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)

During development, the output of the subventricular zone (SZ) becomes increasingly restricted, yet it still harbors multipotential progenitors. The output of the SZ could be gated by selectively eliminating inappropriately specified progenitors. Using in situ end-labeling (ISEL) to identify apoptotic cells, nearly 60% of the ISEL(+) cells in the juvenile forebrain were localized to the SZ. Of these dying cells, at least 9% could be identified as neurons, 4% as astrocytes, and 12% as oligodendrocytes. The remainder were negative for the stem cell marker nestin, as well as other markers evaluated. To test the hypothesis that committed progenitors were under selective pressures, neural stem/progenitor cells were allowed to differentiate in vitro in the presence or absence of the caspase 3 inhibitor z-DEVD-fmk. DEVD increased neuronal production 10-fold over control cultures. By contrast, the development of astrocytes and oligodendrocytes was not affected. Altogether, these data support the hypothesis that selective forces within the postnatal rat forebrain control the types of precursors that emerge from the germinal matrix. Furthermore, they suggest that different mechanisms control neuronal versus glial cell numbers.
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PMID:Selective apoptosis within the rat subependymal zone: a plausible mechanism for determining which lineages develop from neural stem cells. 1065 3

Insulin-like growth factor-1 (IGF-1) has been shown to play a key role during embryonic and postnatal development of the CNS, but its effect on a sensory organ has not been studied in vivo. Therefore, we examined cochlear growth, differentiation, and maturation in Igf-1 gene knock-out mice at postnatal days 5 (P5), P8, and P20 by using stereological methods and immunohistochemistry. Mutant mice showed reduction in size of the cochlea and cochlear ganglion. An immature tectorial membrane and a significant decrease in the number and size of auditory neurons were also evident at P20. IGF-1-deficient cochlear neurons showed increased caspase-3-mediated apoptosis, along with aberrant expression of the early neural markers nestin and Islet 1/2. Cochlear ganglion and fibers innervating the sensory cells of the organ of Corti presented decreased levels of neurofilament and myelin P(0) in P20 mouse mutants. In addition, an abnormal synaptophysin expression in the somata of cochlear ganglion neurons and sensory hair cells suggested the persistence of an immature pattern of synapses distribution in the organ of Corti of these animals. These results demonstrate that lack of IGF-1 in mice severely affects postnatal survival, differentiation, and maturation of the cochlear ganglion cells and causes abnormal innervation of the sensory cells in the organ of Corti.
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PMID:Delayed inner ear maturation and neuronal loss in postnatal Igf-1-deficient mice. 1156 53

The subventricular zone of the adult mammalian brain harbors the neural stem cell population with potential neural regeneration and repair capacity. We describe a nonviral technique to preferentially transfect in vivo the adult neural stem cell population and its immediate progeny based on intraventricular injection of PEI/DNA complexes. The transfected population was identified by cellular and ultra-structural evidence showing their proliferating status and expression of the specific markers GFAP and nestin. Stable activation of the lacZ reporter by cre-recombinase transfection in R26R mice demonstrated survival and migration of stem cell derivatives three months after injection. Apoptosis is thought to be the most common fate of the stem cell progeny. Overexpression of Bcl-X(L) increased number and survival time of transduced progenitors and decreased the frequency of cells immunopositive for activated Caspase-3. This method thus provides selective targeting of the stem cell population and should allow an in-depth understanding of their biology.
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PMID:Preferential transfection of adult mouse neural stem cells and their immediate progeny in vivo with polyethylenimine. 1186 Feb 70

After injury, the striatum displays several morphologic responses that may play a role in both regenerative and degenerative events. One such response is the de novo expression of the low-affinity p75 neurotrophin receptor (p75(NTR)), a gene that plays critical roles in central nervous system (CNS) cell death pathways. The present series of experiments sought to elucidate the cellular origins of this p75(NTR) response, to define the conditions under which p75(NTR) is expressed after striatal injury, and how this receptor expression is associated with neuronal plasticity. After chemical lesions, by using either the excitotoxin quinolinic acid (QA) or the complex II mitochondria inhibitor 3-nitropropionic acid (3-NP), we compared the expression of the p75(NTR) receptor within the rat striatum at different survival times. Intrastriatal administration of QA between 7 days and 21 days postlesion induced p75(NTR) expression in astrocytes that was preferentially distributed throughout the lesion core. P75(NTR) immunoreactivity within astrocytes was seen at high (100-220 nmol) but not low (50 nmol) QA doses. Seven and 21 days after 3-NP lesions, p75(NTR) expression was present in astrocytes at all doses tested (100-1,000 nmol). However, in contrast to QA, these cells were located primarily around the periphery of the lesion and not within the lesion core. At the light microscopic level p75(NTR) immunoreactive elements resembled vasculature: but did not colocalize with the pan endothelium cell marker RecA-1. In contrast, p75(NTR)-containing astrocytes colocalized with nestin, vimentin, and 5-bromo-2-deoxyuridine, indicating that these cells are newly born astrocytes. Additionally, striatal cholinergic neurons were distributed around the lesion core expressed p75(NTR) 3-5 days after lesion in both QA and 3-NP lesions. These cells did not coexpress the pro-apoptotic degradation enzyme caspase-3. Taken together, these data indicate that striatal lesions created by means of excitotoxic or metabolic mechanisms trigger the expression of p75(NTR) in structures related to progenitor cells. The expression of the p75(NTR) receptor after these chemical lesions support the concept that this receptor plays a role in the initiation of endogenous cellular events associated with CNS injury.
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PMID:Excitotoxic and metabolic damage to the rodent striatum: role of the P75 neurotrophin receptor and glial progenitors. 1189 44

