Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and experimental studies clearly demonstrate that prolonged seizures and status epilepticus induce neuronal cell death in the brain. Recent evidence suggests that induction of apoptosis contributes greatly to seizure-induced brain damage. We recently demonstrated that intrahippocampal delivery of botulinum neurotoxin E (BoNT/E) in the rat hippocampus is able to prevent neuronal loss, which occurs after kainic-acid-induced seizures. Here, we investigated the molecular mechanisms of BoNT/E-mediated neuroprotection. We found that intrahippocampal administration of BoNT/E prevents the upregulation of apoptotic proteins (phosphorylated c-Jun and cleaved caspase 3), which occurs in hippocampal neurones following kainic acid seizures. These results demonstrate that the neuroprotective action of BoNT/E on seizure-injured hippocampal neurons involves the blockade of well-characterized apoptotic pathways.
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PMID:BoNT/E prevents seizure-induced activation of caspase 3 in the rat hippocampus. 1744 Dec 89

Allopregnanolone (AP) is a potent GABAergic agonist that suppresses CNS activity, seizure threshold, and excitotoxicity in the adult brain. AP is present in the fetal sheep brain and increases rapidly after asphyxial insult due to increased 5alpha-reductase type-2 (5alphaR-2) expression. The aim of this study was to use finasteride to suppress fetal neurosteroid synthesis, and then determine the effect on brain injury, particularly in the hippocampus, of asphyxia induced in utero by brief occlusion of the umbilical cord. Catheters and an inflatable umbilical cord cuff were implanted in fetal sheep at approximately 125 days gestation. Five days later the fetuses received either finasteride (20 mg/kg/h) or vehicle (40% hydroxypropyl-beta-cyclodextrin) for 2 h. The umbilical cord was occluded (UCO) for 5 min at 30 min after starting the infusion. The fetal brain was obtained 24 h later for examination of activated caspase-3 expression as an index of apoptosis, and to measure AP content. Finasteride treatment alone significantly reduced AP content and increased the number of caspase-3 positive cells in the hippocampus, cerebellum, and the subcallosal bundle, indicating that AP modulates the normal rate of apoptosis in the developing brain. UCO in vehicle and finasteride-treated fetuses produced a similar, marked decrease in O2 saturation (5.8+/-0.6%), but after finasteride treatment UCO caused a significantly greater increase in the number of caspase-3 positive cells in the hippocampal cornu ammonis 3 (CA3) (57.3+/-1.6%) compared with the vehicle-treated fetuses. Thus, 5alpha-reduced steroids such as AP may be protective in reducing cell death following acute fetal asphyxia. Perturbation of normal fetal neurosteroid levels in late gestation (e.g. due to preterm birth, or maternal synthetic steroid treatment to induce fetal lung maturation) could adversely affect brain development and increase its vulnerability to injury.
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PMID:Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in the late gestation fetal sheep. 1744 86

To further confirm at the molecular level that neuronal apoptosis occurs in mesial temporal sclerosis (MTS), the main substrate of mesial temporal lobe epilepsy (MTLE), 24 resected sclerotic hippocampi from 24 patients with drug-resistant MTLE associated with MTS were studied microscopically, electronmicroscopically and immunohistochemically, with detection of expression of apoptosis-associated genes including bcl-2, p53, bax, fas and caspase-3. Early apoptosis changes were found morphologically in hippocampi from three patients with MTLE using transmission electron microscopy. Positive immunostained neurons for bcl-2, p53, fas and caspase-3 were found in the sclerotic hippocampi of 19/24, 14/24, 22/24 and 20/24 patients respectively, which was statistically different from controls. Correlative analysis showed the expression of p53, fas and caspase-3 were positively correlated with seizure frequency. Apoptosis may contribute to MTS, and seizures may induce apoptosis, and thus contribute to neuronal loss in MTS.
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PMID:Neuronal apoptosis in the resected sclerotic hippocampus in patients with mesial temporal lobe epilepsy. 1766 56

Status epilepticus (SE) is a grave condition in which the brain undergoes lasting seizures which can lead to neuronal loss. Our previous study suggested that preconditioning with erythropoietin (Epo) suppressed neuronal apoptosis in hippocampus of rats following SE in vivo by inhibiting caspase-3. In this study, we investigated the mechanisms by which Epo preconditioning may exert its anti-apoptotic effects using a lithium-pilocarpine induced SE model in rats. The effects of Epo on neuronal cell death were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and the role of the Bcl-2 protein family, which have been shown to be anti- (Bcl-2, Bcl-w) or pro- (Bid, Bim) apoptotic, was examined with immunofluorescence. We found Epo preconditioning decreased the total number of TUNEL, Bim and Bid positive cells, but increased the total number of Bcl-w and Bcl-2 positive cells. These results suggest that systemic Epo pretreatment protects neurons in an acute phase of SE and may result in further suppression of neuronal apoptosis in hippocampus by regulating the balance between pro- and anti-apoptotic Bcl-2 family proteins.
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PMID:Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. 1769 Dec 21

