Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we examine the in vivo formation of the Apaf-1/cytochrome c complex and activation of caspase-9 following limbic seizures in the rat. Seizures were elicited by unilateral intraamygdala microinjection of kainic acid to induce death of CA3 neurons within the hippocampus of the rat. Apaf-1 was found to interact with cytochrome c within the injured hippocampus 0-24 h following seizures by co-immunoprecipitation analysis and immunohistochemistry demonstrated Apaf-1/cytochrome c co-localization. Cleavage of caspase-9 was detected approximately 4 h following seizure cessation within ipsilateral hippocampus and was accompanied by increased cleavage of the substrate Leu-Glu-His-Asp-p-nitroanilide (LEHDpNA) and subsequent strong caspase-9 immunoreactivity within neurons exhibiting DNA fragmentation. Finally, intracerebral infusion of z-LEHD-fluoromethyl ketone increased numbers of surviving CA3 neurons. These data suggest seizures induce formation of the Apaf-1/cytochrome c complex prior to caspase-9 activation and caspase-9 may be a potential therapeutic target in the treatment of brain injury associated with seizures.
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PMID:Formation of the Apaf-1/cytochrome c complex precedes activation of caspase-9 during seizure-induced neuronal death. 1175 65

To determine whether Smac/DIABLO (second mitochondrial activator of caspases/direct inhibitor of apoptosis protein-binding protein of low isoelectric point [PI]) and XIAP (X-chromosome-linked inhibitor of apoptosis protein) serve to regulate neuronal apoptosis following seizures, we investigated seizure-induced changes in caspase-9, Smac/DIABLO and XIAP protein expression and the in vivo effect of caspase-9 inhibition. Animals received unilateral intra-amygdaloid injection of kainic acid (0.5 microg) to induce seizures for 1 h. The seizures were then terminated by diazepam (30 mg/kg). Animals were killed 0, 2, 4, 8, 24 or 72 h following diazepam administration. The apoptotic and surviving neurons in hippocampus were observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and cresyl violet staining, the expression of Smac/DIABLO, XIAP and caspase-9 was detected with immunofluorescence and western blot. The results showed that the levels of XIAP and the 46-kDa proenzyme form of caspase-9 were unaffected by the seizures. The expression of Smac increased at 2 h and the 37-kD cleaved fragment of caspase-9 was detected at 4 h, TUNEL-positive neurons appeared at 8 h and reached maximal at 24 h following seizure cessation within the ipsilateral (the same side as the intra-amygdaloid injection of kainic acid) CA3 subfield of the hippocampus. Intracerebroventricular infusion of caspase-9 inhibitor z-LEHD-fluoromethyl ketone (z-LEHD-fmk) significantly decreased TUNEL-positive neurons and increased the number of surviving cells. Caspase-9 immunoreactivity increased and Smac/DIABLO, XIAP immunoreactivity became extensive within the ipsilateral CA3 neurons. TUNEL-positive neurons and the alterations of the expression of Smac/DIABLO and XIAP within the ipsilateral CA3 were not detected within the contralateral hippocampus. These results suggest that seizures lead the translocation of Smac/DIABLO into the cytosol, the activation of caspase-9 and the change of subcellular locoalization of XIAP. These changes may play a role in the brain damage induced by seizures. Caspase-9 is possibly a potential therapeutic target in the treatment of brain injury associated with seizures.
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PMID:[The expression of Smac and XIAP in rat hippocampus following limbic seizure induced by kainic acid injection into amygdaloid nucleus]. 1512 26

Mitochondria play a critical role in the pathogenesis of cerebral ischemia. Acute hyperglycemia has been shown to activate the mitochondria-initiated cell death pathway after an intermediate period of ischemia. The objective of the present study was to determine if diabetic hyperglycemia induced by streptozotocin activates the cell death pathway after a brief period of global ischemia. Five minutes of global ischemia was induced in nondiabetic and diabetic rats. Brain samples were collected after 30 min, 6 h, 1, 3, and 7 days of recirculation as well as from sham-operated controls. Histopathological examination in the hippocampal CA1, CA3, hilus, and dentate gyrus regions, as well as in the cortical and thalamic areas, showed that neuronal death in diabetic animals increased compared to nondiabetic ischemic controls. Neuronal damage maturation occurred after 7 days of recovery in nondiabetic rats, while it was shortened to 3 days of recovery in diabetic animals. Western blot analyses revealed that release of cytochrome c markedly increased after 1 and 3 days of reperfusion in diabetic rats. Caspase-3 activation was evident in the nuclear fraction of the cortex of diabetic rats after 3 days recovery and it was preceded by activation of caspase-9, but not activation of caspase-8. Electron microscopy demonstrated that chromatin condensation and mitochondrial swelling were features of the diabetes-mediated ischemic neuronal damage. However, no apoptotic bodies were observed in any sections examined. These results suggest that a brief period of global ischemia in diabetic animals activates a neuronal cell death pathway involving cytochrome c release, caspase-9 activation, and caspase-3 cleavage, all of which are most likely initiated by early mitochondria damage.
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PMID:Activation of cell death pathway after a brief period of global ischemia in diabetic and non-diabetic animals. 1524 41