Lithium has long been one of the primary drugs used to treat bipolar mood disorder. However, neither the etiology of this disease nor the therapeutic mechanism(s) of this drug is well understood. Several lines of clinical evidence suggest that lithium has neurotrophic actions. For example chronic lithium treatment increases the volume of gray matter and the content of N-acetyl-aspartate, a cell survival marker, in bipolar mood disorder patients (Moore et al., 2000). Moreover, treatment with this mood-stabilizer suppresses the decrease in the volume of the subgenual pre-frontal cortex found in bipolar patients (Drevets, 2001). To elucidate molecular mechanisms underlying the neuroprotective and neurotrophic actions of lithium, we employed a preparation of cultured cortical neurons prepared form embryonic rats. We found that treatment with therapeutic doses (0.2-1.2 mM) of lithium robustly protects cortical neurons from multiple insults, notably glutamate-induced excitotoxicity. The neuroprotection against glutamate excitotoxicity is time-dependent, requiring treatment for 5-6 days for maximal effect, and is associated with a reduction in NMDA receptor-mediated Ca2+ influx. The latter is correlated with a decrease in Tyrosine 1472 phosphorylation levels in the NR2B subunit of NMDA receptors and a loss of Src kinase activity which is involved in NR2B tyrosine phosphorylation. Neither the activity of total tyrosine protein kinase nor that of tyrosine protein phosphatase is affected by this drug, indicating the selectivity of the modulation. Lithium neuroprotection against excitotoxicity is inhibited by a BDNF-neutralizing antibody and K252a, a Trk antagonist. Lithium treatment time-dependently increases the intracellular level of BDNF in cortical neurons and activates its receptor, TrkB. The neuroprotection can be completely blocked by either heterozygous or homozygous knockout of the BDNF gene. These results suggest a central role of BDNF and TrkB in mediating the neuroprotective effects of this mood-stabilizer. Finally, long-term lithium treatment of cortical neurons stimulates the proliferation of their progenitor cells detected by co-labeling with BrdU and nestin. Lithium pretreatment also blocks the decrease in progenitor proliferation induced by glutamate, glucocorticoids and haloperidol, suggesting a role in CNS neuroplasticity. We used animal models to investigate further therapeutic potentials for lithium. In the MCAO/reperfusion model of stroke, we found that post-insult treatment with lithium robustly reduced infarct volume and neurological deficits. These beneficial effects were evident when therapeutic concentrations of lithium were injected at least up to 3 h after ischemic onset. The neuroprotection was associated with activation of heat-shock factor-1 and induction of heat-shock protein-70, a cytoprotective protein. In a rat excitotoxic model of Huntington's disease, the excitotoxin-induced loss of striatal medium-sized neurons was markedly reduced by lithium. This lithium protection was correlated with up-regulation of cytoprotective Bcl-2 and down-regulation of apoptotic proteins p53 and Bax, and neurons showing DNA damage and caspase-3 activation. Taken together, our results provide a new insight into the molecular mechanisms involved in lithium neuroprotection against glutamate excitotoxicity. Moreover, these novel molecular and cellular actions might contribute to the neurotrophic and neuroprotective actions of this mood-stabilizer in patients, and could be related to its clinical efficacy for treating mood disorder patients. Clearly, mood-stabilizers may have expanded use for treating excitotoxin-related neurodegenerative diseases.
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PMID:[Neuroprotective actions of lithium]. 1270 Dec 14

As undifferentiated precursor cells in the CNS, neural progenitor cells (NPCs) supply new neurons and glial cells to repair damage within the adult brain. Recently, NPCs were found to undergo apoptosis. In serum-free basic fibroblast growth factor-containing culture medium, primary culture cells from fetal mouse neuroepithelium expressed nestin, and thus might be regarded as NPCs. These NPCs demonstrated apoptosis under electron microscopy and TUNEL assay. Treatment of NPCs with lithium, a specific inhibitor of glycogen synthase kinase 3beta (GSK3beta), significantly suppressed apoptosis. Activity of pro-apoptotic protease caspase-3 was not detected in either lithium-untreated or -treated NPCs. These findings suggest that lithium may protect NPCs against apoptosis by inhibiting caspase-3-independent apoptotic pathways.
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PMID:Lithium inhibits apoptosis of mouse neural progenitor cells. 1453 19

