of caspase-2 following seizures but suggest that parallel caspase pathways may circumvent deficits in caspase-2 function to complete the cell death process.
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PMID:Caspase-2 activation is redundant during seizure-induced neuronal death. 1133 17

The mechanism by which seizures induce neuronal death is not completely understood. Caspase-8 is a key initiator of apoptosis via extrinsic, death receptor-mediated pathways; we therefore investigated its role in mediating seizure-induced neuronal death evoked by unilateral kainic acid injection into the amygdala of the rat, terminated after 40 min by diazepam. We demonstrate that cleaved (p18) caspase-8 was detectable immediately following seizure termination coincident with an increase in cleavage of the substrate Ile-Glu-Thr-Asp (IETD)-p-nitroanilide and the appearance of cleaved (p15) Bid. Expression of Fas and FADD, components of death receptor signaling, was increased following seizures. In vivo intracerebroventricular z-IETD-fluoromethyl ketone administration significantly reduced seizure-induced activities of caspases 8, 9, and 3 as well as reducing Bid and caspase-9 cleavage, cytochrome c release, DNA fragmentation, and neuronal death. These data suggest that intervention in caspase-8 and/or death receptor signaling may confer protection on the brain from the injurious effects of seizures.
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PMID:Cleavage of bid may amplify caspase-8-induced neuronal death following focally evoked limbic seizures. 1149 22

Neurotrophins support neuronal survival and differentiation via Trk receptors, yet can also induce cell death via the p75 receptor. In these studies, we investigated signaling mechanisms governing p75-mediated death of hippocampal neurons, specifically the role of caspases. Although p75 is structurally a member of the Fas/TNFR1 receptor family, caspase-8 was not required for p75-mediated death, unlike other members of this receptor family. In contrast, p75-mediated neuronal death was associated with mitochondrial loss of cytochrome c and required Apaf-1 and caspase-9, -6, and -3. In particular, caspase-6 plays a central role in mediating neurotrophin-induced death, illuminating a novel role for this caspase. Inhibition of DIABLO/Smac, which blocks inhibitor of apoptosis proteins, protected cells from death, whereas simultaneous inhibition of both DIABLO/Smac and MIAP3 allowed trophin-induced death to proceed. In vivo, pilocarpine-induced seizures, previously shown to up-regulate p75 expression and increase neurotrophin production, caused activation of caspase-6 and -3 and cleavage of poly(ADP-ribose) polymerase in p75-expressing hippocampal neurons. In p75(-/-) mice, no activated caspase-3 was detected, and there was a marked reduction in the number of dying neurons after pilocarpine treatment compared with wild type mice. Neurotrophin-induced p75-mediated death is likely to play an important role in mediating neuronal loss consequent to brain injury.
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PMID:Mechanisms of p75-mediated death of hippocampal neurons. Role of caspases. 1209 34

Death-associated protein (DAP) kinase is calcium-regulated and known to function downstream of death receptors, prompting us to examine its role in the mechanism of seizure-induced neuronal death. Brief seizures were focally evoked in rats, eliciting neuronal death within the CA3 subfield of the hippocampus, and to a lesser extent, cortex. Western blotting confirmed expression of DAP kinase within hippocampus and cortex at the predicted weight of approximately 160 kDa. Immunohistochemistry revealed seizures triggered a significant increase in numbers of DAP kinase-expressing cells within CA3 and cortex, without affecting cell counts within seizure-resistant CA2 or the dentate gyrus. Numbers of DAP kinase-expressing cells were increased in relation to specific patterns of injury-causing seizure activity, electrographically defined. Seizures caused an early increase in DAP kinase binding to actin, and association with calmodulin. Co-immunoprecipitation studies also revealed seizures triggered binding of DAP kinase to the tumor necrosis factor receptor 1 and the Fas-associated death domain protein, commensurate with caspase-8 proteolysis. In contrast, within surviving fields of the hippocampus, DAP kinase interacted with the molecular chaperone 14-3-3. These data suggest DAP kinase is involved in the molecular pathways activated during seizure-induced neuronal death.
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PMID:Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures. 1291 33

The molecular regulation of seizure-induced neuronal death may involve interactions between proteins of the Bcl-2 and 14-3-3 families. To further examine these pathways we performed subcellular fractionation on hippocampi obtained following a brief period of status epilepticus in the rat. Western blotting determined seizures induced caspase-8 cleavage and increased Bcl-w levels within the cytoplasm. Bax, Bad and Bid were largely present within the cytoplasm before and after seizures, although some Bax and, following seizures, truncated Bid was detected in mitochondria. Levels of 14-3-3 were significantly reduced in the cytoplasm and microsomal fractions. These data establish the expression and distribution profile of key Bcl-2 family proteins and the signaling chaperone 14-3-3 in the rat and provide additional evidence for the activation of programmed cell death pathways by seizures.
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PMID:Subcellular distribution of Bcl-2 family proteins and 14-3-3 within the hippocampus during seizure-induced neuronal death in the rat. 1503 20

