UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eighteen and twenty-four hours after intraperitoneal administration of D-galactosamine (1g/kg body weight) to rats, the activity of caspase-3-like protease in the liver increased significantly compared with that in the control group given saline. Histological examinations including the in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method found apoptotic hepatocytes 18 hr after the administration of D-galactosamine. Caspase-3 activity was barely detectable in the plasma of control rats, but increased significantly 24 hr after drug administration along with a dramatic increase in glutamate-oxaloacetate transaminase (GOT). These results indicated that D-galactosamine causes apoptosis in the liver by activating caspase-3, which is released to the plasma by secondary necrosis. The concentration of lipid hydroperoxides in the liver increased significantly 24 hr after D-galactosamine administration. In contrast, the concentration of vitamin C in the liver decreased significantly 18 and 24 hr after D-galactosamine administration. These results suggest that D-galactosamine induces severe oxidative stress in the liver, leading to extensive necrosis.
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PMID:Evaluation of oxidative stress during apoptosis and necrosis caused by D-galactosamine in rat liver. 1247 84

Mature mouse oligodendrocytes (OLs) are susceptible to death in demyelinating diseases such as multiple sclerosis and in brain injury following neurotrauma, ischemia, or stroke. To understand mechanisms leading to death of mature OLs and develop strategies for protection, we utilized cultures of mature mouse OLs to investigate the role of caspases and calpains in OL cell death mediated by different mechanisms. The agents used were (i) staurosporine, which induces apoptotic death via inhibition of protein kinases; (ii) kainate, which activates non-NMDA glutamate receptors; (iii) thapsigargin, which releases intracellular calcium stores; and (iv) SNAP, which releases active NO species and causes necrotic cell death. Inhibitors blocking primary effector caspases (including caspase 3), the FAS (death receptor)-mediated initiator caspases (including caspase 8), and stress-induced caspases (including caspase 9), were tested for their protective effects. Inhibition of caspases 3, 8, and 9 each robustly protected OLs following insult with staurosporine, thapsigargin, or kainate when added at optimal times. The time of addition of the inhibitors for maximal protection varied with the agent, from 1 h of preincubation before addition of staurosporine to 6 h after addition of kainate. Much less protection was seen for the NO generator SNAP under any condition. The role of calcium in OL death in each model was investigated by chelating extracellular Ca++ with EGTA, and by inhibiting the Ca++-activated calpain proteases. Calcium chelation did not protect against staurosporine, but decreased OL death initiated by kainate, thapsigargin, or NO. The calpain inhibitors PD150606 and calpain inhibitor I protected from cell death initiated by staurosporine, kainate, and thapsigargin, but not from cell death initiated by the NO donor SNAP.
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PMID:Protection of mature oligodendrocytes by inhibitors of caspases and calpains. 1258 72

Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate- (NMDA) and 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose- and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) and S-UH-301, respectively. Similarly, dose- and time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca(2+) influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP(+). Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.
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PMID:5-hydroxytryptamine 1A receptor activation protects against N-methyl-D-aspartate-induced apoptotic cell death in striatal and mesencephalic cultures. 1260 65

Both endogenous and exogenous glucocorticoids (GCs) are known to cause apoptosis in a number of peripheral tissues and in some cases in the CNS. Additionally, GCs can exacerbate the neuron loss associated with such acute neurological insults as hypoxia-ischemia, excitotoxicity, and metabolic disruption. This exacerbation is accompanied by increased accumulation of glutamate in the synapse, excessive cytosolic calcium, and increased oxygen radical activity, markers usually attributed to pathways of necrotic cell death. It is also known that acute insults can involve apoptotic mediators. In this context, one outstanding question that has received little attention is whether the exacerbation of insult-mediated cell death in neurons is apoptotic in mechanism. In this study we investigate whether the GC-mediated exacerbation of hippocampal excitotoxicity in culture involves apoptosis. Specifically, we show that while the magnitude of hippocampal neuron death caused by the excitotoxin kainic acid is indeed worsened in the presence of GCs, there is no evidence of increased markers of apoptosis. Specifically, we show that neither kainic acid nor GCs alone, or in combination, cause activation of caspase 3, a critical executor of insult-induced apoptosis. Furthermore, while kainic acid causes a significant incidence of apoptotic nuclear condensation, the incidence of this morphological indicator of apoptosis is not worsened by GCs. Thus, GCs appear to augment excitotoxic death in hippocampal neurons without augmenting the occurrence of apoptosis. We suggest that this finding is to be expected, given some energetic features of GC action and the energetic demands of apoptosis.
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PMID:The exacerbation of hippocampal excitotoxicity by glucocorticoids is not mediated by apoptosis. 1262 38

