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

Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer's disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic-limbic-neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, Abeta and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.
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PMID:Early involvement of small inhibitory cortical interneurons in Alzheimer's disease. 1675 65

Age-dependent, neuronal apoptosis following N-methyl-D-aspartate receptor blockade has been linked to loss of calcium. To further explore this relationship, we examined expression of activated caspase-3, as well as the calcium binding proteins, calbindin-D 28K, calretinin and parvalbumin, following injection of vehicle or the N-methyl-D-aspartate receptor blocker, MK801, in postnatal day 7 or 21 rats. At postnatal day 7, MK801-induced activated caspase-3 expression was most frequently found in mutually exclusive cell populations to those expressing any of the three calcium binding proteins. For example, in the somatosensory cortex, most immunoreactivity for activated caspase-3 was found in layers IV/V, layered between areas of high calbindin or calretinin expression. Further, in the caudate putamen, activated caspase-3 rarely invaded zones of intense calbindin immunoreactivity. Suggesting expression patterns of these proteins were inversely related, these same brain regions no longer displayed MK801-induced activated caspase-3 at postnatal day 21, but instead robustly expressed calcium binding proteins. This later surge in expression was especially true for parvalbumin in regions such as the somatosensory and retrosplenial cortex, as well as the subicular complex. Calbindin-D 28K was also found to increase in the same regions though not as impressively as parvalbumin. Thus, developmental regulation of calcium binding protein expression may be a critical factor in age-dependent sensitivity to agents that disrupt calcium homeostasis in maturing neurons, providing a possible mechanistic explanation for age-dependent MK801 toxicity.
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PMID:MK801-induced caspase-3 in the postnatal brain: inverse relationship with calcium binding proteins. 1678 80

Calcium toxicity remains the central focus of ischemic brain injury. Calcium channel antagonists have been reported to be neuroprotective in ischemic animal models but have failed in clinical trials. Rather than block the calcium channels, calbindin proteins can buffer excessive intracellular Ca2+, and as a result, maintain the calcium homeostasis. In the present study, we investigated the effect of calbindin D 28k (CaBD) in ischemic brain using the novel technique protein transduction domain (PTD)-mediated protein transduction. We generated PTD-CaBD in Escherichia coli, tested its biologic activity in N-methyl-D-aspartate (NMDA)- and oxygen-glucose deprivation (OGD)-induced hippocampal injury models, and examined the protection of the fusion protein using a rat brain focal ischemia model. Infarct volume was determined using 2,3,5-triphenyl-tetrazolium chloride staining; neuronal injury was examined using terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining and cleaved caspase-3 assay. The results showed that the PTD-CaBD was efficiently delivered into Cos7 cells, hippocampal slice cells, and brain tissue. Pretreatment with PTD-CaBD decreased intracellular free calcium concentration and reduced cell death in NMDA- or OGD-exposed hippocampal slices (P<0.05). Intraperitoneal administration of PTD-CaBD before transient middle cerebral artery occlusion decreased brain infarct volume (280+/-47 versus 166+/-70 mm3, P<0.05), and improved neurologic outcomes compared with the control. Further studies showed that, compared with the control animals, PTD-CaBD decreased TUNEL (58%+/-7% versus 29%+/-3%, P<0.05)- and cleaved caspase-3 (62+/-4/field versus 31+/-6/field, P<0.05)-positive cells in the ischemic boundary zone. These results indicate that systemic administration of PTD-CaBD could attenuate ischemic brain injury, suggesting that PTD-mediated protein transduction might provide a promising and effective approach for the therapies of brain diseases, including cerebral ischemia.
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PMID:Pretreatment with PTD-calbindin D 28k alleviates rat brain injury induced by ischemia and reperfusion. 1686 56

Loss of neuronal calcium is associated with later apoptotic injury but observing reduced calcium and increased apoptosis in the same cell would provide more definitive proof of this apparent correlation. Thus, following exposure to vehicle or the calcium chelator, BAPTA (1-20 microM), primary cortical neurons were labeled with Calcium Green-1 which was then cross-linked with EDAC, prior to immuno-staining for various proteins. We found that BAPTA-induced changes in calcium were highly correlated with changes in expression of activated caspase-3 as well as the calcium binding proteins calbindin, calretinin, and parvalbumin. Additionally, in brain slices from P7 neonatal rats, BAPTA induced significant loss of calcium in a brain region we have previously shown to express only moderate levels of calcium binding proteins as well as display robust apoptosis following calcium entry blockade. In contrast, BAPTA had little influence on calcium levels in a brain region we have previously shown to express robust calcium binding proteins as well as display far less apoptosis following calcium entry blockade. These data suggest that the ability of developing neurons to buffer changes in calcium may be critical to their long-term survival.
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PMID:Loss of calcium and increased apoptosis within the same neuron. 1712 51

