Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Compelling evidence has shown that extracellular signal-regulated kinase (ERK) is widely expressed in many tissues, including the brain. In the present work, we investigated the temporospatial alterations of ERK1 immunoreactivity in hippocampus and perifocal cortex, and the expression involved in NGF/VEGF-induced neuroprotective effect. We demonstrated that ERK1 expression was first increased in hippocampal CA3/DG 1 h after reperfusion, then it was also increased 6 h after reperfusion in other brain regions, with a peak at day 1-3, and then gradually decreased to basal level at day 14. The expression of caspase-3 was strongly increased 1 h after reperfusion, with peak demonstrated at 3d. NGF/VEGF significantly inhibited the expression of ERK1 and caspase-3. These results suggest that ERK1 signaling pathway may be involved in neuronal cell death and NGF/VEGF-induced neuroprotective effect and there appeared an association between ERK and caspase-3. Inhibition of the ERK signaling pathway might therefore provide an efficient way to prevent neuronal cell death after ischemic cerebral injuries.
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PMID:Extracellular signal-regulated kinase involved in NGF/VEGF-induced neuroprotective effect. 1832 26

Various neurons in the central nervous system (CNS) exhibit selective vulnerability to AMPA-induced delayed neurotoxicity known as dark cell degeneration. Hippocampal pyramidal neurons in the CA1 and CA3 regions display such vulnerability that encompasses morphological changes including cytoplasmic and nuclear condensation, neuronal shrinkage, formation of cytoplasmic vacuoles, and general failure of physiology. The present study was undertaken to ascertain the potential involvement of initiator (caspase-9) and executor (caspase-3) caspases in AMPA-receptor-induced dark cell degeneration in pyramidal neurons. Immunohistochemical analyses revealed that immunoreactivity of the active form of caspase-9 and -3 was increased in pyramidal neurons in CA1 and CA3 regions of the hippocampus following AMPA (100 microM). Elevated levels of active caspase-9 immunoreactivity generally preceded elevations in active caspase-3 immunoreactivity. The pan caspase inhibitor FK011 effectively attenuated AMPA-induced dark cell degeneration in both CA1 and CA3 regions. Collectively, the data suggest a role for these caspases in mediating AMPA-induced toxicity in pyramidal neurons of the rat hippocampus.
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PMID:AMPA-induced dark cell degeneration is associated with activation of caspases in pyramidal neurons of the rat hippocampus. 1841 89

Recent studies indicate that caspase-3 has distinct characteristics in postmitotic and neuronal progenitor apoptosis. Pyramidal neurons in CA1 and CA3 of the hippocampus become postmitotic during early postnatal development, whereas granule cells in the dentate gyrus (DG) undergo self-renewal throughout life. The distribution of caspase-3 in the hippocampal subfields during postnatal development is largely unknown. We used immunofluorescent staining for two isoforms of caspase-3 (an active 17 kDa isoform and an inactive 35 kDa precursor) and the Hoechst 33342 staining for nuclear chromatin to assess caspase-3 expression in the CA1, CA3, and DG of rat hippocampus during postnatal development. The expression of active caspase-3 reached a peak at P7 in CA1, at P2 in CA3, and then decreased with age. Whereas in DG, active caspase-3 expression increased slightly after P7, and remained at high levels for the rest of the investigated period. Procaspase-3 immunoreactivity was strong at P2 and decreased gradually to a basal plateau by P21 in the three regions examined. In addition, the number of apoptotic cells in the three regions all reached maximum levels at P7, and then decreased with age. These data indicate that there were specific spatio-temporal patterns of expression of active and precursor caspase-3 in the postnatally developing rat hippocampal subregions, and that the activation of caspase-3 in neuronal progenitor cells of DG and that in the postmitotic neurons of CA1 and CA3 may have distinct roles and mechanisms during postnatal development.
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PMID:Different expression of caspase-3 in rat hippocampal subregions during postnatal development. 1845 32