After experimental traumatic brain injury (TBI), widespread neuronal loss is progressive and continues in selectively vulnerable brain regions, such as the hippocampus, for months to years after the initial insult. To clarify the molecular mechanisms underlying secondary or delayed cell death in hippocampal neurons after TBI, we compared long-term changes in gene expression in the CA1, CA3 and dentate gyrus (DG) subfields of the rat hippocampus at 24 h and 3, 6, and 12 months after TBI with changes in gene expression in sham-operated rats. We used laser capture microdissection to collect several hundred hippocampal neurons from the CA1, CA3, and DG subfields and linearly amplified the nanogram samples of neuronal RNA with T7 RNA polymerase. Subsequent quantitative analysis of gene expression using ribonuclease protection assay revealed that mRNA expression of the anti-apoptotic gene, Bcl-2, and the chaperone heat shock protein 70 was significantly downregulated at 3, 6 (Bcl-2 only), and 12 months after TBI. Interestingly, the expression of the pro-apoptotic genes caspase-3 and caspase-9 was also significantly decreased at 3, 6 (caspase-9 only), and 12 months after TBI, suggesting that long-term neuronal loss after TBI is not mediated by increased expression of pro-apoptotic genes. The expression of two aging-related genes, p21 and integrin beta3 (ITbeta3), transiently increased 24 h after TBI, returned to baseline levels at 3 months and significantly decreased below sham levels at 12 months (ITbeta3 only). Expression of the gene for the antioxidant glutathione peroxidase-1 also significantly increased 6 months after TBI. These results suggest that decreased levels of neuroprotective genes may contribute to long-term neurodegeneration in animals and human patients after TBI. Conversely, long-term increases in antioxidant gene expression after TBI may be an endogenous neuroprotective response that compensates for the decrease in expression of other neuroprotective genes.
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PMID:Analysis of long-term gene expression in neurons of the hippocampal subfields following traumatic brain injury in rats. 1568 Jun 94

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

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

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

Alzheimer's disease is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stress level glucocorticoids are correlated with dementia progression in patients with Alzheimer's disease. In this study, twelve month old male mice were chronically treated for 21 days with stress-level dexamethasone (5mg/kg). We investigated the pathological consequences of dexamethasone administration on learning and memory impairments, amyloid precursor protein processing and neuronal cell apoptosis in 12-month old male mice. Our results indicate that dexamethasone can induce learning and memory impairments, neuronal cell apoptosis, and mRNA levels of the amyloid precursor protein, beta-secretase and caspase-3 are selectively increased after dexamethasone administration. Immunohistochemistry demonstrated that amyloid precursor protein, caspase-3 and cytochrome c in the cortex and CA1, CA3 regions of the hippocampus are significantly increased in 12-month old male mice. Furthermore, dexamethasone treatment induced cortex and hippocampus neuron apoptosis as well as increasing the activity of caspase-9 and caspase-3. These findings suggest that high levels of glucocorticoids, found in Alzheimer's disease, are not merely a consequence of the disease process but rather play a central role in the development and progression of Alzheimer's disease. Stress management or pharmacological reduction of glucocorticoids warrant additional consideration of the regimen used in Alzheimer's disease therapies.
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PMID:Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice. 1994 64

The role of caspases in the regulation of apoptosis of neurons during development is well established. An emerging body of evidence indicates that caspases may also play significant roles which are nonapoptotic. We have demonstrated previously that the executor caspase-3 exhibited a unique pattern of spatiotemporal expression in the postnatal rat hippocampal subregions, and the activation of caspase-3 in different hippocampal neurons appeared to have distinct roles during postnatal development. In the present study, we examined the expressions of initiator caspases in the hippocampus, using immunofluorescent staining for caspase-8 and caspase-9, and Hoechst 33342 staining for nuclear chromatin to assess caspase-8 and -9 expression in the CA1, CA3, and the dentate gyrus (DG) on postnatal days (P) 0, P2, P4, P7, P14, P21, P28, P56. The results indicate that caspase-8 and caspase-9 were expressed in pyramidal neurons of CA1 and CA3 fields, and granular neurons of the DG during development. Caspase-8 was expressed in a general upward trend while caspase-9 showed a slight downward pattern, but still remained at high levels in the adult hippocampus. The expression profiles of caspases-8 and -9 are distinct from that of the apoptotic cells. These data indicate that caspase-8 may be involved not only in the classical apoptotic function, but also in the cell death of necrosis, and in response to different insults and other nonapoptotic functions. Caspase-9 plays a role in apoptosis during postnatal development, but it may have other functions as well.
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PMID:Expression of caspase-8 and caspase-9 in rat hippocampus during postnatal development. 2127 3

Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stress-level glucocorticoids are correlated with dementia progression in patients with AD. In this study, 12-month male mice were chronically treated with stress-level dexamethasone (DEX, 5 mg/kg) and extract of Astragalus (EA, 10, 20, and 40 mg/kg) or Ginsenoside Rg1 (Rg1, 6.5 mg/kg) for 21 days. We investigated the protective effect of EA against DEX injury in mice and its action mechanism. Our results indicate that DEX can induce learning and memory impairments and neuronal cell apoptosis. The mRNA levels of caspase-3 are selectively increased after DEX administration. The results of immunohistochemistry demonstrate that caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex are significantly increased. Furthermore, DEX treatment increased the activity of caspase-9 and caspase-3. Treatment groups with EA (20 and 40 mg/kg) or Rg1 (6.5 mg/kg) significantly improve learning and memory, downregulate the mRNA level of caspase-3, decrease expression of caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex, and inhibit activity of caspase-9 and caspase-3. The present findings highlight a possible mechanism by which stress level of DEX accelerates learning and memory impairments and increases neuronal apoptosis and the potential neuronal protection of EA.
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PMID:Protective effect of extract of Astragalus on learning and memory impairments and neurons' apoptosis induced by glucocorticoids in 12-month-old male mice. 2153 32


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