Age-dependent, MK801-induced, activated caspase-3 expression in the postnatal brain is generally not observed in neurons expressing calcium-binding proteins (CaBPs), suggesting that apoptosis and calcium buffering are inversely related. In regions such as the cingulate and retrosplenial cortex, injury peaks at postnatal Day 7 (P7) and rapidly diminishes thereafter, whereas expression of calbindin (CB) and calretinin (CR) was relatively low from P0 to P7 and steadily increased from P7 to P14. At ages thereafter, CB and CR expression either remained stable then declined or rapidly declined. Parvalbumin (PV) was generally low-absent prior to P7 but expression dramatically increased from P10 onwards, peaking at P21. These studies suggest calcium entry (through N-methyl-D-aspartate receptor (NMDARs)) and buffering (by CaBPs) are integral to normal CNS maturation. Because schizophrenia is associated with glutamate hypo-function, developmental injury, and aberrant CaBP expression, our data indicate that this postnatal brain injury model may offer important insights into the nature of this disorder.
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PMID:Decline in age-dependent, MK801-induced injury coincides with developmental switch in parvalbumin expression: cingulate and retrosplenial cortex. 1768 Jun 8

Time-of-day-dependent variation in neuronal ischemia is well documented. Whether this results from changes in time-of-day variation in susceptibility or from other causative factors remains unclear. We hypothesize that hippocampal cells exhibit variation in activation of cell death predictive markers in response to ischemia induced at different times-of-day. Changes in hippocampal circadian clock gene rhythmicity may also be associated with ischemia. Transient global ischemia was induced in rats at three times of day and animals were sacrificed 24 h later. Hippocampal caspase-3, -8 and -9 transcripts and active proteins and calbindin protein were measured in the CA1 region of the hippocampus. In a second study, 24-h rhythms of circadian regulatory transcripts were determined in hippocampus after global ischemia. Caspase-3, -8 and -9 transcripts and active protein levels were increased substantially when ischemia occurred in early night (ZT14); smaller changes were observed in late night (ZT20, or day ZT6). Calbindin levels decreased following ischemia, especially at ZT14. Ischemia shifted the rhythm of the Per1 transcript; peak expression occurred 6 h earlier following ischemia. Rhythms of Cry1 and Bmal1 were not altered. Greater induction of caspases and decline of calbindin when ischemia was performed at ZT14 than at ZT20 or ZT6 support the concept of increased hippocampal susceptibility to ischemia at ZT14. Alteration of the Per1 transcript suggests a potential role for the circadian clock in this process. Notably, ZT14 represents the beginning of the rats' nocturnal period of activity, corresponding to the time when humans experience the greatest neuronal ischemic damage from stroke.
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PMID:Time-of-day affects expression of hippocampal markers for ischemic damage induced by global ischemia. 1793 74

Ginkgolide B, one of the major components of Ginkgo biloba extracts, is a potent platelet-activating factor (PAF) receptor antagonist, which is also regarded as having neuroprotective effects on the CNS. The aim of this research is to observe the effects of Ginkgolide B on the PC12 apoptosis induced by 6-hydroxydopamine (6-OHDA) and to explore whether these effects are related to the changes of intracellular Ca(2+) and Calbindin D28K mRNA in PC12 cells. In the present work, the damage of PC12 cells was induced by 100 microM 6-OHDA. The cells survival rate was examined by MTT assays. The intracellular free calcium concentration in PC12 cells was measured by using the fluorescent Ca(2+) indicator fluo-3/AM. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was employed to determine the expression of Calbindin D28K mRNA in PC12. The data show that the Ginkgolide B inhibited PC12 cells apoptosis induced by 6-OHDA in a dose-dependent manner, and decreased the activity of caspase-3. In addition, Ginkgolide B increased the expression of Calbindin D28K mRNA and inhibited 6-OHDA-induced elevation in the intracellular calcium concentration. Our results showed that the Ginkgolide B inhibited the apoptosis of PC12 induced by 6-OHDA, and the protective effects of Ginkgolide B on PC12 cells are mediated, at least in part, by up-regulating the Calbindin D28K mRNA and by decreasing the intracellular calcium concentration.
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PMID:Effects of Ginkgolide B on 6-OHDA-induced apoptosis and calcium over load in cultured PC12. 1798 25