We have shown successful in vitro expansion of rodent and human neural precursor cells (NPC) derived from fetal midbrain and forebrain. Here, we show that mouse neural precursor cells growing in neurospheres proliferate, but also undergo spontaneous apoptosis in vitro. On average, 30.7 +/- 3.4% cells of midbrain-derived neural precursors and 32.1 +/- 2.5% of forebrain-derived neural precursors were found apoptotic within neurospheres. Spontaneous apoptosis involved mitochondrial cytochrome c release and activation of effector caspase-3. Caspase-3 was activated in 26.9 +/- 3.4% of mesencephalic neural precursor cells. Virtually all nuclei with morphological signs of apoptosis belong to caspase-3-positive cells. The great majority of dying cells within neurospheres was positive for CNS precursor cell marker nestin. Pro-apoptotic proteins of the Bcl-2 family, Bax and Bak, exhibited conformational changes in neural precursors expanding in vitro. Key molecules such as executioner caspase-3 may be useful targets to reduce the amount of apoptosis.
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PMID:Spontaneous apoptosis in murine free-floating neurospheres. 1498 Apr 96

Using primary cultures of neural precursor cells of cortex from developing rat brain, we demonstrated the involvement of caspase-3 in the apoptotic process induced by gamma irradiation. The precursor nature of cells was confirmed by nestin and GFAP immunoreactivity and by the capacity of differentiation in neuronal and glial cells after 5 days in culture. Neural precursors were irradiated with single doses ranging from 0.1 to 4Gy. Cellular death, determined 24 h post-irradiation (pi) was dose-dependent and the induction of apoptosis was confirmed by nuclear condensation, DNA fragmentation and hypodiploid DNA peak represented by the "sub G1" region. For the higher doses, apoptosis was evident after 4-6 h pi and increased during 24 h. Caspase-3 activity increased with doses and was maximal at 4-6 h pi with 3Gy and remained similar with 4Gy. The protection from radiation-induced apoptosis by caspase-3 inhibitor, zDEVD-fmk, confirmed that this enzyme is involved in the apoptotic mechanism in this system. The possibility of using this tissue culture system for studying the effects of ionizing radiation on morphological and molecular differentiation was considered.
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PMID:Increased activity and involvement of caspase-3 in radiation-induced apoptosis in neural cells precursors from developing rat brain. 1501 1

The in vivo actions of insulin-like growth factor-I (IGF-I) on prenatal and early postnatal brain development were investigated in transgenic (Tg) mice that overexpress IGF-I prenatally under the control of regulatory sequences from the nestin gene. Tg mice demonstrated increases in brain weight of 6% by embryonic day (E) 18 and 27% by postnatal day (P) 12. In Tg embryos at E16, the volume of the cortical plate was significantly increased by 52% and total cell number was increased by 54%. S-phase labeling with 5-bromo-2'-deoxyuridine revealed a 13-15% increase in the proportion of labeled neuroepithelial cells in Tg embryos at E14. In Tg mice at P12, significant increases in regional tissue volumes were detected in the cerebral cortex (29%), subcortical white matter (52%), caudate-putamen (37%), hippocampus (49%), dentate gyrus (71%) and habenular complex (48%). Tg mice exhibited significant increases in the total number of neurons in the cerebral cortex (27%), caudate-putamen (27%), dentate gyrus (69%), medial habenular nucleus (61%) and lateral habenular nucleus (36%). In the cerebral cortex and subcortical white matter of Tg mice, the total numbers of glial cells were significantly increased by 37% and 42%, respectively. The numerical density of apoptotic cells in the cerebral cortex, labeled by antibodies against active caspase-3, was reduced by 26% in Tg mice at P7. Our results demonstrate that IGF-I can both promote proliferation of neural cells in the embryonic central nervous system in vivo and inhibit their apoptosis during postnatal life.
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PMID:In vivo effects of insulin-like growth factor-I (IGF-I) on prenatal and early postnatal development of the central nervous system. 1509 33

Perinatal hypoxic-ischemic (H/I) brain injury remains a major cause of neurologic disability. Because we have previously demonstrated that this insult depletes cells from the subventricular zone (SVZ), the goal of the present investigation was to compare the relative vulnerability to H/I of neural stem cells versus progenitors. The dorsolateral SVZs of P6 rats were examined at 2 to 48 hours of recovery from H/I using hematoxylin and eosin, in situ end labeling (ISEL), terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL), electron microscopy, and immunofluorescence. Pyknotic nuclei and ISEL cells were observed by 4 hours of recovery, peaked at 12 hours, and persisted for at least 48 hours. Many active-caspase-3 cells were observed at 12 hours and they comprised one third of the total TUNEL population. Electron microscopy revealed that hybrid cell deaths predominated at 12 hours of recovery. Importantly, few dying cells were observed in the medial SVZ, where putative stem cells reside, and no nestin medial SVZ cells showed caspase-3 activation. By contrast, active-caspase-3/PSA-NCAM progenitors were prominent in the lateral SVZ. These data demonstrate that early progenitors are vulnerable to H/I, whereas neural stem cells are resilient. The demise of these early progenitors may lead to the depletion of neuronal and late oligodendrocyte progenitors, contributing to cerebral dysgenesis after perinatal insults.
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PMID:Neural stem cells in the subventricular zone are resilient to hypoxia/ischemia whereas progenitors are vulnerable. 1524 Nov 90


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