Memory loss in Alzheimer's disease (AD) may be related to synaptic defects in damaged hippocampal neurons. We investigated the relationship between amyloid peptide A beta 25-35-induced neuronal death pattern and presynaptic changes in organotypic hippocampal slice cultures. In propidium iodide (PI) uptake and annexin V labeling, A beta 25-35-induced neuronal damage dramatically increased in a concentration dependent manner, indicating both types of cell death. In ultrastructural analysis, apoptotic features in CA1 and CA3 area and synaptic disruption in stratum lucidum were detected in A beta 25-35-treated slices. Immunofluorescence and Western blot analysis for caspase-3 showed A beta 25-35 concentration dependently induced caspase-3 activation. Immunofluorescence and Western blot analysis to determine changes in presynaptic marker proteins demonstrated that expression of synaptosomal-associated protein-25 (SNAP-25) and synaptophysin were reduced by A beta 25-35 in CA1, CA3 and DG area at concentrations >2.5 microM. In conclusion, A beta 25-35-induced apoptotic cell death and caspase-3 activation at relatively low concentration, and induced synaptic disruption and loss of synaptic marker protein at concentrations >2.5 microM in organotypic hippocampal slice cultures. These suggest that A beta 25-35-induced apoptosis via triggering caspase-3 activation and lead to synaptic dysfunction in organotypic hippocampal slice cultures.
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PMID:A beta 25-35 induces presynaptic changes in organotypic hippocampal slice cultures. 1850 14

Maternal heroin abuse has been shown to result in teratogenic neurobehavioral defects in the offspring, but the underlying mechanisms remain largely unknown. This study was designed to explore the role of neuronal apoptosis in the heroin-induced neurobehavioral defects of learning and memory. Pregnant BALB/c mice were treated with either heroin or saline. The animals in the heroin group received heroin subcutaneously at a dosage of 10 mg/kg/day on embryonic days (E) 9-18, while those in the saline group were treated as drug-naive. Offspring were grouped as prenatal heroin exposure (HER), prenatal saline exposure (SAL), and control (CON) groups, according to the maternal treatment regimen. Some of the mice were killed and their hippocampus harvested on postnatal day (P) 14, and the tissue subjected to reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to reveal the mRNA and protein expressions of caspase-3, Bcl-2, and Bax. The Morris water maze was applied to assess the learning and memory capability of the mice at P30; poor maze performances were observed for the animals in the HER group. The results also showed that the mRNA and protein expressions of caspase-3 and Bax were significantly increased, while that of Bcl-2 was markedly decreased in the HER group compared with both the SAL and CON groups. The immunohistochemistry revealed significant caspase-3 immunoreactivity in the dentate gyrus and cornu ammonis (CA) 1 subareas of the hippocampal formation, whereas, no significant changes were seen in subarea CA3. These findings suggest that prenatal heroin exposure during the E9-18 period enhances neuronal apoptosis by altering the expressions of caspase-3, Bcl-2, and Bax in the mouse hippocampus, and leads to impairment in hippocampus-dependent learning and memory.
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PMID:Prenatal exposure to heroin in mice elicits memory deficits that can be attributed to neuronal apoptosis. 1927 31

Status epilepticus results in mitochondrial damage or dysfunction and preferential neuronal cell loss in the hippocampus. Since a critical determinant of the eventual cell death fate resides in intracellular ATP concentration, we investigated whether mitochondrial integrity and level of energy metabolism are related with apoptotic cell death in specific hippocampal neuronal populations. A kainic acid (KA)-induced experimental temporal lobe status epilepticus model was used. Qualitative and quantitative analysis of DNA fragmentation, TUNEL immunohistochemistry, double immunofluorescence staining for activated caspase-3, electron microscopy or measurement of ATP level in the bilateral hippocampus was carried out 1, 3 or 7 days after microinjection unilaterally of a low dose of KA (0.5 nmol) into the CA3 hippocampal subfield. Characteristic biochemical (DNA fragmentation), histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were presented bilaterally in the hippocampus 7 days after the elicitation of sustained hippocampal seizure activity by microinjection of KA into the unilateral CA3 subfield. At the same time, CA3 or CA1 subfield on either side manifested a maintained ATP level; alongside relatively intact mitochondria, rough endoplasmic reticulum, Golgi apparatus or cytoplasmic membrane in hippocampal neurons that exhibited ultrastructural features of apoptotic cell death. Our results demonstrated that preserved mitochondrial ultrastructural integrity and maintained energy metabolism during experimental temporal lobe status epilepticus is associated specifically with apoptotic, not necrotic, cell death in hippocampal CA3 or CA1 neurons.
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PMID:Preservation of mitochondrial integrity and energy metabolism during experimental status epilepticus leads to neuronal apoptotic cell death in the hippocampus of the rat. 1937 59