The protective effect of topiramate (TPM) on seizure-induced neuronal injury is well known; however, its molecular basis has yet to be elucidated. We investigated the effect and signaling mediators of TPM on seizure-induced hippocampal cell death in kainic acid (KA)-treated ICR mice. KA-induced hippocampal cell death was identified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Immunoreactivity (IR) of p-Erk, p-Jnk, p-P38, and caspase-3, and caspase-3 activity were observed in the hippocampal region 3 h after KA (0.1 microg/5 microL, i.c.v.) administration, and/or TPM (100 mg/kg, i.p.) pretreatment. TPM attenuated seizure-induced neuronal cell death and reduced KA-induced p-Erk IR in the CA3 region of the hippocampus, but did not affect p-Jnk and p-P38. In addition, TPM reduced caspase-3 IR and activation by KA. KA-induced seizures were also suppressed by TPM pretreatment. TPM inhibits seizures, and decreases Erk phosphorylation and caspase-3 activation by KA, thereby contributing to protection from neuronal injury.
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PMID:Protective effect of topiramate on kainic acid-induced cell death in mice hippocampus. 1786 53

Bacterial meningitis due to Streptococcus pneumoniae is associated with an significant mortality rate and persisting neurologic sequelae including sensory-motor deficits, seizures, and impairments of learning and memory. The histomorphological correlate of these sequelae is a pattern of brain damage characterized by necrotic tissue damage in the cerebral cortex and apoptosis of neurons in the hippocampal dentate gyrus. Different animal models of pneumococcal meningitis have been developed to study the pathogenesis of the disease. To date, the infant rat model is unique in mimicking both forms of brain damage documented in the human disease. In the present study, we established an infant mouse model of pneumococcal meningitis. Eleven-days-old C57BL/6 (n = 299), CD1 (n = 42) and BALB/c (n = 14) mice were infected by intracisternal injection of live Streptococcus pneumoniae. Sixteen hours after infection, all mice developed meningitis as documented by positive bacterial cultures of the cerebrospinal fluid. Sixty percent of infected C57BL/6 mice survived more than 40 h after infection (50% of CD1, 0% of BALB/c). Histological evaluations of brain sections revealed apoptosis in the dentate gyrus of the hippocampus in 27% of infected C57BL/6 and in 5% of infected CD1 mice. Apoptosis was confirmed by immunoassaying for active caspase-3 and by TUNEL staining. Other forms of brain damage were found exclusively in C57BL/6, i.e. caspase-3 independent (pyknotic) cell death in the dentate gyrus in 2% and cortical damage in 11% of infected mice. This model may prove useful for studies on the pathogenesis of brain injury in childhood bacterial meningitis.
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PMID:An infant mouse model of brain damage in pneumococcal meningitis. 1793 41

Marked hippocampal changes in response to excitatory amino acid agonists occur during pregnancy (e.g. decreased frequency in spontaneous recurrent seizures in rats with KA lesions of the hippocampus) and lactation (e.g. reduced c-Fos expression in response to N-methyl-d,l-aspartic acid but not to kainic acid). In this study, the possibility that lactation protects against the excitotoxic damage induced by KA in hippocampal areas was explored. We compared cell damage induced 24 h after a single systemic administration of KA (5 or 7.5 mg/kg bw) in regions CA1, CA3, and CA4 of the dorsal hippocampus of rats in the final week of lactation to that in diestrus phase. To determine cellular damage in a rostro-caudal segment of the dorsal hippocampus, we used NISSL and Fluorojade staining, immunohistochemistry for active caspase-3 and TUNEL, and we observed that the KA treatment provoked a significant loss of neurons in diestrus rats, principally in the pyramidal cells of CA1 region. In contrast, in lactating rats, pyramidal neurons from CA1, CA3, and CA4 in the dorsal hippocampus were significantly protected against KA-induced neuronal damage, indicating that lactation may be a natural model of neuroprotection.
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PMID:Neuroprotective effects of lactation against kainic acid treatment in the dorsal hippocampus of the rat. 1796 58