Although mice are amenable to gene knockout, they have not been exploited in the setting of seizure-induced neurodegeneration due to the resistance to injury of key mouse strains. We refined and developed models of seizure-induced neuronal death in the C57BL/6 and BALB/c strains by focally evoking seizures using intra-amygdala kainic acid. Seizures in adult male BALB/c mice, or C57BL/6 mice as reference, caused ipsilateral death of CA1 and CA3 neurons within the hippocampus. Termination of seizures by lorazepam was more effective than diazepam in both strains, largely restricting neuronal loss to the CA3 sector. Electroencephalography (EEG) recordings defined injurious and non-injurious seizure patterns, which could not be separated adequately by behavioral observation alone. Degenerating neurons in the hippocampus were positive for DNA fragmentation and approximately a third of these exhibited morphologic features of programmed cell death. Western blot analysis revealed the cleavage of caspase-8 after seizures in both strains. These data refine our C57BL/6 model and establish a companion model of focally evoked limbic seizures in the BALB/c mouse that provides further evidence for activation of programmed cell death after seizures.
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PMID:Development of a model of seizure-induced hippocampal injury with features of programmed cell death in the BALB/c mouse. 1504 36

There is increasing evidence that neuronal cell death induced by seizures occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Caspase-8 cleaves Bid, which releases cytochrome c, bridging the "extrinsic" and "intrinsic" pathways. Cleavage of Bid may amplify caspase-8-induced neuronal cell death following seizures. In the present study, we explored the effect of an inhibitor of caspase-8 (z-IETD-fmk) on the release of Smac/DIABLO and cytochrome c from mitochondria. Rats received intra-amygdaloid injection of kainic acid (KA) to induce seizures for 1 h. The seizures were then terminated by diazepam (30 mg/kg). The damaged and surviving neurons in hippocampus were observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and cresyl violet staining, the expression of caspase-8, Bid, XIAP, caspase-9, cytochrome c and Smac/DIABLO were detected with immunofluorescence and Western blot. The cleavage of caspase-8 and Bid increased at 0 h, cytosolic fraction of cytochrome c and Smac/DIABLO increased by 2 h, cleavage of caspase-9 was detected by 4 h, TUNEL-positive neurons appeared at 8 h and reached a maximum at 24 h following administration of diazepam in the ipsilateral CA3 subfield of hippocampus. Inhibition of caspase-8 significantly decreased neuronal cell death, accompanied by reduction of t-Bid, cleaved caspase-9 and cytosol cytochrome c. Smac/DIABLO from mitochondria was not affected. These results suggest that seizures can lead the translocation of cytochrome c into the cytosol, and the activation of caspase-8 occurs upstream the mitochondria release of cytochrome c and Smac/DIABLO. Inhibition of caspase-8 attenuated neuronal cell death following seizures by decreasing mitochondria release of cytochrome c but not Smac/DIABLO.
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PMID:Inhibition of caspase-8 attenuates neuronal death induced by limbic seizures in a cytochrome c-dependent and Smac/DIABLO-independent way. 1677 49

Seizures, particularly when prolonged, may cause neuronal loss within vulnerable brain structures such as the hippocampus, in part by activating programmed (apoptotic) cell death pathways. Experimental modeling suggests that seizures activate tumor necrosis factor receptor 1 (TNFR1) and engage downstream pro- and anti-apoptotic signaling cascades. Whether such TNFR1-mediated signaling occurs in human temporal lobe epilepsy (TLE) is unknown. Presently, we examined this pathway in hippocampus surgically obtained from refractory TLE patients and contrasted findings to matched autopsy controls. Western blotting established that total protein levels of the TNFR1 proximal signaling adaptor TNFR-associated protein with death domain (TRADD), cleaved initiator caspase-8 and apoptosis signal-regulating kinase 1 (ASK1) were higher in TLE samples than controls. Intracellular distribution analyses revealed raised cytoplasmic levels of TNFR1, TRADD and the caspase-8 recruitment adaptor Fas-associated protein with death domain (FADD), and higher levels of TRADD and cleaved caspase-8 in the microsomal fraction, in TLE samples. Immunoprecipitation studies detected TRADD-FADD binding, and fluorescence microscopy revealed TRADD co-localization with FADD in TLE hippocampus. These data suggest that TNFR1 signaling is engaged in the hippocampus of patients with refractory temporal lobe epilepsy.
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PMID:Evidence of tumor necrosis factor receptor 1 signaling in human temporal lobe epilepsy. 1691 73

Activation of the caspase-dependent cell death pathways has been shown in focal seizures, but whether this occurs in prolonged generalized seizures is not known. We investigated whether the initiator caspase in the extrinsic pathway, caspase-8, or the intrinsic pathway, caspase-9, is activated during the first 24 h following lithium-pilocarpine-induced status epilepticus, when neuronal death is maximal and widespread. The thymuses of rats given methamphetamine were used as positive controls for caspase-3-activated cellular apoptosis. Following methamphetamine treatment, caspase-9 but not caspase-8 was activated in thymocytes. However, 6 or 24 h following status epilepticus, none of 26 brain regions studied showed either caspase-8 or -9 activation by immunohistochemistry, western blotting and enzyme activity assays. Our results provide evidence against the activation of the extrinsic and intrinsic caspase pathways in generalized seizures, which produce morphologically necrotic neurons with internucleosomal DNA cleavage (DNA laddering), a programmed process. In contrast, there is increasing evidence that caspase-independent programmed mechanisms play a prominent role in seizure-induced neuronal death.
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PMID:Caspase-dependent programmed cell death pathways are not activated in generalized seizure-induced neuronal death. 1720 52

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


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