Dietary zinc deficiency may affect zinc homeostasis in the brain and lead to reductions of neurogenesis and neuronal survival. However, the mechanisms responsible for the effects of zinc deficiency on hippocampal neurogenesis and neuronal death remain obscure. In the present study, young CD-1 mice were fed with zinc-deficient diet (0.85 ppm) for 5 weeks. The vesicular zinc was reduced at CA1 and CA3 regions of the hippocampus in zinc-deficient mice. The significant decreased zinc ions was associated with a reduction in proliferating cells labeled with bromo-deoxyuridine (BrdU) and immature neurons labeled with doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus. The processes of DCX-positive neurons were shortened, and flexuously went through into the granular cell layer in zinc-deficient hippocampus. There was also a conspicuous increase in the number of TUNEL-positive cells in the hippocampus after zinc-deficient diet treatment. Meanwhile, the apoptosis proteins, including Fas, Fas ligand (FasL), apoptosis inducing factor (AIF), and caspase-3, were significantly activated in zinc-deficient mouse hippocampus. These data suggest that chronic treatment with zinc-deficient diet results in reduction in hippocampal neurogenesis and increases neuronal apoptosis, indicating that zinc deficiency is associated with destroying structural plasticity in the hippocampus.
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PMID:Zinc deficiency reduces neurogenesis accompanied by neuronal apoptosis through caspase-dependent and -independent signaling pathways. 1954 52

The neurosteroid allopregnanolone (AP) is a GABAergic agonist that suppresses central nervous system (CNS) activity in the adult brain, and by reducing excitotoxicity is considered to be neuroprotective. A role for neurosteroids in the developing brain, particularly in late gestation, is still debated. The aim of this study was to investigate effects on proliferation and cell death in the brain of late gestation fetal sheep after inhibition of AP synthesis using finasteride, a 5alpha-reductase type 2 (5alpha-R2) inhibitor. Catheters were implanted in fetal sheep at approximately 125 days of gestation. At 3-4 days postsurgery, fetuses received infusions of either finasteride (20 mg/kg/h; n=5), the AP analogue alfaxalone (5 mg/kg/h; n=5), or finasteride and alfaxalone together (n=5). Brains were obtained at 24 h after infusion to determine cell death (apoptotic or necrotic) and cell proliferation in the hippocampus and cerebellum, areas known to be susceptible to excitotoxic damage. Finasteride treatment significantly increased apoptosis (activated caspase-3 expression) in hippocampal CA3 and CA1, and cerebellar molecular and granular layers, an effect abolished by co-infusion of alfaxalone and finasteride. Double-label immunohistochemistry showed that both neurons and astrocytes were caspase-3 positive. Finasteride treatment also increased the number of dead (pyknotic) cells in the hippocampus and cerebellum (Purkinje cells), but not when finasteride+alfaxalone was infused. Cell proliferation (Ki-67-immunoreactivity) increased after finasteride treatment; double-labeling showed the majority of Ki-67-positive cells were astrocytes. Thus, steroids such as AP appear to influence the constitutive rate of apoptosis and proliferation in the hippocampus and cerebellum of the fetal brain, and suggest an important role for neurosteroids in the development of the brain.
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PMID:Role of neurosteroids in regulating cell death and proliferation in the late gestation fetal brain. 1959 3


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