Cultured rat cerebellar granule neurons are widely used as a model system for studying neuronal apoptosis. Either low K(+) (5 mM) or low concentrations of glutamate (1-10 microM) induce apoptosis in cerebellar neurons in culture. However, the molecular mechanism(s) involved remain unclear. We show that long-term treatment with ammonia prevents glutamate-induced but not low K(+)-induced apoptosis in cerebellar neurons, as assessed by measuring DNA fragmentation and activation of caspase 3. Ammonia prevented glutamate-induced increase of intracellular calcium, depolarization of the inner mitochondrial membrane, release of cytochrome c to the cytosol, activation of caspase 3 and fragmentation of DNA. However, ammonia did not prevent low K(+)-induced activation of caspase 3 and fragmentation of DNA. These results indicate that the initial steps involved in the induction of apoptosis by low K(+) or by glutamate are different and that ammonia prevents glutamate-induced apoptosis by reducing glutamate-induced rise of intracellular Ca(2+), thus avoiding the activation of subsequent events of the apoptotic process.
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PMID:Ammonia prevents glutamate-induced but not low K(+)-induced apoptosis in cerebellar neurons in culture. 1265 41

Blockade of ionotropic glutamate receptors induces neuronal cell apoptosis. We investigated if mitochondria-mediated death signals would contribute to neuronal apoptosis following administration of glutamate antagonists. The administration of MK-801 and CNQX (MK-801/CNQX), the selective antagonists of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors, produced widespread neuronal death in neonatal rat brain and cortical cell cultures. MK-801/CNQX-induced neuronal apoptosis was prevented by zVAD-fmk, a broad inhibitor of caspases, but insensitive to inhibitors of calpain or cathepsin D. Activation of caspase-3 was observed within 6-12 h and sustained over 36 h after exposure to MK-801/CNQX, which cleaved PHF-1 tau, the substrate for caspase-3. Activation of caspase-3 was blocked by high K+ and mimicked by BAPTA-AM, a selective Ca2+ chelator. Reducing extracellular Ca2+, but not Na+, activated caspase-3, suggesting an essential role of Ca2+ deficiency in MK-801/CNQX-induced activation of caspases. Cortical neurons treated with MK-801/CNQX triggered activation of caspase-9, release of cytochrome c from mitochondria, and translocation of Bax into mitochondria. The present study suggests that blockade of ionotropic glutamate receptors causes caspase-3-mediated neuronal apoptosis due to Ca2+ deficiency that is coupled to the sequential mitochondrial death pathway.
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PMID:Blockade of ionotropic glutamate receptors produces neuronal apoptosis through the Bax-cytochrome C-caspase pathway: the causative role of Ca2+ deficiency. 1267 29

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

Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.
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PMID:Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. 1272 91

The role of glutamate in the mechanism of spinal neuron death is not fully understood. With addition of glutamate to primary culture of 11-day-old rat spinal cord, the number of caspase-3 positive small neurons of the dorsal horn greatly increased at 6-24 h in contrast to the case with vehicle. The addition of glutamate made caspase-3 immunoreactivity stronger in the cytoplasm of large motor neurons in the ventral horn. The present results show that excessive amount of glutamate enhances apoptotic pathway through caspase-3 in cultured spinal neurons of newborn rat.
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PMID:Glutamate enhances caspase-3 immunoreactivity in cultured spinal cord neurons of newborn rats. 1273 45

Gangliosides protect cerebellar granule cells from excitotoxicity; however, their mechanism of action remains to be fully characterized. GM1 ganglioside has been shown to activate Trk, the tyrosine kinase receptor implicated in the neuroprotective properties of the neurotrophins. In these studies, we used primary cultures of cerebellar granule cells to determine whether gangliosides exert neuroprotective effect via the activation of Trk receptors. We first examined the relative potency of the neurotrophins, brain derived neurotrophic factor (BDNF), neurotrophin-3 and nerve growth factor to prevent glutamate-mediated apoptosis. BDNF was the only neurotrophin that elicited a complete neuronal protection against glutamate. GM1 and its semisynthetic compound LIGA20 also prevented glutamate toxicity, however, LIGA20 was more potent than GM1. Both LIGA20 and BDNF blocked glutamate-mediated activation of caspase-3 and consequently apoptosis; however, the anticaspase-3 activity was seen only when these compounds were added to the cultures several hours before glutamate, suggesting that LIGA20 and BDNF share an identical molecular mechanism. To test this hypothesis, we compared the ability of LIGA20 and BDNF to activate TrkB. Both compounds elicited a similar time-dependent increase in Trk tyrosine phosphorylation. Moreover, the neuroprotective effect of BDNF and LIGA20 was abolished in neurons exposed to the Trk tyrosine kinase inhibitor k252a, demonstrating a relationship between neuroprotection and activation of Trk receptors. Our data suggest that by activating the Trk neurotrophin receptors, gangliosides may be used as neuroprotective agents.
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PMID:Gangliosides prevent excitotoxicity through activation of TrkB receptor. 1282 3

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