Ischemic brain injury and epilepsy are common neurodegenerative diseases caused by excitotoxicity. Their pathogenesis includes microglial production of inflammatory cytokines. Our studies were designed to examine whether a growth compromised HSV-2 mutant (Delta RR) prevents excitotoxic injury through modulation of microglial responses by the anti-apoptotic HSV-2 protein ICP10PK. EOC2 and EOC20 microglial cells, which are differentially activated, were infected with Delta RR or the ICP10PK deleted virus (Delta PK) and examined for virus-induced neuroprotective activity. Both cell lines were non-permissive for virus growth, but expressed ICP10PK (Delta RR) or the PK deleted ICP10 protein p95 (Delta PK). Conditioned medium (CM) from Delta RR-, but not Delta PK-infected cells prevented N-methyl-D-aspartate (NMDA)-induced apoptosis of primary hippocampal cultures, as determined by TUNEL and caspase-3 activation (76.9 +/- 5.3% neuroprotection). Neuroprotection was associated with inhibition of TNF-alpha and RANTES and production of IL-10. The CM from Delta PK-infected EOC2 and EOC20 cells did not contain IL-10, but it contained TNF-alpha and RANTES. IL-10 neutralization significantly (p < 0.01) decreased, but did not abrogate, the neuroprotective activity of the CM from Delta RR-infected microglial cultures indicating that ICP10PK modulates the neuronal-microglial axis, also through induction of various microglial neuroprotective factors. Rats given Delta RR (but not Delta PK) by intranasal inoculation were protected from kainic acid (KA)-induced seizures and neuronal loss in the CA1 hippocampal fields. Protection was associated with a significant (p < 0.001) increase in the numbers of IL-10+ microglia (CD11b+) as compared to Delta PK-treated animals. Delta RR is a promising vaccination/therapy platform for neurodegeneration through its pro-survival functions in neurons as well as microglia modulation.
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PMID:DeltaRR vaccination protects from KA-induced seizures and neuronal loss through ICP10PK-mediated modulation of the neuronal-microglial axis. 1817 17

Neonatal hypoxic/ischemic (H/I) brain injury causes neurological impairment, including cognitive and motor dysfunction as well as seizures. However, the molecular mechanisms regulating neuron death after H/I injury are poorly defined and remain controversial. Here we show that Atg7, a gene essential for autophagy induction, is a critical mediator of H/I-induced neuron death. Neonatal mice subjected to H/I injury show dramatically increased autophagosome formation and extensive hippocampal neuron death that is regulated by both caspase-3-dependent and -independent execution. Mice deficient in Atg7 show nearly complete protection from both H/I-induced caspase-3 activation and neuron death indicating that Atg7 is critically positioned upstream of multiple neuronal death executioner pathways. Adult H/I brain injury also produces a significant increase in autophagy, but unlike neonatal H/I, neuron death is almost exclusively caspase-3-independent. These data suggest that autophagy plays an essential role in triggering neuronal death execution after H/I injury and Atg7 represents an attractive therapeutic target for minimizing the neurological deficits associated with H/I brain injury.
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PMID:Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. 1820 99

We have demonstrated that kainate (KA) induces a reduction in mitochondrial Mn-superoxide dismutase (Mn-SOD) expression in the rat hippocampus and that KA-induced oxidative damage is more prominent in senile-prone (SAM-P8) than senile-resistant (SAM-R1) mice. To extend this, we examined whether KA seizure sensitivity contributed to mitochondrial degeneration in these mouse strains. KA-induced seizure susceptibility in SAM-P8 mice paralleled prominent increases in lipid peroxidation and protein oxidation and was accompanied by significant impairment in glutathione homeostasis in the hippocampus. These findings were more pronounced in the mitochondrial fraction than in the hippocampal homogenate. Consistently, KA-induced decreases in Mn-SOD protein expression, mitochondrial transmembrane potential, and uncoupling protein (UCP)-2 expression were more prominent in SAM-P8 than SAM-R1 mice. Marked release of cytochrome c from mitochondria into the cytosol and a higher level of caspase-3 cleavage were observed in KA-treated SAM-P8 mice. Additionally, electron microscopic evaluation indicated that KA-induced increases in mitochondrial damage and lipofuscin-like substances were more pronounced in SAM-P8 than SAM-R1 animals. These results suggest that KA-mediated mitochondrial oxidative stress contributed to hippocampal degeneration in the senile-prone mouse.
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PMID:Kainate-induced mitochondrial oxidative stress contributes to hippocampal degeneration in senescence-accelerated mice. 1824 56


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