Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Programmed cell death (apoptosis) signaling pathways have been implicated in seizure-induced neuronal death and the pathogenesis of human temporal lobe epilepsy (TLE). End-stage DNA fragmentation during cell death may be mediated by nucleases including caspase-activated DNase (CAD), apoptosis-inducing factor (AIF) and endonuclease G. In the present study, we investigated the subcellular localization of these nucleases in resected hippocampus from TLE patients and autopsy controls. Subcellular fractionation determined levels of CAD were significantly higher in the nuclear fraction of TLE samples compared with controls, and semiquantitative immunohistochemistry revealed cleaved caspase-3 positive cells in TLE sections but not controls. While mitochondrial levels of AIF and endonuclease G were higher in TLE samples than controls, nuclear localization of AIF was limited and restricted to cells that were negative for cleaved caspase-3. Nuclear accumulation of endonuclease G was not found in TLE samples. These data support ongoing caspase-dependent apoptosis signaling in human TLE and suggest that interventions targeting such pathways may have potential as adjunctive neuroprotective therapy in epilepsy.
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PMID:Caspase-3 cleavage and nuclear localization of caspase-activated DNase in human temporal lobe epilepsy. 1612 Nov 24

Although minocycline has been generally thought to have neuroprotective properties, the neuroprotective role of minocycline has not been investigated in the animal model of epilepsy. In this study, we investigated whether minocycline is neuroprotective against kainic acid (KA)-induced cell death through the caspase-dependent or -independent mitochondrial apoptotic pathways. Adult male ICR mice were subjected to seizures by intrahippocampal KA injection with vehicle or with minocycline. For cell death analysis, TdT-mediated dUTP-biotin nick end labeling and cresyl-violet staining were performed. Western blot analysis and immunofluorescent staining for cytochrome c and apoptosis-inducing factor (AIF) were performed. Cell death was reduced in minocycline-treated mice. Cytosolic translocation of cytochrome c and subsequent activation of caspase-3 were diminished by minocycline treatment. AIF nuclear translocation and subsequent large-scale DNA fragmentation were also reduced in minocycline-treated mice. Thus, this study suggests that minocycline inhibits both caspase-dependent and -independent apoptotic pathways and may be neuroprotective against hippocampal damage after KA treatment.
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PMID:Minocycline inhibits caspase-dependent and -independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. 1646 40

3-Aminobenzamide (3-AB), an inhibitor of poly(ADP-ribose) polymerase (PARP), has been proved to have neuroprotective properties. In this study, we examined the role of 3-AB in rat hippocampal neuron death induced by seizures. Our data showed that the seizures resulted in PARP activation and translocation of the apoptosis-inducing factor from the mitochondria to the nucleus, leading to neuron death. These effects could, however, all be abolished by 3-AB. Moreover, we showed that 3-AB facilitated Akt activation and decreased the activity of its downstream target, glycogen synthase kinase-3beta. Altogether, our data suggested that 3-AB might have a therapeutic value in seizure-induced hippocampal neuron damage, probably due to the inhibition of apoptosis and activation of Akt cell survival signaling.
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PMID:Poly(ADP-ribose) polymerase inhibitor is neuroprotective in epileptic rat via apoptosis-inducing factor and Akt signaling. 1763 84

We have shown that generalized seizures produce necrotic neurons with caspase-independent nuclear pyknosis and DNA fragmentation. In this study, we determined the time course of translocation of mitochondrial cytochrome c, apoptosis-inducing factor, endonuclease G, lysosomal cathepsins B and D, and DNase II with respect to signs of irreversible neuronal damage. Adult male Wistar rats underwent lithium-pilocarpine-induced seizures lasting for 60 min, 3 hr, and 3 hr with 6- or 24-hr survival periods, after which the brains were prepared for immunofluorescence microscopic examination of piriform cortex. Contrary to expectation, cytochrome c and cathepsins B and D translocated to neuronal nuclei with DNase II, endonuclease G, and apoptosis-inducing factor within 60 min of seizure onset and persisted for 24 hr after 3-hr seizures. After 60-min seizures, some neurons showed translocation of the death-promoting proteins in normal-appearing neurons, prior to their appearance in irreversibly damaged neurons. Western blots of subcellular fractions of cytochrome c and cathepsins B and D confirmed their nuclear translocation. This is the first evidence of nuclear translocation of cathepsins B and D and the first in vivo evidence of nuclear translocation of cytochrome c. The appearance of these mitochondrial proteins and lysosomal enzymes before signs of irreversible neuronal death suggests that they could contribute to seizure-induced nuclear pyknosis and DNA fragmentation.
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PMID:Nuclear translocation of mitochondrial cytochrome c, lysosomal cathepsins B and D, and three other death-promoting proteins within the first 60 minutes of generalized seizures. 2007 27