Transient postnatal NMDA receptor blockade by phencyclidine (PCP), ketamine, or MK-801 induces developmental neuroapoptosis and adult behavioral deficits, which resemble abnormal human behaviors typically present in schizophrenia. This study tested the hypothesis that PCP-induced developmental apoptosis causes a specific deficit of GABAergic interneurons containing parvalbumin (PV), calretinin (CR), or calbindin (CB). Young adult (PND56) rats that were given a single dose of PCP (10 mg/kg) on PND7 exhibited no densitometric change of either CR or CB neurons in any brain region studied, but demonstrated a selective deficit of PV-containing neurons in the superficial layers (II-IV) of the primary somatosensory (S1), motor (M), and retrosplenial cortices, but not in the striatum (CPu) or hippocampus. Further, CR and CB neurons, which were expressed at the time of PCP administration, showed no colocalization with cellular markers of apoptosis (terminal dUTP nick-end labeling (TUNEL) of broken DNA or cleaved caspase-3), indicating that CR- and CB-containing neurons were protected from the toxic effect of PCP and survived into adulthood. This suggests that the deletion of PV neurons occurred during development, but cleaved caspase-3 showed no colocalization with BrdU, a specific marker of S-phase proliferation. These data suggest that the loss of PV-containing neurons was not due to an effect of PCP on proliferating neurons, but rather an effect on post-mitotic neurons. The developmental dependence and neuronal specificity of this effect of PCP provides further evidence that this model may be valuable in exploring the pathophysiology of schizophrenia.
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PMID:Postnatal phencyclidine administration selectively reduces adult cortical parvalbumin-containing interneurons. 1805 37

MK801-induced activation of caspase-3 is developmentally regulated, peaking at postnatal day (P) 7 and decreasing with increasing postnatal age thereafter. Further, at P7, cells displaying activation of caspase-3 lack expression of calcium binding proteins (CaBPs). To further explore this relationship, we investigated postnatal expression of calbindin (CB), calretinin (CR) and parvalbumin (PV) in two brain regions susceptible to MK801-induced injury, the somatosensory cortex (S1) and layer II/III of motor cortex (M1/M2). Expression of CB and especially PV was low to absent prior to P7 but substantially increased from P7 through to P21 and adulthood. In contrast, CR expression was more variable at early developmental ages, stabilized to lower levels after P7 and showed a marked decline by P21. The results suggest that not only does calcium buffering capacity increase developmentally but also acquisition of enhanced buffering may be one mechanism by which neurons survive agent-induced alterations in calcium homeostasis.
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PMID:Decline in age-dependent, MK801-induced injury coincides with developmental switch in parvalbumin expression: somatosensory and motor cortex. 1868 10

Immunohistochemistry for neuron-specific nuclear protein (NeuN), caspase-3, calcitonin gene-related peptide (CGRP), and calcium-binding proteins was performed on the trigeminal ganglion (TG) in wild type and Brn-3a knockout mice at embryonic days 12.5-16.5 (E12.5-E16.5). In Brn-3a knockout mice, the number of NeuN-immunoreactive (ir) neuron profiles increased at E14.5 (40.0% increase) and decreased at E16.5 (28.3% reduction) compared to wild type mice. Caspase-3-ir neuron profiles were abundant in the TG of wild type mice at E12.5-E16.5. However, the loss of Brn-3a decreased the number of caspase-3-ir neuron profiles at E12.5 (69.7% reduction) and E14.5 (51.7% reduction). At E16.5, the distribution of caspase-3-ir neuron profiles was barely affected by the deficiency. CGRP-ir neuron profiles were observed in the TG of wild type mice but not knockout mice at E12.5. At E14.5 and E16.5, CGRP-ir neuron profiles were abundant in both wild type and knockout mice. Calbindin D-28 k (CB)-ir neuron profiles decreased in the TG of mutant mice at E12.5 compared to wild type mice (56.4% reduction). At E14.5, however, Brn-3a deficiency transiently increased CB-ir neuron profiles (169.4% increase as compared to wild type mice). Calretinin (CR)-ir neuron profiles could not be detected in the TG of wild type mice at E12.5-16.5. However, numerous CR-ir neuron profiles transiently appeared in the knockout mouse at E14.5. Parvalbumin (PV)-ir neurons appeared in wild type and knockout mice at E14.5. At this stage, the number of large (>50 mum(2)) PV-ir neuron profiles in knockout mice was fewer than that in wild type mice. The number and cell size of PV-ir neuron profiles were barely affected by the deficiency at E16.5. The present study indicates that the loss of Brn-3a causes increase of TG neurons at E14.5 and decrease of TG neurons at E16.5. It is also suggested that Brn-3a deficiency affects the number and cell size of CGRP- and calcium-binding protein-containing neurons at E12.5 and E14.5. Caspase-3-dependent cell death of CB- and CR-ir neurons may be suppressed by the deficiency at E14.5.
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PMID:Brn-3a deficiency transiently increases expression of calbindin D-28 k and calretinin in the trigeminal ganglion during embryonic development. 1928 86


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