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

Diazoxide (DZ), a highly selective opener of the mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, has neuroprotective effects. However, the mechanism of DZ protecting hippocampal neurons against cell death in pilocarpine-induced seizures is unknown. In this study, we investigated DZ attenuating neuronal loss caused by pilocarpine-induced seizures in rat hippocampus. DZ inhibited seizure-induced change in phospho-Akt expression, translocation of apoptosis-inducing factor (AIF), release of cytochrome c (CytC) and caspase-3 activation, which could be abolished by preincubation with 5-hydroxydecanoic acid, an inhibitor of mitoK(ATP). In addition, wortmannin, an inhibitor of phosphatidylinositol-3-kinase (PI3K), attenuated the translocation of AIF, CytC release and caspase-3 activation after seizures. DZ could reduce neuronal death induced by seizures in hippocampus by suppressing the translocation of AIF, CytC release and the activation of caspase-3 via the PI3K/Akt pathway.
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PMID:Role of PI3K/Akt in diazoxide preconditioning against rat hippocampal neuronal death in pilocarpine-induced seizures. 2125 20

Inhibition of poly(ADP-ribose) polymerase (PARP) has been proposed to have a neuroprotective effect on hippocampal neurons in animal models of epilepsy. However, the mechanisms of PARP-mediated epileptic neuron apoptosis in vitro are still not thoroughly understood. Therefore, we investigated the effect of PARP inhibition and the underlying mechanisms in the hippocampal neuronal culture model of acquired epilepsy which is generally accepted as the neuronal culture model of spontaneous seizure discharge in vitro. As a result, PARP was activated and the administration of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ), an inhibitor of PARP, significantly decreased the percentage of neuron apoptosis induced by Mg(2+)-free treatment. Western blot and confocal laser scanning microscopy (CLSM) analysis showed that DPQ increased the phosphorylation of Akt and attenuated mitochondria-nucleus translocation of the apoptosis-inducing factor (AIF). Furthermore, wortmannin, an inhibitor of PI-3K, inhibited the translocation of AIF to the nucleus. The results of the present study demonstrated that the inhibition of PARP might have therapeutic value in seizure-induced hippocampal neuron damage in vitro via suppressing Akt-mediated AIF translocation.
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PMID:Poly(ADP-ribose) polymerase inhibition protects epileptic hippocampal neurons from apoptosis via suppressing Akt-mediated apoptosis-inducing factor translocation in vitro. 2320 Dec 56

Mdivi-1 is a selective inhibitor of a mitochondrial fission protein Drp1. Recent studies demonstrated that inhibition of Drp1 provides neuroprotection in vitro and in vivo. In this study, we examined the role of mdivi-1 in hippocampal neuron death after seizures induced by pilocarpine. Our data showed that pretreatment with mdivi-1 (1.25 mg/kg) significantly attenuated the neuronal death in hippocampus induced by seizures. This neuroprotective effect was dose-dependent. In addition, the seizures resulted in up-regulation of Drp1 expression and mdivi-1 treatment had no effect on the expression. Moreover, we also found that mdivi-1 (1.25 mg/kg) treatment reversed the release of cytochrome c (CytC), translocation of apoptosis-inducing factor (AIF) induced by seizures while inhibiting the activated caspase-3. Altogether, our data suggested that mdivi-1 exerts neuroprotective effects against cell death of hippocampal neurons induced by seizures, and the underlying mechanism may be through inhibiting CytC release, AIF translocation and suppression of the mitochondrial apoptosis pathway.
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PMID:A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. 2362 72

The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1, a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5 years he developed hearing loss and severe ataxia and at age 10 years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G>T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5 years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent.
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PMID:From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1. 2558 28


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